AU2016278990A1 - Novel CRISPR enzymes and systems - Google Patents

Abstract

The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA. Methods for making and using and uses of such systems, methods, and compositions and products from such methods and uses are also disclosed and claimed.

Description

The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA. Methods for making and using and uses of such systems, methods, and compositions and products from such methods and uses are also disclosed and claimed.

WO 2016/205711 Al IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIN

HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

(84) Designated States (unless otherwise indicated, for every kind of regional protection available)·. ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,

TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG).

Published:

— with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a))

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NOVEL CRISPR ENZYMES AND SYSTEMS

RELATED APPLICATIONS AND INCORPORATION BY REFERENCE [0001] This application claims benefit of and priority to E^TS Provisional 62/181,739, filed on June 18, 2015; US Provisional 62/193,507, filed on July 16, 2015, US Provisional 62/201,542, filed August 5, 2015, U.S. Provisional 62/205,733, filed August 16, 2015, U.S. Provisional 62/232,067, filed September 24, 2015, U.S. Application Ser, No. 14/975,085, filed December 18, 2015, and European application No. 16150428.7.

[0002] The foregoing applications, and all documents cited therein or during their prosecution (“appln cited documents”) and all documents cited or referenced in herein cited documents, together with any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0003] This invention was made with government support under Grant No. MH100706, awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING [0004] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 17, 2015, is named 47627.05.2123 SL.txt and is 2,467,205 bytes bytes in size.

FIELD OF THE INVENTION [0005] The present invention generally relates to systems, methods and compositions used for the control of gene expression involving sequence targeting, such as perturbation of gene transcripts or nucleic acid editing, that may use vector systems related to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and components thereof.

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BACKGROUND OF THE INVENTION [0006] Recent advances in genome sequencing techniques and analysis methods have significantly accelerated the ability to catalog and map genetic factors associated with a diverse range of biological functions and diseases. Precise genome targeting technologies are needed to enable systematic reverse engineering of causal genetic variations by allowing selective perturbation of individual genetic elements, as well as to advance synthetic biology, biotechnological, and medical applications. Although genome-editing techniques such as designer zinc fingers, transcription activator-like effectors (TALEs), or homing meganucleases are available for producing targeted genome perturbations, there remains a need for new genome engineering technologies that employ novel strategies and molecular mechanisms and are affordable, easy to set up, scalable, and amenable to targeting multiple positions within the eukaryotic genome. This would provide a major resource for new⁷ applications in genome engineering and biotechnology.

[0007] The CRISPR-Cas systems of bacterial and archaeai adaptive immunity show extreme diversity of protein composition and genomic loci architecture. The CRISPR-Cas system loci has more than 50 gene families and there is no strictly universal genes indicating fast evolution and extreme diversity of loci architecture. So far, adopting a multi-pronged approach, there is comprehensive cas gene identification of about 395 profiles for 93 Cas proteins. Classification includes signature gene profiles plus signatures of locus architecture. A new classification of CRISPR-Cas systems is proposed in which these systems are broadly divided into two classes. Class 1 with multisubunit effector complexes and Class 2 with single-subunit effector modules exemplified by the Cas9 protein. Novel effector proteins associated with Class 2 CRISPR-Cas systems may be developed as powerful genome engineering tools and the prediction of putative novel effector proteins and their engineering and optimization is important.

[0008] Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.

SUMMARY OF THE INVENTION [0009] There exists a pressing need for alternative and robust systems and techniques for targeting nucleic acids or polynucleotides (e.g, DNA or RNA or any hybrid or derivative thereof) with a wide array of applications. This invention addresses this need and provides related

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PCT/US2016/038181 advantages. Adding the novel DNA or RNA-targeting systems of the present application to the repertoire of genomic and epigenomic targeting technologies may transform the study and perturbation or editing of specific target sites through direct detection, analysis and manipulation. To utilize the DNA or RNA-targeting systems of the present application effectively for genomic or epigenomic targeting without deleterious effects, it is critical to understand aspects of engineering and optimization of these DNA or RNA targeting tools.

[0010] The invention provides a method of modifying sequences associated with or at a target locus of interest, the method comprising delivering to said locus a non-naturally occurring or engineered composition comprising a putative Type V CRISPR-Cas loci effector protein and one or more nucleic acid components, wherein the effector protein forms a complex with the one or more nucleic acid components and upon binding of the said complex to the locus of interest the effector protein induces the modification of the sequences associated with or at the target locus of interest. In a preferred embodiment, the modification is the introduction of a strand break. In a preferred embodiment, the sequences associated with or at the target locus of interest comprises DNA and the effector protein is encoded by a subtype V-A CRISPR-Cas loci or a subtype V-B CRISPR-Cas loci.

[0011] It will be appreciated that the terms Cas enzyme, CRISPR enzyme, CRISPR protein Cas protein and CRISPR Cas are generally used interchangeably and at all points of reference herein refer by analogy to novel CRISPR effector proteins further described in this application, unless otherwise apparent, such as by specific reference to Cas9. The CRISPR effector proteins described herein are preferably Cpf 1 effector proteins.

[0012] The invention provides a method of modifying sequences associated with or at a target locus of interest, the method comprising delivering to said sequences associated with or at the locus a non-naturally occurring or engineered composition comprising a Cpfl loci effector protein and one or more nucleic acid components, wherein the Cpfl effector protein forms a complex with the one or more nucl eic acid components and upon binding of the said complex to the locus of interest the effector protein induces the modification of the sequences associated with or at the target locus of interest. In a preferred embodiment, the modification is the introduction of a strand break. In a preferred embodiment the Cpfl effector protein forms a complex with one nucleic acid component; advantageously an engineered or non-naturally occurring nucleic acid component. The induction of modification of sequences associated with or

J

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PCT/US2016/038181 at the target locus of interest can be Cpfl effector protein-nucleic acid guided. In a preferred embodiment the one nucleic acid component is a CRISPR RNA (crRNA). In a preferred embodiment the one nucleic acid component is a mature crRNA or guide RNA, wherein the mature crRNA or guide RNA comprises a spacer sequence (or guide sequence) and a direct repeat sequence or derivatives thereof. In a preferred embodiment the spacer sequence or the derivative thereof comprises a seed sequence, wherein the seed sequence is critical for recognition and/or hybridization to the sequence at the target locus. In a preferred embodiment, the seed sequence of a FnCpfl guide RNA is approximately within the first 5 nt on the 5’ end of the spacer sequence (or guide sequence). In a preferred embodiment the strand break is a staggered cut with a 5’ overhang. In a preferred embodiment, the sequences associated with or at the target locus of interest comprise linear or super coiled DNA.

[0013] Aspects of the invention relate to Cpfl effector protein complexes having one or more non-naturally occurring or engineered or modified or optimized nucleic acid components. In a preferred embodiment the nucleic acid component of the complex may comprise a guide sequence linked to a direct repeat sequence, wherein the direct repeat sequence comprises one or more stem loops or optimized secondary structures. In a preferred embodiment, the direct repeat has a minimum length of 16 nts and a single stem loop. In further embodiments the direct repeat has a length longer than 16 nts, preferrably more than 17 nts, and has more than one stem loop or optimized secondary structures. In a preferred embodiment the direct repeat may be modified to comprise one or more protein-binding RNA aptamers. In a preferred embodiment, one or more aptamers may be included such as part of optimized secondary structure. Such aptamers may be capable of binding a bacteriophage coat protein. The bacteriophage coat protein may be selected from the group comprising i> F2, GA, fr, JP501, MS2, M12, R17, BZ13, JP34, JP500, KU1, Mi l, MX1, TW18, VK, SP, FI, ID2, NL95, TW19, AP205, φθ)5, i|)Cb8r, <J>Cbl2r, <|>Cb23r, 7s and PRR1. In a preferred embodiment the bacteriophage coat protein is MS2. The invention also provides for the nucleic acid component of the complex being 30 or more, 40 or more or 50 or more nucleotides in length.

[0014] The invention provides methods of genome editing wherein the method comprises two or more rounds of Cpfl effector protein targeting and cleavage. In certain embodiments, a first round comprises the Cpfl effector protein cleaving sequences associated with a target locus far away from the seed sequence and a second round comprises the Cpfl effector protein

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PCT/US2016/038181 cleaving sequences at the target locus. In preferred embodiments of the invention, a first round of targeting by a Cpfl effector protein results in an indel and a second round of targeting by the Cpfl effector protein may be repaired via homology directed repair (HDR). In a most preferred embodiment of the invention, one or more rounds of targeting by a Cpfl effector protein results in staggered cleavage that may be repaired with insertion of a repair template.

[0015] The invention provides methods of genome editing or modifying sequences associated with or at a target locus of interest wherein the method comprises introducing a Cpfl effector protein complex into any desired cell type, prokaryotic or eukaryotic cell, whereby the Cpfl effector protein complex effectively functions to integrate a DNA insert into the genome of the eukaryotic or prokaryotic cell. In preferred embodiments, the cell is a eukaryotic ceil and the genome is a mammalian genome. In preferred embodiments the integration of the DNA insert is facilitated by non-homologous end joining (NHEJ)-based gene insertion mechanisms. In preferred embodiments, the DNA insert is an exogenously introduced DNA template or repair template. In one preferred embodiment, the exogenously introduced DNA template or repair template is delivered with the Cpfl effector protein complex or one component or a polynucleotide vector for expression of a component of the complex. In a more preferred embodiment the eukaryotic ceil is a non-dividing cell (e.g. a non-dividing cell in which genome editing via HDR is especially challenging). In preferred methods of genome editing in human cells, the Cpfl effector proteins may include but are not limited to FnCpfi, AsCpfl and LbCpfl effector proteins.

[0016] The invention also provides a method of modifying a target locus of interest, the method comprising delivering to said locus a non-naturally occurring or engineered composition comprising a C2cl loci effector protein and one or more nucleic acid components, wherein the C2cl effector protein forms a complex with the one or more nucleic acid components and upon binding of the said complex to the locus of interest the effector protein induces the modification of the target locus of interest. In a preferred embodiment, the modification is the introduction of a strand break.

[0017] In such methods the target locus of interest may be comprised in a DNA molecule in vitro. In a preferred embodiment the DNA molecule is a plasmid.

[0018] In such methods the target locus of interest may be comprised in a DNA molecule within a cell. The cell may be a prokaryotic cell or a eukaryotic cell. The cell may be a

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PCT/US2016/038181 mammalian cell. The mammalian cell many be a non-human primate, bovine, porcine, rodent or mouse cell. The cell may be a non-mammalian eukaryotic cell such as poultry, fish or shrimp. The cell may also be a plant cell. The plant cell may be of a crop plant such as cassava, corn, sorghum, wheat, or rice. The plant cell may also be of an algae, tree or vegetable. The modification introduced to the cell by the present invention may be such that the cell and progeny of the cell are altered for improved production of biologic products such as an antibody, starch, alcohol or other desired cellular output. The modification introduced to the cell by the present invention may be such that the ceil and progeny of the cell include an alteration that changes the biologic product produced.

[0019] The invention provides a method of modifying a target locus of interest, the method comprising delivering to said locus a non-naturally occurring or engineered composition comprising a Type VI CRISPR-Cas loci effector protein and one or more nucleic acid components, wherein the effector protein forms a complex with the one or more nucleic acid components and upon binding of the said complex to the locus of interest the effector protein induces the modification of the target locus of interest. In a preferred embodiment, the modification is the introduction of a strand break.

[0020] In a preferred embodiment, the target locus of interest comprises DNA.

[0021] In such methods the target locus of interest may be comprised in a DNA molecule within a cell. The cell may be a prokaryotic cell or a eukaryotic cell. The cell may be a mammalian cell. The mammalian cell many be a non-human mammal, e.g,, primate, bovine, ovine, porcine, canine, rodent, Leporidae such as monkey, cow, sheep, pig, dog, rabbit, rat or mouse cell. The ceil may be a non-mammalian eukaryotic cell such as poultry bird (e.g., chicken), vertebrate fish (e.g., salmon) or shellfish (e.g., oyster, claim, lobster, shrimp) cell. The cell may also be a plant cell. The plant cell may be of a monocot or dicot or of a crop or grain plant such as cassava, corn, sorghum, soybean, wheat, oat or rice. The plant cell may also be of an algae, tree or production plant, fiuit or vegetable (e.g., trees such as citrus trees, e.g,, orange, grapefruit or lemon trees; peach or nectarine trees; apple or pear trees; nut trees such as almond or walnut or pistachio trees; nightshade plants; plants of the genus Brassica, plants of the genus Laciuca, plants of the genus Spinacia'. plants of the genus Capsicum', cotton, tobacco, asparagus, carrot, cabbage, broccoli, cauliflower, tomato, eggplant, pepper, lettuce, spinach, strawberry', blueberry, raspberry, blackberry, grape, coffee, cocoa, etc).

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PCT/US2016/038181 [0022] In any of the described methods the target locus of interest may be a genomic or epigenomic locus of interest. In any of the described methods the complex may be delivered with multiple guides for multiplexed use. In any of the described methods more than one protein(s) may be used, [0023] In preferred embodiments of the invention, biochemical or in vitro or in vivo cleavage of sequences associated with or at a target locus of interest results without a putative transactivating crRNA (tracr RNA) sequence, e.g. cleavage by an FnCpfl effector protein. In other embodiments of the invention, cleavage may result with a putative transactivating crRNA (tracr RNA) sequence, e.g. cleavage by other CRISPR family effector proteins, however after evaluation of the FnCpfl locus, Applicants concluded that target DNA cleavage by a Cpfl effector protein complex does not require a tracrRNA. Applicants determined that Cpfl effector protein complexes comprising only a Cpfl effector protein and a crRNA (guide RNA comprising a direct repeat sequence and a guide sequence) were sufficient to cleave target DNA, Accordingly, the invention provides methods of modifying a target locus of interest as described herein above, wherein the effector protein is a Cpfl protein and the effector protein complexes with the target sequence without the presence of a tracr.

[0024] In any of the described methods the effector protein (e.g., Cpfl) and nucleic acid components may be provided via one or more polynucleotide molecules encoding the protein and/or nucleic acid component(s), and wherein the one or more polynucleotide molecules are operably configured to express the protein and/or the nucleic acid component(s). The one or more polynucleotide molecules may comprise one or more regulatory elements operably configured to express the protein and/or the nucleic acid component(s). The one or more polynucleotide molecules may be comprised within one or more vectors. The invention comprehends such polynucleotide molecule(s), for instance such polynucleotide molecules operably configured to express the protein and/or the nucleic acid component(s), as well as such vector(s).

[0025] In any of the described methods the strand break may be a single strand break or a double strand break.

[0026] Regulatory elements may comprise inducible promoters. Polynucleotides and/or vector systems may comprise inducible systems.

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PCT/US2016/038181 [0027] In any of the described methods the one or more polynucleotide molecules may be comprised in a delivery system, or the one or more vectors may be comprised in a delivery system.

[0028] In any of the described methods the non-naturally occurring or engineered composition may be delivered via liposomes, particles (e.g. nanoparticles), exosomes, microvesicles, a gene-gun or one or more vectors, e.g,, nucleic acid molecule or viral vectors. [0029] The invention also provides a non-naturally occurring or engineered composition which is a composition having the characteristics as discussed herein or defined in any of the herein described methods.

[0030] The invention also provides a vector system comprising one or more vectors, the one or more vectors comprising one or more polynucleotide molecules encoding components of a non-naturally occurring or engineered composition which is a composition having the characteristics as discussed herein or defined in any of the herein described methods.

[0031] The invention also provides a deliver)' system comprising one or more vectors or one or more polynucleotide molecules, the one or more vectors or polynucleotide molecules comprising one or more polynucleotide molecules encoding components of a non-naturally occurring or engineered composition which is a composition having the characteristics as discussed herein or defined in any of the herein described methods.

[0032] The invention also provides a non-naturally occurring or engineered composition, or one or more polynucleotides encoding components of said composition, or vector or delivery systems comprising one or more polynucleotides encoding components of said composition for use in a therapeutic method of treatment. The therapeutic method of treatment may comprise gene or genome editing, or gene therapy.

[0033] The invention also encompasses computational methods and algorithms to predict new Class 2 CRISPR-Cas systems and identify the components therein.

[0034] The invention also provides for methods and compositions wherein one or more amino acid residues of the effector protein may be modified, e,g, an engineered or non-naturallyoccurring effector protein or Cpfl. In an embodiment, the modification may comprise mutation of one or more antino acid residues of the effector protein. The one or more mutations may be in one or more catalytically active domains of the effector protein. The effector protein may have reduced or abolished nuclease activity compared with an effector protein lacking said one or

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PCT/US2016/038181 more mutations. The effector protein may not direct cleavage of one or other DNA or RNA strand at the target locus of interest. The effector protein may not direct cleavage of either DNA or RNA strand at the target locus of interest. In a preferred embodiment, the one or more mutations may comprise two mutations. In a preferred embodiment the one or more amino acid residues are modified in a Cpfl effector protein, e,g, an engineered or non-naturally-occurring effector protein or Cpfl. In a preferred embodiment the Cpfl effector protein is a FnCpfl effector protein. In a preferred embodiment, the one or more modified or mutated amino acid residues are D917A, E1006A or D1255A with reference to the amino acid position numbering of the FnCpfl effector protein. In further preferred embodiments, the one or more mutated amino acid residues are D908A, E993 A, DI263A with reference to the amino acid positions in AsCpfl or LbD832A, E925A, D947A or DI 180A with reference to the amino acid positions in LbCpfl. [0035] The invention also provides for the one or more mutations or the two or more mutations to be in a catalytically active domain of the effector protein comprising a RuvC domain. In some embodiments of the invention the RuvC domain may comprise a RuvCI, RuvCII or RuvCIII domain, or a catalytically active domain which is homologous to a RuvCI, RuvCII or RuvCIII domain etc or to any relevant domain as described in any of the herein described methods. The effector protein may comprise one or more heterologous functional domains. The one or more heterologous functional domains may comprise one or more nuclear localization signal (NLS) domains. The one or more heterologous functional domains may comprise at least two or more NLS domains. The one or more NLS domain(s) may be positioned at or near or in promixity to a terminus of the effector protein (e.g., Cpfl) and if two or more NLSs, each of the two may be positioned at or near or in promixity to a terminus of the effector protein (e.g., Cpfl) The one or more heterologous functional domains may comprise one or more transcriptional activation domains. In a preferred embodiment the transcriptional activation domain may comprise VP64. The one or more heterologous functional domains may comprise one or more transcriptional repression domains. In a preferred embodiment the transcriptional repression domain comprises a KRAB domain or a SID domain (e.g, SID4X). The one or more heterologous functional domains may comprise one or more nuclease domains. In a preferred embodiment a nuclease domain comprises Fokl.

[0036] The invention also provides for the one or more heterologous functional domains to have one or more of the following activities: methylase activity, demethylase activity,

Q

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PCT/US2016/038181 transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, nuclease activity, single-strand RNA cleavage activity, double-strand RNA cleavage activity, single-strand DNA cleavage activity, double-strand DNA cleavage activity and nucleic acid binding activity. At least one or more heterologous functional domains may be at or near the amino-terminus of the effector protein and/or wherein at least one or more heterologous functional domains is at or near the carboxy-terminus of the effector protein. The one or more heterologous functional domains may be fused to the effector protein. The one or more heterologous functional domains may be tethered to the effector protein. The one or more heterologous functional domains may be linked to the effector protein by a linker moiety.

[0037] The invention also provides for the effector protein (e.g,, a Cpfl) comprising an effector protein (e.g., a Cpfl) from an organism from a genus comprising Streptococcus, Campylobacter, Nitraiifractor, Staphylococcus, Parvihaculum, Poseburia, Neisseria, Gluconacetobacter, Azospirillum, Sphaerochaeta, Lactobacillus, Eubacterium, Coryriebacter, Carnobacterium, Pkodobacter, Listeria, LSdudibacter, Clostridium, Lachnospiraceae, Clostridiaridium, Leptotrichia. Francisella, Legionella, Alicyclobacillus, NLethanomethyophilus, Porphyromonas, Prevotella, Bacteroidet.es, Helcococcus, Lelospira, De sulfovibrio, Desulfonatronum, Opiiutaceae, Tuberibacillus, Bacillus, Brevibacilus, Methylobacterium or Acidaminococcus.

[0038] The invention also provides for the effector protein (e.g,, a Cpfl) comprising an effector protein (e.g., a Cpfl) from an organism from S. mutans, S. agalactiae, S. equisimilis, S. sanguinis, S. pneumonia; C. jejuni, C. coli; N salsuginis, N. tergarcus; S. auricularis, S. carnosus; N. meningitides, N gonorrhoeae; L. monocytogenes, L. ivanovii; C. botulinum, C. difficile, C. tetani, C. sordellii.

[0039] The effector protein may comprise a chimeric effector protein comprising a first fragment from a first effector protein (e.g., a Cpfl) ortholog and a second fragment from a second effector (e.g., a Cpfl) protein ortholog, and wherein the first and second effector protein orthologs are different. At least one of the first and second effector protein (e.g., a Cpfl) orthologs may comprise an effector protein (e.g,, a Cpfl) from an organism comprising Streptococcus, Campylobacter, Nitratifr actor, Staphylococcus, Parvihaculum, Poseburia, Neisseria, Gluconacetobacter, Azospirillum, Sphaerochaeta, Lactobacillus. Eubacterium,

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Corynebacter, Carnobacterium, Rhodobacter, Listeria, Paludibacter, Clostridium, Lachnospiraceae, Clostridiaridium, Leptotrichia, Francisella, Legionella, Alicyclobacillus, Methanomethyophilus, Porphyromonas, Prevotella, Bacteroidetes, Helcococcus, Letospira, Desulfovibrio, Desulfonatronum, Opitutaceae, Tuberibacillus, Bacillus, Brevibacilus, Methylobacterium or Acidaminococcus·, e.g., a chimeric effector protein comprising a first fragment and a second fragment wherein each of the first and second fragments is selected from a Cpfl of an organism comprising Streptococcus, Campylobacter, Nitratifractor, Staphylococcus, Parvibaculum, Roseburia, Neisseria, Gluconacetobacter, Azospirilium, Sphaerochaeta, Lactobacillus, Eubacterium, Corynebacter, Carnobacterium, Rhodobacter, Listeria, Paludibacter, Clostridium, Lachnospiraceae, Clostridiaridium, Leptotrichia, Francisella, Legionella, AlicyclobaciUus, Methanomethyophilus, Porphyromonas, Prevotella, Bacteroidetes, Helcococcus, Letospira, Desulfovibrio, Desulfonatronum, Opitutaceae, Tuberibacillus, Bacillus, Brevibacilus, Methylobacterium or Acidaminococcus wherein the first and second fragments are not from the same bacteria; for instance a chimeric effector protein comprising a first fragment and a second fragment wherein each of the first and second fragments is selected from a Cpfl of S. mutans, S. agalactiae, S. equisimilis, S. sanguinis, S. pneumonia; ('. jejuni, ('. coli; N. salsuginis, N. tergarcus; S. auricularis, S. carnosus; N meningitides, N. gonorrhoeae; /.. monocytogenes, I. ivanovii; C. botulinum, C. difficile, C. tetani, C. sordellii; Francisella tularensis 1, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011 GWA2 33 10, Parcubacteria bacterium GW2011 GWC2 44 17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens and Porphyromonas macacae, wherein the first and second fragments are not from the same bacteria.

[0040] In preferred embodiments of the invention the effector protein is derived from a Cpfl locus (herein such effector proteins are also referred to as “Cpflp”), e.g,, a Cpfl protein (and such effector protein or Cpfl protein or protein derived from a Cpfl locus is also called “CRISPR enzyme”), Cpfl loci include but are not limited to the Cpfl loci of bacterial species listed in Figure 64. In a more preferred embodiment, the Cpflp is derived from a bacterial species selected from .Francisella tularensis I, Prevotella albensis, Lachnospiraceae bacterium

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MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011 GWA2 33 10, Parcubacteria bacterium (7W2011 (1WC2_44_17, Smitheila sp. SC ADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidalus Methanoplasma termitum, Eubacterium eligens, Moraxella hovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens and Porphyromonas macacae. In certain embodiments, the Cpflp is derived from a bacterial species selected from Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020. In certain embodiments, the effector protein is derived from a subspecies of Francisella lularensis 1, including but not limited to Francisella tularensis subsp. Novicida.

[0041] In further embodiments of the invention a protospacer adjacent motif (PAM) or PAM-like motif directs binding of the effector protein complex to the target locus of interest. In a preferred embodiment of the invention, the PAM is 5’ TTN, where N is A/C/G or T and the effector protein is FnCpflp. In another preferred embodiment of the invention, the PAM is 5’ TTTV, where V is A'C or G and the effector protein is AsCpfl, LbCpfl or PaCpflp. In certain embodiments, the PAM is 5’ TTN, where N is A/C/G or T, the effector protein is FnCpflp, and the PAM is located upstream of the 5’ end of the protospacer. In certain embodiments of the invention, the PAM is 5’ CTA, where the effector protein is FnCpflp, and the PAM is located upstream of the 5’ end of the protospacer or the target locus. In preferred embodiments, the invention provides for an expanded targeting range for RNA guided genome editing nucleases wherein the T-rich PAMs of the Cpfl family allow for targeting and editing of AT-rich genomes. [0042] In certain embodiments, the CRISPR enzyme is engineered and can comprise one or more mutations that reduce or eliminate a nuclease activity. The amino acid positions in the FnCpflp RuvC domain include but are not limited to D917A, E1006A, E1028A, D1227A, D1255A, N1257A, D917A, E1006A, E1028A, D1227A, D1255A and N1257A. Applicants have also identified a putative second nuclease domain which is most similar to PD-(D/E)XK nuclease superfamily and Hindi endonuclease like. The point mutations to be generated in this putative nuclease domain to substantially reduce nuclease activity include but are not limited to N580A, N584A, T587A, W609A, D610A, K613A, E614A, D616A, K624A D625A, K627A and Y629A. In a preferred embodiment, the mutation in the FnCpflp RuvC domain is D917A or El006A, wherein the D917A or EI006A mutation completely inactivates the DNA cleavage activity of the FnCpfi effector protein. In another embodiment, the mutation in the FnCpflp iz

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RuvC domain is D1255A, wherein the mutated FnCpfl effector protein has significantly reduced nucleolytic activity.

[0043] The amino acid positions in the AsCpflp RuvC domain include but are not limited to 908, 993, and 1263. In a preferred embodiment, the mutation in the AsCpflp RuvC domain is D908A, E993A, and D1263A, wherein the D908A, E993A, and D1263A mutations completely inactivates the DNA cleavage activity of the AsCpfl effector protein. The amino acid positions in the LbCpflp RuvC domain include but are not limited to832, 947 or 1180. In a preferred embodiment, the mutation in the LbCpflp RuvC domain is LbD832A, E925A, D947A or D1180A, wherein the LbD832A E925A, D947A or D1180A mutations completely inactivates the DNA cleavage activity of the LbCpfl effector protein.

[0044] Mutations can also be made at neighboring residues, e.g., at amino acids near those indicated above that participate in the nuclease acrivity. In some embodiments, only the RuvC domain is inactivated, and in other embodiments, another putative nuclease domain is inactivated, wherein the effector protein complex functions as a nickase and cleaves only one DNA strand. In a preferred embodiment, the other putative nuclease domain is a HincII-like endonuclease domain. In some embodiments, two FnCpfl, AsCpfl or LbCpfl variants (each a different nickase) are used to increase specificity, two nickase variants are used to cleave DNA at a target (where both nickases cleave a DNA strand, while miminizing or eliminating off-target modifications where only one DNA strand is cleaved and subsequently repaired). In preferred embodiments the Cpfl effector protein cleaves sequences associated with or at a target locus of interest as a homodimer comprising two Cpfl effector protein molecules. In a preferred embodiment the homodimer may comprise two Cpfl effector protein molecules comprising a different mutation in their respective RuvC domains.

[0045] The invention contemplates methods of using two or more nickases, in particular a dual or double nickase approach. In some aspects and embodiments, a single type FnCpfl, AsCpfl or LbCpfl nickase may be delivered, for example a modified FnCpfl, AsCpfl or LbCpfl or a modified FnCpfl, AsCpfl or LbCpfl nickase as described herein. This results in the target DNA being bound by two FnCpfl nickases. In addition, it is also envisaged that different orthologs may be used, e.g, an FnCpfl, AsCpfl or LbCpfl nickase on one strand (e.g,, the coding strand) of the DNA and an ortholog on the non-coding or opposite DNA strand. The ortholog can be, but is not limited to, a Cas9 nickase such as a SaCas9 nickase or a SpCas9

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PCT/US2016/038181 nickase. It may be advantageous to use two different orthologs that require different PAMs and may also have different guide requirements, thus allowing a greater deal of control for the user. In certain embodiments, DNA cleavage will involve at least four types of niekases, wherein each type is guided to a different sequence of target DNA, wherein each pair introduces a first nick into one DNA strand and the second introduces a nick into the second DNA strand. In such methods, at least two pairs of single stranded breaks are introduced into the target DNA wherein upon introduction of first and second pairs of single-strand breaks, target sequences between the first and second pairs of single-strand breaks are excised. In certain embodiments, one or both of the orthologs is controllable, i.e. inducible.

[0046] In certain embodiments of the invention, the guide RNA or mature crRNA comprises, consists essentially of, or consists of a direct repeat sequence and a guide sequence or spacer sequence. In certain embodiments, the guide RNA or mature crRNA comprises, consists essentially of or consists of a direct repeat sequence linked to a guide sequence or spacer sequence. In certain embodiments the guide RNA or mature crRNA comprises 19 nts of partial direct repeat followed by 20-30 nt of guide sequence or spacer sequence, advantageously about 20 nt, 23-25 nt or 24 nt. In certain embodiments, the effector protein is a FnCpfl, AsCpfl or LbCpfl effector protein and requires at least 16 nt of guide sequence to achieve detectable DNA cleavage and a minimum of 17 nt of guide sequence to achieve efficient DNA cleavage in vitro. In certain embodiments, the direct repeat sequence is located upstream (i.e., 5’) from the guide sequence or spacer sequence. In a preferred embodiment the seed sequence (i.e. the sequence essential critical for recognition and/or hybridization to the sequence at the target locus) of the FnCpfl, AsCpfl or LbCpfl guide RNA is approximately within the first 5 nt on the 5’ end of the guide sequence or spacer sequence.

[0047] In preferred embodiments of the invention, the mature crRNA comprises a stem loop or an optimized stem loop structure or an optimized secondary structure. In preferred embodiments the mature crRNA comprises a stein loop or an optimized stem loop structure in the direct repeat sequence, wherein the stem ioop or optimized stem loop structure is important for cleavage activity. In certain embodiments, the mature crRNA preferably comprises a single stem loop. In certain embodiments, the direct repeat sequence preferably comprises a single stem loop. In certain embodiments, the cleavage activity of the effector protein complex is modified by introducing mutations that affect the stem loop RNA duplex structure. In preferred

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PCT/US2016/038181 embodiments, mutations which maintain the RNA duplex of the stem loop may be introduced, whereby the cleavage activity of the effector protein complex is maintained. In other preferred embodiments, mutations which disrupt the RNA duplex structure of the stem loop may be introduced, whereby the cleavage activity of the effector protein complex is completely abolished.

[0048] The invention also provides for the nucleotide sequence encoding the effector protein being codon optimized for expression in a eukaryote or eukaryotic cell in any of the herein described methods or compositions. In an embodiment of the invention, the codon optimized effector protein is FnCpflp, AsCpfl or LhCpfl and is codon optimized for operability in a eukaryotic cell or organism, e.g., such cell or organism as elsewhere herein mentioned, for instance, without limitation, a yeast cell, or a mammalian cell or organism, including a mouse cell, a rat cell, and a human cell or non-human eukaryote organism, e.g., plant.

[0049] In certain embodiments of the invention, at least one nuclear localization signal (NFS) is attached to the nucleic acid sequences encoding the Cpfl effector proteins. In preferred embodiments at least one or more C-terminal or N-terminal NLSs are attached (and hence nucleic acid molecule(s) coding for the the Cpfl effector protein can include coding for NLS(s) so that the expressed product has the NLS(s) attached or connected). In a preferred embodiment a C-terminal NFS is attached for optimal expression and nuclear targeting in eukaryotic cells, preferably human cells. In a preferred embodiment, the codon optimized effector protein is FnCpflp, AsCpfl or LhCpfl and the spacer length of the guide RNA is from 15 to 35 nt. In certain embodiments, the spacer length of the guide RNA is at least 16 nucleotides, such as at least 17 nucleotides. In certain embodiments, the spacer length is from 15 to 17 nt, from 17 to 20 nt, from 20 to 24 nt, eg. 20, 21, 22, 23, or 24 nt, from 23 to 25 nt, e.g., 23, 24, or 25 nt, from 24 to 27 nt, from 27-30 nt, from 30-35 nt, or 35 nt or longer. In certain embodiments of the invention, the codon optimized effector protein is FnCpflp and the direct repeat length of the guide RNA is at least 16 nucleotides. In certain embodiments, the codon optimized effector protein is FnCpfl p and the direct repeat length of the guide RNA is from 16 to 20 nt, e.g., 16, 17, 18, 19, or 20 nucleotides, hi certain preferred embodiments, the direct repeat length of the guide RNA is 19 nucleotides, [0050] The invention also encompasses methods for delivering multiple nucleic acid components, wherein each nucleic acid component is specific for a different target locus of

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PCT/US2016/038181 interest thereby modifying multiple target loci of interest. The nucleic acid component of the complex may comprise one or more protein-binding RNA aptamers. The one or more aptamers may be capable of binding a bacteriophage coat protein. The bacteriophage coat protein may be selected from the group comprising Qp, F2, GA, fr, JP501, MS2, Ml 2, RI7, BZ13, JP34, JP500, KU1, MIL MXI, TW18, VK, SP, FI, ID2, NL95, TW19, AP205, φθ>5, <|)Cb8r, <()Cbl2r, 4>Cb23r, 7s and PRR1. In a preferred embodiment the bacteriophage coat protein is MS2. The invention also provides for the nucleic acid component of the complex being 30 or more, 40 or more or 50 or more nucleotides in length.

[0051] The invention also encompasses the cells, components and/or systems of the present invention having trace amounts of cations present in the cells, components and/or systems. Advantageously, the cation is magnesium, such as Nig²”. The cation may be present in a trace amount. A preferred range may be about 1 mM to about 15 mM for the cation, which is advantageously Mg^iT. A preferred concentration may be about 1 mM for human based cells, components and/or systems and about 10 mM to about 15 mM for bacteria based cells, components and/or systems. See, e.g., Gasiunas et al., PNAS, published online September 4, 2012, www.pnas.org/cgi/doi/10.1073/pnas.1208507109.

[0052] Accordingly, it is an object of the invention not to encompass within the invention any previously known product, process of making the product, or method of using the product such that Applicants reserve the right and hereby disclose a disclaimer of any previously known product, process, or method. It is further noted that the invention does not intend to encompass within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the written description and enablement requirements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and hereby disclose a disclaimer of any previously described product, process of making the product, or method of using the product. It may be advantageous in the practice of the invention to be in compliance with Art. 53(c) EPC and Rule 28(b) and (c) EPC. Nothing herein is to be construed as a promise.

[0053] It is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as comprises, comprised, comprising and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean includes, included, including, and

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PCT/US2016/038181 the like, and that terms such as consisting essentially of and consists essentially of have the meaning ascribed to them in U.S. Patent law.

[0054] These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS [0055] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and ad vantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0056] FIGS. 1A-1B depict a new classification of CRISPR-Cas systems. Class 2 includes multisubunit crRNA-effector complexes (Cascade) and Class 2 includes Single-subunit crRNAeffector complexes (Cas9-like).

[0057] FIG. 2 provides a molecular organization of CRISPR-Cas.

[0058] FIGS. 3A-3D provide structures of Type I and III effector complexes: common architecture/common ancestry' despite extensive sequence divergence.

[0059] FIG. 4 shows CRISPR-Cas as a RNA recognition motif (RRM)-centered system. [0060] FIGS. 5A-5D show Cast phylogeny where recombination of adaptation and crRNAeffector modules show a major aspect of CRISPR-Cas evolution.

[0061] FIG. 6 shows a CRISPR-Cas census, specifically a distribution of CRISPR-Cas types/subtypes among archaea and bacteria [0062] FIG. 7 depicts a pipeline for identifying Cas candidates.

[0063] FIGS. 8A-8D depict an organization of complete loci of Class 2 systems, [0064] FIGS. 9A-9B depict C2cl neighborhoods.

[0065] FIGS, 10A-10C depict a Casl tree.

[0066] FIGS. 11 A-l IB depict a domain organization of class 2 families.

[0067] FIGS. 12A-12B depict TnpB homology regions in Class 2 proteins (SEQ ID NOS 246-428, respectively, in order of appearance).

[0068] FIGS. 13A-13B depict C2c2 neighborhoods.

[0069] FIGS, 14A-14E depict HEPN RxxxxH motif in C2c2 family (SEQ ID NOS 4291032, respectively, in order of appearance).

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PCT/US2016/038181 [0070] FIG. 15 depicts C2C1: I. Alicyclobacillus acidoterrestris ATCC 4902,5 (SEQ ID NOS 1034-1037, respectively, in order of appearance).

[0071] FIG. 16 depicts C2C1: 4. Desulfonatronum thiodismutans strain MLF-1 (SEQ ID NOS 1038-1041, respectively, in order of appearance).

[0072] FIG. 17 depicts C2C1: 5. Opitutaceae bacterium TAV5 (SEQ ID NOS 1042-1045, respectively, in order of appearance).

[0073] FIG. 18 depicts C2C1: 7. Bacillus thennoamylovorans strain B4166 (SEQ ID NOS 10461049, respectively, in order of appearance).

[0074] FIG. 19 depicts C2C1: 9. Bacillus sp. NSP2.1 (SEQ ID NOS 1050-1053, respectively, in order of appearance).

[0075] FIG. 20 depicts C2C2: 1. Lachnospiraceae bacterium MA2020 (SEQ ID NOS 10541057, respectively, in order of appearance).

[0076] FIG, 21 depicts C2C2: 2. Lachnospiraceae bacterium NK4A179 (SEQ ID NOS 10581064, respectively, in order of appearance).

[0077] FIG. 22 depicts C2C2: 3. [Clostridium] aminophilum DSM 10710 (SEQ ID NOS 10651068, respectively, in order of appearance).

[0078] FIG. 23 depicts C2C2: 4. Lachnospiraceae bacterium NK4A144 (SEQ ID NOS 1069 and 1070, respectively, in order of appearance).

[0079] FIG. 24 depicts C2C2: 5. Carnobacterium gallinarum DSM 4847 (SEQ ID NOS 1071-1074, respectively, in order of appearance), [0080] FIG. 25 depicts C2C2: 6. Carnobacterium gallinarum DSM 4847 (SEQ ID NOS 1075-1081, respectively, in order of appearance).

[0081] FIG. 26 depicts C2C2: 7. Paludibacter propionicigenes WB4 (SEQ ID NO: 1082).

[0082] FIG. 27 depicts C2C2: 8. Listeria seeligeri serovar l/2b (SEQ ID NOS 1083-1086, respectively, in order of appearance).

[0083] FIG. 28 depicts C2C2: 9. Listeria weihenstephanensis FSL R.9-0317 (SEQ ID NO: 1087). [0084] FIG, 29 depicts C2C2: 10. Listeria bacterium FSL M6-0635 (SEQ ID NOS 1088 and 1091, respectively, in order of appearance).

[0085] FIG. 30 depicts C2C2: 11. Leptotrichia wadei F0279 (SEQ ID NO: 1092).

[0086] FIG. 31 depicts C2C2: 12. Leptotrichia wadei F0279 (SEQ ID NOS 1093-1099, respectively, in order of appearance).

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PCT/US2016/038181 [0087] FIG. 32 depicts C2C2: 14. Leptotiichia shahii DSM 19757 (SEQ ID NOS 1100-1103, respectively, in order of appearance).

[0088] FIG. 33 depicts C2C2: 15. Rhodobacter capsulatus SB 1003 (SEQ ID NOS 1104 and 1105, respectively, in order of appearance), [0089] FIG. 34 depicts C2C2: 16. Rhodobacter capsulatus R121 (SEQ ID NOS 1106 and 1107, respectively, in order of appearance).

[0090] FIG. 35 depicts C2C2: 17. Rhodobacter capsulatus DE442 (SEQ ID NOS 1108 and 1109, respectively, in order of appearance).

[0091] FIG. 36 depicts a tree of DRs [0092] FIG. 37 depicts a tree of C2C2s [0093] FIGS, 38A-38BB show the sequence alignment of Cas-Cpfl orthologs (SEQ ID NOS 103 3 and 1110-1166, respectively, in order of appearance).

[0094] FIGS. 39A-39B show the overview of Cpfl loci alignment [0095] FIGS. 40A-40X shows the PACYC184 FnCpfl (PY001) vector contact (SEQ ID NO: 1167 and SEQ ID NOS 1168-1189, respectively, in order of appearance).

[0096] FIGS. 41A-41I shows the sequence of humanized PaCpfl, with the nucleotide sequence as SEQ ID NO: 1190 and the protein sequence as SEQ ID NO: 1191.

[0097] FIG. 42 depicts a PAM challenge assay [0098] FIG. 43 depicts a schematic of an endogenous FnCpfl locus. pYOOOl is a pACY184 backbone (from NEB) with a partial FnCpfl locus. The FnCpfl locus was PCR amplified in three pieces and cloned into Xbal and Hind3 cut pACYCI84 using Gibson assembly. PYOOOl contains the endogenous FnCpfl locus from 255bp of the acetyltransferase 3’ sequence to the fourth spacer sequence. Only spacer 1-3 are potentially active since space 4 is no longer flanked by direct repeats.

[0099] FIG. 44 depicts PAM libraries, which discloses discloses SEQ ID NOS 1192-1195, respectively, in order of appearance.. Both PAM libraries (left and right) are in pUC19. The complexity of left PAM library is 48 ~ 65k and the complexity of the right PAM library is 47 ~ 16k. Both libraries were prepared with a representation of > 500.

[00100] FIG. 45A-4E depicts FnCpfl PAM Screen Computational Analysis. After sequencing of the screen DNA, the regions corresponding to either the left PAM or the right PAM were extracted. For each sample, the number of PAMs present in the sequenced library' were compared

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PCT/US2016/038181 to the number of expected PAMs in the library (4^Λ8 for the left library, 4^Λ7 for the right). FIG. 44A depicts the left library showed PAM depletion. To quantify this depletion, an enrichment ratio was calculated. For both conditions (control pACYC or FnCpfl containing pACYC) the sample + 0,01 ratio was calculated for each PAM in the library as ratio log·;

initial library + 0.01 p|₀^jj the distribution shows little enrichment in the control sample and enrichment in both bioreps. FIGS. 44B-44D depict PAM ratio distributions. FIGS. 44E shows PAMs above a ratio of 8 were collected, and the frequency distributions were plotted, revealing a 5’ YYN PAM.

[00101] FIG. 46 depicts RNAseq analysis of the Francisella tolerances Cpfl locus, which shows that the CRISPR locus is actively expressed. In addition to the Cpfl and Cas genes, two small non-coding transcript are highly transcribed, which might be the putative tracrRNAs. The CRISPR array is also expressed. Both the putative tracrRNAs and CRISPR array are transcribed in the same direction as the Cpfl and Cas genes. Here all RNA transcripts identified through the RNAseq experiment are mapped against the locus. After further evaluation of the FnCpf l locus, Applicants concluded that target DNA cleavage by a Cpfl effector protein complex does not require a tracrRNA. Applicants determined that Cpfl effector protein complexes comprising only a Cpfl effector protein and a crRNA (guide RNA comprising a direct repeat sequence and a guide sequence) were sufficient to cleave target DNA.

[00102] FIG. 47 depicts zooming into the Cpfl CRISPR array. Many different short transcripts can be identified. In this plot, all identified RN'A transcripts are mapped against the Cpfl locus.

[00103] FIG. 48 depicts identifying two putative tracrRNAs after selecting transcripts that are less than 85 nucleotides long [00104] FIG. 49 depicts zooming into putative tracrRNA I (SEQ ID NO: 1196) and the CRISPR array [00105] FIG. 50 depicts zooming into putative tracrRNA 2 which discloses SEQ ID NOS 11971203, respectively, in order of appearance.

[00106] FIG. 51 depicts putative crRNA sequences (repeat in blue, spacer in black) (SEQ ID NOS 1205 and 1206, respectively, in order of appearance).

[00107] FIG. 52 shows a schematic of the assay to confirm the predicted FnCpfl PAM in vivo.

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PCT/US2016/038181 [00108] FIG. 53 shows FnCpfl locus carrying cells and control cells transformed with pUC19 encoding endogenous spacer 1 with 5’ TTN PAM.

[00109] FIG. 54 shows a schematic indicating putative tracrRNA sequence positions in the FnCpfl locus, the erRNA (SEQ ID NO: 1207) and the pUC protospacer vector.

[00110] FIG. 55 is a gel showing the PCR fragment with TTa PAM and proto-spacerl sequence incubated in cell lysate.

[00111] FIG. 56 is a gel showing the pUC-spacerl with different PAMs incubated in cell lysate.

[00112] FIG. 57 is a gel showing the BasI digestion after incubation in cell lysate.

[00113] FIG. 58 is a gel showing digestion results for three putative erRNA sequences (SEQ ID NO; 1208).

[00114] FIG. 59 is a gel showing testing of different lengths of spacer against a piece of target DNA containing the target site: 5'-TTAgagaagtcatttaataaggccactgttaaaa-3' (SEQ ID NO: 1209). The results show that crRNAs 1-7 mediated successful cleavage of the target DNA in vitro with FnCpfl. crRNAs 8-13 did not facilitate cleavage of the target DNA. SEQ ID NOS 1210-1248 are disclosed, respectively, in order of appearance.

[00115] FIG. 60 is a schematic indicating the minimal FnCpfl locus.

[00116] FIG. 61 is a schematic indicating the minimal Cpfl guide (SEQ ID NO: 1249).

[00117] FIG. 62A-62E depicts PaCpfl PAM Screen Computational Analysis. After sequencing of the screen DNA, the regions corresponding to either the left PAM or the right

PAM were extracted. For each sample, the number of PAMs present in the sequenced library were compared to the number of expected PAMs in the library (4^Λ7). (FIG. 62A) The left library showed very slight PAM depletion. To quantify this depletion, an enrichment ratio was calculated. For both conditions (control pACYC or PaCpfl containing pACYC) the ratio was calculated for each PAM in the library as , sample 4- 0.01 ratio = — log·.,----' initial library 4- 0.01

Plotting the distribution show’s little enrichment in the control sample and enrichment in both bioreps. FIGS. 62B-62D depict PAM ratio distributions. FIG. 62E shows all PAMs above a ratio of 4.5 were collected, and the frequency distributions were plotted, revealing a 5’ TTTV PAM, where V is A or C or G.

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PCT/US2016/038181 [00118] FIG. 63 shows a vector map of the human codon optimized PaCpfl sequence depicted as CBh-NLS-huPaCpfl-NLS-3xHA-pA.

[00119] FIGS. 64A-64B show a phylogenetic tree of 51 Cpfl loci in different bacteria. Highlighted boxes indicate Gene Reference #s: 1-17. Boxed/numbered orthologs were tested for in vitro cleavage activity with predicted mature crRNA; orthologs with boxes around their numbers showed activity in the in vitro assay.

[00120] FIGS. 65A-65H show the details of the human codon optimized sequence for Lachnospiraceae bacterium MC2017 1 Cpfl having a gene length of 3849 nts (Ref #3 in FIG. 64). FIG. 65A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 65B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 65C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 65D: Restriction Enzymes and CIS-Acting Elements. FIG. 65E: Remove Repeat Sequences. FIG. 65F-G: Optimized Sequence (Optimized Sequence Length: 3849, GC% 54.70) (SEQ ID NO: 1250). FIG. 65H: Protein Sequence (SEQ ID NO: 1251).

[00121] FIGS, 66A-66H show the details of the human codon optimized sequence for Butyrivibrio proteoclasticus Cpfl having a gene length of 3873 nts (Ref #4 in FIG. 64). FIG. 66A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 66B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism, FIG. 66C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 66D: Restriction Enzymes and CIS-Acting Elements. FIG. 66E: Remove Repeat Sequences. FIG. 66F-G: Optimized Sequence (Optimized Sequence

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Length: 3873, GC% 54.05) (SEQ ID NO: 1252). FIG. 66H: Protein Sequence (SEQ ID NO: 1253).

[00122] FIGS. 67A-67H show the details of the human codon optimized sequence for Peregrinibacteria bacterium GW201 l_GWA2_33_10 Cpfl having a gene length of 4581 nts (Ref #5 in FIG. 64). FIG. 67A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAT of 1,0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 67B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 67C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 67D: Restriction Enzymes and CISActing Elements. FIG, 67E: Remove Repeat Sequences, FIG, 67F-G: Optimized Sequence (Optimized Sequence Length: 4581, GC% 50.81) (SEQ ID NO: 1254). FIG. 67H: Protein Sequence (SEQ ID NO: 1255).

[00123] FIGS. 68A-68H show the details of the human codon optimized sequence for Parcubacteria bacterium GW2011 GWC2 44 17 Cpfl having a gene length of 4206 nts (Ref #6 in FIG. 64). FIG. 68A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAT of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 68B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 68C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 68D: Restriction Enzymes and CISActing Elements. FIG. 68E: Remove Repeat Sequences. FIG. 68F-G: Optimized Sequence (Optimized Sequence Length: 4206, GC% 52.17) (SEQ ID NO: 1256). FIG, 68H: Protein Sequence (SEQ ID NO: 1257).

[00124] FIGS, 69A-69H show the details of the human codon optimized sequence for Smithella sp. SCADC Cpfl having a gene length of 3900 nts (Ref #7 in FIG. 64). FIG. 69A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of

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PCT/US2016/038181 the gene sequence. A CAT of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 69B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 69C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 69D: Restriction Enzymes and CIS-Acting Elements. FIG. 69E: Remove Repeat Sequences. FIG. 69F-G: Optimized Sequence (Optimized Sequence Length: 3900, GC% 51.56) (SEQ ID NO: 1258). FIG. 69H: Protein Sequence (SEQ ID NO: 1259).

[00125] FIGS. 70A-70H show the details of the human codon optimized sequence for Acidaminococcus sp. BV3L6 Cpfl having a gene length of 4071 nts (Ref #8 in FIG, 64). FIG. 70A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 70B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 70C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 70D: Restriction Enzymes and CIS-Acting Elements. FIG. 70E: Remove Repeat Sequences. FIG. 70F-G: Optimized Sequence (Optimized Sequence Length: 4071, GC% 54.89) (SEQ ID NO: 1260). FIG. 70H: Protein Sequence (SEQ ID NO: 1261).

[00126] FIGS. 71A-71H show the details of the human codon optimized sequence for Lachnospiraceae bacterium MA2020 Cpfl having a gene length of 3768 nts (Ref #9 in FIG. 64). FIG. 71 A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAT of > 0,8 is regarded as good, in terms of high gene expression level. FIG, 71B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given anrino acid in the desired expression organism. FIG. 71C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp

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PCT/US2016/038181 window have been removed. FIG. 71D: Restriction Enzymes and CIS-Acting Elements. FIG. 71E: Remove Repeat Sequences. FIG. 71F-G: Optimized Sequence (Optimized Sequence Length: 3768, GC% 51.53) (SEQ ID NO: 1262). FIG. 71H: Protein Sequence (SEQ ID NO: 1263).

[00127] FIGS. 72A-72H show the details of the human codon optimized sequence for Candidatus Methanoplasma termitum Cpfl having a gene length of 3864 nts (Ref #10 in FIG. 64). FIG. 72A: Codon Adaptation Index (CAl). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 72B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 72C: GC Content Adjustment, The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 72D: Restriction Enzymes and CIS-Acting Elements. FIG. 72E: Remove Repeat Sequences. FIG. 72F-G: Optimized Sequence (Optimized Sequence Length: 3864, GC% 52.67) (SEQ ID NO: 1264). FIG. 72H: Protein Sequence (SEQ ID NO: 1265).

[00128] FIGS. 73A-73H show the details of the human codon optimized sequence for Eubacterium eligens Cpfl having a gene length of 3996 nts (Ref #11 in FIG. 64). FIG. 73A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 73B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 73C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed, FIG. 73D: Restriction Enzymes and CIS-Acting Elements. FIG, 73E: Remove Repeat Sequences. FIG. 73F-G: Optimized Sequence (Optimized Sequence Length: 3996, GC% 50.52) (SEQ ID NO: 1266). FIG. 731 f Protein Sequence (SEQ ID NO: 1267). [00129] FIGS. 74A-74H show the details of the human codon optimized sequence for Moraxella bovoculi 237 Cpfl having a gene length of 4269 nts (Ref #12 in FIG. 64). FIG. 74A:

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Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 74B: Frequency of Optimal Codons (FOP), The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism, FIG, 74C: GO Content Adjustment, The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 74D: Restriction Enzymes and CIS-Acting Elements. FIG. 74E: Remove Repeat Sequences. FIG. 74F-G: Optimized Sequence (Optimized Sequence Length: 4269, GC% 53.58) (SEQ ID NO: 1268). FIG. 74H: Protein Sequence (SEQ ID NO: 1269). [00130] FIGS, 75A-75H show the details of the human codon optimized sequence for Leptospira inadai Cpfl having a gene length of 3939 nts (Ref #13 in FIG. 64). FIG. 75A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 75B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 75C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 75D: Restriction Enzymes and CIS-Acting Elements. FIG. 75E: Remove Repeat Sequences. FIG. 75F-G: Optimized Sequence (Optimized Sequence Length: 3939, GC% 51.30) (SEQ ID NO: 1270), FIG. 7511. Protein Sequence (SEQ ID NO: 1271). [00131] FIGS. 76A-76H show⁷ the details of the human codon optimized sequence for Lachnospiraceae bacterium ND2006 Cpfl having a gene length of 3834 nts (Ref #14 in FIG. 64). FIG. 76A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0,8 is regarded as good, in terms of high gene expression level. FIG, 76B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 76C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp

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PCT/US2016/038181 window have been removed. FIG. 76D: Restriction Enzymes and CIS-Acting Elements. FIG. 76E: Remove Repeat Sequences. FIG. 76F-G: Optimized Sequence (Optimized Sequence Length: 3834, GC% 51.06) (SEQ ID NO: 1272). FIG. 76H: Protein Sequence (SEQ ID NO: 1273).

[00132] FIGS. 77A-77H show the details of the human codon optimized sequence for Porphyromonas crevioricanis 3 Cpfl having a gene length of 3930 nts (Ref #15 in FIG. 64). FIG. 77A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 77B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 77C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%, Peaks of %GC content in a 60 bp window have been removed. FIG. 77D: Restriction Enzymes and CIS-Acting Elements. FIG. 77E: Remove Repeat Sequences. FIG. 77F-G: Optimized Sequence (Optimized Sequence Length: 3930, GC% 54.42) (SEQ ID NO: 1274). FIG. 77H: Protein Sequence (SEQ ID NO: 1275).

[00133] FIGS. 78A-78H show the details of the human codon optimized sequence for Prevotella disiens Cpfl having a gene length of 4119 nts (Ref #16 in FIG. 64). FIG. 78A: Codon Adaptation Index (CAI). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 78B: Frequency of Optimal Codons (FOP). The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism. FIG. 78C: GC Content Adjustment. The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed, FIG. 78D: Restriction Enzymes and CIS-Acting Elements. FIG, 78E: Remove Repeat Sequences. FIG. 78F-G: Optimized Sequence (Optimized Sequence Length: 4119, GC% 51.88) (SEQ ID NO: 1276). FIG. 78H: Protein Sequence (SEQ ID NO: 1277). [00134] FIGS. 79A-79H shows the details of the human codon optimized sequence for Porphyromonas macacae Cpfl having a gene length of 3888 nts (Ref #17 in FIG. 64). FIG. 79A:

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Codon Adaptation Index (CAT). The distribution of codon usage frequency along the length of the gene sequence. A CAI of 1.0 is considered to be perfect in the desired expression organism, and a CAI of > 0.8 is regarded as good, in terms of high gene expression level. FIG. 79B: Frequency of Optimal Codons (FOP), The percentage distribution of codons in computed codon quality groups. The value of 100 is set for the codon with the highest usage frequency for a given amino acid in the desired expression organism, FIG, 79C: GO Content Adjustment, The ideal percentage range of GC content is between 30-70%. Peaks of %GC content in a 60 bp window have been removed. FIG. 79D: Restriction Enzymes and CIS-Acting Elements. FIG 79E: Remove Repeat Sequences. FIG. 79F-G: Optimized Sequence (Optimized Sequence Length: 3888, GC% 53.26) (SEQ ID NO: 1278). FIG. 79H: Protein Sequence (SEQ ID NO: 1279). [00135] FIG. 80A-80I shows direct repeat (DR) sequences for each ortholog (refer to numbering Ref# 3-17 in FIG. 64) and their predicted fold structure. SEQ ID NOS 1280-1313, respectively, are disclosed in order of appearance.

[00136] FIG. 81 shows cleavage of a PCR amplicon of the human Emxl locus. SEQ ID NOS 1314-1318, respectively, are disclosed in order of appearance.

[00137] FIG. 82A-82B shows the effect of truncation in 5’ DR on cleavage Activity. FIG. 82A shows a gel in which cleavage results with 5 DR truncations is indicated. FIG. 82B shows a diagram in which crDNA deltaDR5 disrupted the stem loop at the 5’ end. This indicates that the stemloop at the 5’ end is essential for cleavage activity. SEQ ID NOS 1319-1324, respectively, are disclosed in order of appearance.

[00138] FIG. 83 shows the effect of crRNA-DNA target mismatch on cleavage efficiency. SEQ ID NOS 1325-1335, respectively, are disclosed in order of appearance, [00139] FIG. 84 shows the cleavage of DNA using purified Francisella and Prevotella Cpfl. SEQ ID NO: 1336 is disclosed.

[00140] FIG. 85A-85B show diagrams of DR secondary structures. FIG. 85A shows a FnCpfl DR secondary structure (SEQ ID NO: 1337) (stem loop highlighted). FIG. 85B shows a PaCpfl DR secondary structure (SEQ ID NO: 1338) (stem loop highlighted, identical except for a single base difference in the loop region).

[00141] FIG. 86 shows a further depiction of the RNAseq analysis of the FnCpl locus.

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PCT/US2016/038181 [00142] FIG. 87A-87B show schematics of mature crRNA sequences. FIG. 87A shows a mature crRNA sequences for FnCpfl. FIG. 87B shows a mature crRNA sequences for PaCpfl. SEQ ID NOS 1339-1342, respectively, are disclosed in order of appearance.

[00143] FIG, 88 shows cleavage of DNA using human codon optimized Francisella novicida FnCpfl. The top band corresponds to un-cleaved full length fragment (606bp). Expected cleavage product sizes of ~345bp and -261 bp are indicated by triangles.

[00144] FIG. 89 shows in vitro ortholog assay demonstrating cleavage by Cpfl orthologs. [00145] FIGS. 90A-90C show computationally derived PAMs from the in vitro cutting assay. [00146] FIG. 91 shows Cpfl cutting in a staggered fashion with 5’ overhangs. SEQ ID NOS 1343-1345, respectively, are disclosed in order of appearance.

[00147] FIG. 92 shows effect of spacer length on cutting. SEQ ID NOS 1346-1352, respectively, are disclosed in order of appearance.

[00148] FIG, 93 shows SURVEYOR data for FnCpfl mediated indels in HEK293T ceils. [00149] FIGS. 94A-94F show⁷ the processing of transcripts when sections of the FnCpf l locus are deleted as compared to the processing of transcripts in a wild type FnCpfl locus. FIGS. 95B, 95D and 95F zoom in on the processed spacer. SEQ ID NOS 1353-1401, respectively, are disclosed in order of appearance.

[00150] FIGS. 95A-95E show the Francisella tularensis subsp. novicida U112 Cpfl CRISPR locus provides immunity against transformation of plasmids containing protospacers flanked by a 5’-TTN PAM. FIG. 95A show the organization of two CRISPR loci found in Francisella tularensis subsp. novicida 11112 (NC 008601). The domain organization of FnCas9 and FnCpfl are compared. FIG. 95B provide a schematic illustration of the plasmid depletion assay for discovering the PAM position and identity. Competent E. coli harboring either the heterologous FnCpfl locus plasmid (pFnCpfl) or the empty vector control were transformed with a library of plasmids containing the matching protospaeer flanked by randomized 5’ or 3’ PAM sequences and selected with antibiotic to deplete plasmids carrying successfully-targeted PAM. Plasmids from surviving colonies were extracted and sequenced to determine depleted PAM sequences, FIGS. 95C-95D show sequence logos for the FnCpfl PAM as determined by the plasmid depletion assay. Letter height at position is determined by information content, error bars show 95% Bayesian confidence interval. FIG. 95Eshows E. coli harboring pFnCpfl demonstrate

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PCT/US2016/038181 robust interference against plasmids carrying 5’-TTN PAMs (n = 3, error bars represent mean ± S.E.M.).

[00151] FIGS. 96A-96C shows heterologous expression of FnCpfi and CRISPR array in E. coli is sufficient to mediate plasmid DNA interference and crRNA maturation. Small RNA-seq of Francisella tularensis subsp. novicida U112 (FIG. 96A) reveals transcription and processing of the FnCpfi CRISPR array. The mature crRNA begins with a 19 nt partial direct repeat followed by 23-25 nt of spacer sequence. Small RNA-seq of E. coli transformed with a plasmid carrying synthetic promoter-driven FnCpfi and CRISPR array (FIG. 96B) shows crRNA processing independent of Cas genes and other sequence elements in the FnCpfi locus. FIG. 96C depicts E. coli harboring different truncations of the FnCpfi CRISPR locus and shows that only FnCpfi and the CRISPR array are required for plasmid DNA interference (n == 3, error bars show mean ± S.E.M.). SEQ ID NO: 1580 is disclosed.

[00152] FIGS. 97A-97E shows FnCpfi is targeted by crRNA to cleave DNA in vitro. FIG, 97A is a schematic of the FnCpfi crRNA-DNA targeting complex. Cleavage sites are indicated by red arrows (SEQ ID NOS 1402 and 1403, respectively, disclosed in order of appearance). FnCpfi and crRNA alone mediated RNA-guided cleavage of target DNA in a crRNA- and Mg²⁺dependent manner (FIG. 97B). FIG. 97C shows FnCpfi cleaves both linear and supercoiled DNA. FIG. 97D shows Sanger sequencing traces from FnCpfi -digested target show staggered overhangs (SEQ ID NOS 1404 and 1406, respectively, disclosed in order of appearance). The non-tempiated addition of an additional adenine, denoted as N, is an artifact of the polymerase used in sequencing. Reverse primer read represented as reverse complement to aid visualization. FIG. 97E shows cleavage is dependent on base-pairing at the 5’ PAM. FnCpfi can only recognize the PAM in correctly Watson-Crick paired DNA.

[00153] FIGS. 98A-98B shows catalytic residues in the C-terminal RuvC domain of FnCpfi are necessary for DNA cleavage. FIG. 98A shows the domain structure of FnCpfi with RuvC catalytic residues highlighted. The catalytic residues were identified based on sequence homology to Thermus thermophihis RuvC (PDB ID: 4EP5), FIG. 98B depicts a native TBE PAGE gel showing that mutation of the RuvC catalytic residues of FnCpfi (D9I7A and E1006A) and mutation of the RuvC (D10A) catalytic residue of SpCas9 prevents double stranded DNA cleavage. Denaturing TBE-Urea PAGE gel showing that mutation of the RuvC

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PCT/US2016/038181 catalytic residues of FnCpfl (D917A and E1006A) prevents DNA nicking activity, whereas mutation of the RuvC (D10A) catalytic residue of SpCas9 results in nicking of the target site. [00154] FIGS. 99A-99E shows crRNA requirements for FnCpfl nuclease activity in vitro. FIG. 99A shows the effect of spacer length on FnCpfl cleavage activity, FIG. 99B shows the effect of crRNA-target DNA mismatch on FnCpfl cleavage activity. FIG. 99C demonstrates the effect of direct repeat length on FnCpfl cleavage activity. FIG. 99D shows FnCpfl cleavage activity depends on secondary structure in the stem of the direct repeat RNA structure. FIG. 99E shows FnCpfl cleavage activity is unaffected by loop mutations but is sensitive to mutation in the 3’-most base of the direct repeat. SEQ ID NOS 1407-1433, respectively, disclosed in order of appearance.

[00155] FIGS, 100A-100F provides an analysis of Cpfl -family protein diversity and function. FIGS. 100A-100B show a phylogenetic comparison of 16 Cpfl orthologs selected for functional analysis. Conserved sequences are shown in dark gray. The RuvC domain, bridge helix, and zinc finger are highlighted. FIG. 100C shows an alignment of direct repeats from the 16 Cpfl-family proteins. Sequences that are removed post crRNA maturation are colored gray. Non-conserved bases are colored red. The stem duplex is highlighted in gray. FIG. 100D depicts RNAfold (Lorenz et al., 2011) prediction of the direct repeat sequence in the mature crRNA. Predictions for FnCpfl along with three less-conserved orthologs shown. FIG. 100E shows ortholog crRNAs with similar direct repeat sequences are able to function with FnCpfl to mediate target DNA cleavage. FIG. 100F shows PAM sequences for 8 Cpfl-family proteins identified using in vitro cleavage of a plasmid library containing randomized PAMs flanking the protospacer. SEQ ID NOS 1434-1453, respectively, disclosed in order of appearance.

[00156] FIGS. 101A-101E shows Cpfl mediates robust genome editing in human cell lines. FIG. 101A is a schemative showing expression of individual Cpfl-family proteins in HEK 293FT cells using CMV-driven expression vectors. The corresponding crRNA is expressed using a PCR fragment containing a U6 promoter fused to the crRNA sequence. Transfected cells were analyzed using either Surveyor nuclease assay or targeted deep sequencing, FIG. 101B (top) depicts the sequence of DNMT1 -targeting crRNA 3, and sequencing reads (bottom) show representative indels. IG. I01B discloses SEQ ID NOS 1454-1465, respectively, in order of appearance. FIG. 101C provides a comparison of in vitro and in vivo cleavage activity. The DNMT1 target region was PCR amplified and the genomic fragment was used to test Cpfl31

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PCT/US2016/038181 mediated cleavage. All 8 Cpf l-family proteins showed DNA cleavage in vitro (top). Candidates 7 - AsCpfl and 13 - LbSCpfl facilitated robust indel formation in human cells (bottom). FIG. I01D show^?s Cpfl and SpCas9 target sequences in the human DNMT1 locus (SEQ ID NOS 1466-1473, respectively, disclosed in order of appearance), FIG. 10IE provides a comparison of Cpfl and SpCas9 genome editing efficiency. Target sites correspond to sequences shown in FIG. I01D.

[00157] FIGS. 102A-102D show's an in vivo plasmid depletion assay for identifying FnCpfl PAM. (See also FIG. 95). FIG. 102A; Transformation of E. coli harboring pFnCpfl with a library of plasmids carrying randomized 5’ PAM sequences. A subset of plasmids were depleted. Plot shows depletion levels in ranked order. Depletion is measured as the negative log₂ fold ratio of normalized abundance compared pACYC184 E. coli controls, PAMs above a threshold of 3.5 are used to generate sequence logos. FIG. I02B: Transformation of E. coli harboring pFnCpfl with a library of plasmids carrying randomized 3’ PAM sequences. A subset of plasmids were depleted. Plot show's depletion levels in ranked order. Depletion is measured as the negative log₂ fold ratio of normalized abundance compared pACYC184 E. coli controls and PAMs above a threshold of 3.5 are used to generate sequence logos. FIG. 102C: Input library' of plasmids carrying randomized 5’ PAM sequences. Plot shows depletion levels in ranked order. Depletion is measured as the negative log₂ fold ratio of normalized abundance compared pACYCI84 E. coli controls. PAMs above a threshold of 3.5 are used to generate sequence logos. FIG. I02D: The number of unique PAMs passing significance threshold for pairwise combinations of bases at the 2 and 3 positions of the 5’ PAM.

[00158] FIGS. 103A-103D shows FnCpfl Protein Purification, (See also FIG. 97). FIG. 103/k depicts a Coomassie blue stained acrylamide gel of FnCpfl showing stepwise purification. A band just above 160 kD eluted from the Ni-NTA column, consistent with the size of a MBPFnCpfl fusion (189.7 kD). Upon addition of TEV protease a lower molecular weight band appeared, consistent with the size of 147 kD free FnCpfl. FIG. 103B: Size exclusion gel filtration of fnCpfl. FnCpfl eluted at a size approximately 300 kD (62.65 mL), suggesting Cpfl may exist in solution as a dimer. FIG. 103C shows protein standards used to calibrate the Superdex 200 column. BDex == Blue Dextran (void volume), Aid == Aldolase (158 kD), Ov == Ovalbumin (44 kD), RibA = Ribonuclease A (13.7 kD), Apr = Aprotinin (6.5 kD). FIG. I03D: Calibration curve of the Superdex 200 column. K_a is calculated as (elution volume - void

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PCT/US2016/038181 volume)/(geometric column volume - void volume). Standards were plotted and fit to a logarithmic curve.

[00159] FIGS. 104A-104E shows cleavage patterns of FnCpfl. (See also FIG. 97). Sanger sequencing traces from FnCpfl-digested DNA targets show staggered overhangs. The nontemplated addition of an additional adenine, denoted as N, is an artifact of the polymerase used in sequencing. Sanger traces are shown for different TTN PAMs with protospacer 1 (FIG. 104A), protospacer 2 (FIG. 104B), and protospacer 3 (FIG. 104C) and targets DNMT1 and EMX1 (FIG. 104D). The (-) strand sequence is reverse-complemented to show the top strand sequence. Cleavage sites are indicated by red triangles. Smaller triangles indicate putative alternative cleavage sites. FIG. 104E shows the effect of PAM-distal crRNA-target DNA mismatch on FnCpfl cleavage activity, SEQ ID NOS 1474-1494, respectively, disclosed in order of appearance.

[00160] FIGS. 105A-105B shows an amino acid sequence alignment of FnCpfl (SEQ ID NO; 1495), AsCpfl (SEQ ID NO: 1496), and LbCpfl (SEQ ID NO: 1497). (See also FIG 100). Residues that are conserved are highlighted with a red background and conserved mutations are highlighted with an outline and red font. Secondary structure prediction is highlighted above (FnCpfl) and below (LbCpfl) the alignment. Alpha helices are shown as a curly symbol and beta strands are shown as dashes. Protein domains identified in FIG. 95A are also highlighted. [00161] FIGS. 106A-106D provides maps bacterial genomic loci corresponding to the 16 Cpfl-family proteins selected for mammalian experimentation. (See also FIG. 100). FIGS. I06A-I06D disclose SEQ ID NOS 1498-1513, respectively, in order of appearance.

[00162] FIGS. 107A-107E shows in vitro characterization of Cpfl-family proteins. FIG, 107A is a schematic for in vitro PAM screen using Cpfl-family proteins. A library of plasmids bearing randomized 5’ PAM sequences were cleaved by individual Cpfl-family proteins and their corresponding crRNAs. Uncleaved plasmid DNA was purified and sequenced to identify specific PAM motifs that were depleted. FIG. 107B indicates the number of unique sequences passing significance threshold for pairwise combinations of bases at the 2 and 3 positions of the 5’ PAM for 7 - AsCpfl. FIG. 107C indicates the number of unique PAMs passing significance threshold for triple combinations of bases at the 2, 3, and 4 positions of the 5’ PAM for 13 LbCpfl. FIGS. I07D-I07E E and F show Sanger sequencing traces from 7 - AsCpfl-digested target (FIGS. 107E) and 13 - LbCpfl-digested target (FIG. 107F) and show staggered

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PCT/US2016/038181 overhangs. The non-templated addition of an additional adenine, denoted as N, is an artifact of the polymerase used in sequencing. Cleavage sites are indicated by red triangles. Smaller triangles indicate putative alternative cleavage sites. FIG. 107D-E discloses SEQ ID NOS 15 ΜΙ 519, respectively, in order of appearance.

[00163] FIGS. 108A-108F indicates human cell genome editing efficiency at additional loci. Surveyor gels show quantification of indel efficiency achieved by each Cpfl -family protein at DNMT1 target sites 1 (FIG. 108A), 2 (FIG. 108B), and 4 (FTG. 108C). FTGS. 108A-108C indicate human cell genome editing efficiency at additional loci and Sanger sequencing of cleaved of DNMT target sites. Surveyor gels show quantification of indel efficiency achieved by each Cpfl-family protein at EMX1 target sites I (FIG. 108D) and 2 (FIG. 108E). Indel distributions for AsCpfl and LbCpfl and DNMT1 target sites 2, 3, and 4 (FIG, 108F). Cyan bars represent total indel coverage; blue bars represent distribution of 3’ ends of indels. For each target, PAM sequence is in red and target sequence is in light blue.

[00164] FIGS. 109A-109C depicts a computational analysis of the primary structure of Cpfl nucleases reveals three distinct regions. First a C-terminal RuvC like domain, which is the only functional characterized domain. Second a N-terminal alpha-helical region and thirst a mixed alpha and beta region, located between the RuvC like domain and the alpha-helical region. [00165] FIGS. 110A-110E depict an AsCpfl Rad50 alignment (PDB 4W9M). SEQ ID NOS 1520 and 1521, respectively, disclosed in order of appearance. FIG. HOC depicts an AsCpfl RuvC alignment (PDB 4LD0). SEQ ID NOS 1522 and 1523, respectively, disclosed in order of appearance. FIGS. IIOD-IIOE depicts an alignment of AsCpfl and FnCpfl which identifies Rad50 domain in FnCpfl, SEQ ID NOS 1524 and 1525, respectively, disclosed in order of appearance.

[00166] FIG. Ill depicts a structure of Rad50 (4W9M) in complex with DNA. DNA interacting residues are highlighted (in red).

[00167] FIG. 112 depicts a structure of RuvC (4LD0) in complex with holiday junction. DNA interacting residues are highlighted in red.

[00168] FIG. 113 depicts a blast of AsCpf l aligns to a region of the site specific recombinase XerD. An active site regions of XerD is LYWTGMR (SEQ ID NO: 1) with R being a catalytic residue. SEQ ID NOS 1526-1527, respectively, disclosed in order of appearance.

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PCT/US2016/038181 [00169] FIG. 114 depicts a region is conserved in Cpfl orthologs (Yellow box) and although the R is not conserved, a highly conserved aspartic acid (orange box) is just C-terminal of this region and a nearby conserved region (blue box) with an absolutely conserved arginine. The aspartic acid is D732 in LbCpfl. SEQ ID NOS 1204 and 1528-1579, respectively, disclosed in order of appearance.

[00170] FIG. 115A shows an experiment where 150,000 HEK293T cells were plated per 24well 24h before transfection. Cells were transfected with 400ng huAsCpfl plasmid and lOOng of tandem guide plasmid comprising one guide sequence directed to GRIN28 and one directed to EMX1 placed in tandem behind the U6 promoter, using Lipofectamin2000. Cells were harvested 72h after transfection and AsCpfl activity mediated by tandem guides was assayed using the SURVEYOR nuclease assay, [00171] FIG. 115B demonstrates INDEL formation in both the GRIN28 and the EMX1 gene. [00172] FIG, 116 shows FnCpfl cleavage of an array with increasing concentrations of EDTA (and decreasing concentrations of Mg2+). The buffer is 20 mM TrisHCl pEl 7 (room temperature), 50 mM KC1, and includes a murine RNAse inhibitor to prevent degradation of RNA due to potential trace amount of non-specific RNase carried over from protein purification. [00173] The figures herein are for illustrative purposes only and are not necessarily drawn to scale.

DETAILED DESCRIPTION OF THE INVENTION [00174] The present application describes novel RNA-guided endonucleases (e.g. Cpfl effector proteins) which are functionally distinct from the CR1SPR-Cas9 systems described previously and hence the terminology of elements associated with these novel endonulceases are modified accordingly herein. Cpfl-associated CRISPR arrays described herein are processed into mature crRNAs without the requirement of an additional tracrRNA. The crRNAs described herein comprise a spacer sequence (or guide sequence) and a direct repeat sequence and a CpflpcrRNA complex by itself is sufficient to efficiently cleave target DNA. The seed sequence described herein, e.g. the seed sequence of a FnCpfl guide RNA is approximately within the first 5 nt on the 5’ end of the spacer sequence (or guide sequence) and mutations within the seed sequence adversely affect cleavage activity of the Cpfl effector protein complex.

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PCT/US2016/038181 [00175] In general, a CRISPR system is characterized by elements that promote the formation of a CRISPR complex at the site of a target sequence (also referred to as a protospacer in the context of an endogenous CRISPR system). In the context of formation of a CRISPR complex, “target sequence” refers to a sequence to which a guide sequence is designed to target, e.g. have complementarity, where hybridization between a target sequence and a guide sequence promotes the formation of a CRISPR complex. The section of the guide sequence through which complementarity to the target sequence is important for cleavage acitivity is referred to herein as the seed sequence. A target sequence may comprise any polynucleotide, such as DNA or RNA polynucleotides and is comprised within a target locus of interest. In some embodiments, a target sequence is located in the nucleus or cytoplasm of a cell. The herein described invention encompasses novel effector proteins of Class 2 CRISPR-Cas systems, of which Cas9 is an exemplar)' effector protein and hence terms used in this application to describe novel effector proteins, may correlate to the terms used to describe the CRISPR-Cas9 system, [00176] The CRISPR-Cas loci has more than 50 gene families and there is no strictly universal genes. Therefore, no single evolutionary tree is feasible and a multi-pronged approach is needed to identify new families. So far, there is comprehensive cas gene identification of 395 profiles for 93 Cas proteins. Classification includes signature gene profiles plus signatures of locus architecture. A new classification of CRISPR-Cas systems is proposed in FIG. 1. Class 1 includes multisubunit crRNA-effector complexes (Cascade) and Class 2 includes Single-subunit crRNA-effector complexes (Cas9-like). FIG. 2 provides a molecular organization of CRISPRCas. FIG. 3 provides structures of Type I and III effector complexes: common architecture/common ancestry despite extensive sequence divergence, FIG, 4 shows CRISPRCas as a RNA recognition motif (RRM)-centered system. FIG. 5 shows Casl phylogeny where recombination of adaptation and crRNA-effector modules show a major aspect of CRISPR-Cas evolution. FIG. 6 shows a CRISPR-Cas census, specifically a distribution of CRISPR-Cas types/subtypes among archaea and bacteria.

[00177] The action of the CRISPR-Cas system is usually divided into three stages: (1) adaptation or spacer integration, (2) processing of the primary transcript of the CRISPR locus (pre-crRNA) and maturation of the crRNA which includes the spacer and variable regions corresponding to 5' and 3' fragments of CRISPR repeats, and (3) DNA (or RNA) interference. Two proteins, Casl and Cas2, that are present in the great majority of the known CRISPR-Cas

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PCT/US2016/038181 systems are sufficient for the insertion of spacers into the CRISPR cassettes. These two proteins form a complex that is required for this adaptation process; the endonuclease activity of Casl is required for spacer integration whereas Cas2 appears to perform a nonenzymatic function. The Casl-Cas2 complex represents the highly conserved “information processing” module of CRISPR-Cas that appears to be quasi-autonomous from the rest of the system. (See Annotation and Classification of CRISPR-Cas Systems. Makarova KS, Koonin EV. Methods Mol Biol. 2015;1311:47-75).

[00178] The previously described Class 2 systems, namely Type II and the putative Type V, consisted of only three or four genes in the cas operon, namely the casl and cas2 genes comprising the adaptation module (the casl-cas2 pair of genes are not involved in interference), a single multidomain effector protein that is responsible for interference but also contributes to the pre-crRNA processing and adaptation, and often a fourth gene with uncharacterized functions that is dispensable in at least some Type II systems (and in some cases the fourth gene is cas4 (biochemical or in silico evidence shows that Cas4 is a PD-(DE)xK superfamily nuclease with three-cysteine C-terminal cluster; possesses 5'-ssDNA exonuclease activity) or esn2, which encodes an inactivated ATPase). In most cases, a CRISPR array and a gene for a distinct RNA species known as tracrRNA, a trans-encoded small CRISPR RNA, are adjacent to Class 2 cas operons. The tracrRNA is partially homologous to the repeats within the respective CRISPR array and is essential for the processing of pre-crRNA that is catalyzed by RNAse III, a ubiquitous bacterial enzyme that is not associated with the CRISPR-Cas loci.

[00179] Casl is the most conserved protein that is present in most of the CRISPR-Cas systems and evolves slower than other Cas proteins. Accordingly, Casl phylogeny has been used as the guide for CRISPR-Cas system classification. Biochemical or in silico evidence shows that Casl is a metal-dependent deoxyribonuclease. Deletion of Casl in E. coli results in increased sensitivity to DNA damage and impaired chromosomal segregation as described in “A dual function of the CRISPR-Cassystem in bacterial antivirus immunity and DNA repair,” Babu M et al. Mol Microbiol 79:484-502 (2011). Biochemical or in silico evidence shows that Cas 2 is a RNase specific to U-rich regions and is a double- stranded DNase.

[00180] Aspects of the invention relate to the identification and engineering of novel effector proteins associated with Class 2 CRISPR-Cas systems. In a preferred embodiment, the effector protein comprises a single-subunit effector module. In a further embodiment the effector protein

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PCT/US2016/038181 is functional in prokaryotic or eukaryotic cells for in vitro, in vivo or ex vivo applications. An aspect of the invention encompasses computational methods and algorithms to predict new Class 2 CRISPR-Cas systems and identify the components therein.

[00181] In one embodiment, a computational method of identifying novel Class 2 CRISPRCas loci comprises the following steps: detecting all contigs encoding the Cast protein; identifying all predicted protein coding genes within 20kB of the casl gene; comparing the identified genes with Cas protein-specific profiles and predicting CRISPR arrays; selecting unclassified candidate CRISPR-Cas loci containing proteins larger than 500 amino acids (>500 aa); analyzing selected candidates using PSI-BLAST and HHPred, thereby isolating and identifying novel Class 2 CRISPR-Cas loci. In addition to the above mentioned steps, additional analysis of the candidates may be conducted by searching metagenomics databases for additional homologs.

[00182] In one aspect the detecting all contigs encoding the Casl protein is performed by GenemarkS which a gene prediction program as further described in “GeneMarkS: a self-training method for prediction of gene starts in microbial genomes. Implications for finding sequence motifs in regulatory' regions.” John Besemer, Alexandre Lomsadze and Mark Borodovsky, Nucleic Acids Research (2001) 29, pp 2607-2618, herein incorporated by reference.

[00183] In one aspect the identifying all predicted protein coding genes is carried out by comparing the identified genes with Cas protein-specific profiles and annotating them according to NCBI Conserved Domain Database (CDD) which is a protein annotation resource that consists of a collection of well-annotated multiple sequence alignment models for ancient domains and full-length proteins. These are available as position-specific score matrices (PSSMs) for fast identification of conserved domains in protein sequences via RPS-BLAST. CDD content includes NCBI-curated domains, which use 3D-structure information to explicitly define domain boundaries and provide insights into sequence/structure/function relationships, as well as domain models Imported from a number of external source databases (Pfam, SMART, COG, PRK, TIGRFAM). In a further aspect, CRISPR arrays were predicted using a PILER-CR program which is a public domain software for finding CRISPR repeats as described in “PILERCR: fast and accurate identification of CRISPR repeats”, Edgar, R.C., BMC Bioinformatics, Jan 20;8:18(2007), herein incorporated by reference.

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PCT/US2016/038181 [00184] In a further aspect, the case by case analysis is performed using PSI-BLAST (Position-Specific Iterative Basie Local Alignment Search Tool). PSI-BLAST derives a position-specific scoring matrix (PSSM) or profile from the multiple sequence alignment of sequences detected above a given score threshold using protein-protein BLAST. This PSSM is used to further search the database for new matches, and is updated for subsequent iterations with these newly detected sequences. Thus, PSI-BLAST provides a means of detecting distant relationships between proteins.

[00185] In another aspect, the ease by case analysis is performed using HHpred, a method for sequence database searching and structure prediction that is as easy to use as BLAST or PSIBLAST and that is at the same time much more sensitive in finding remote homologs. In fact, HHpred’s sensitivity is competitive with the most powerful servers for structure prediction currently available. HHpred is the first server that is based on the pairwise comparison of profile hidden Markov models (HMMs). Whereas most conventional sequence search methods search sequence databases such as UniProt or the NR, HHpred searches alignment databases, like Pfam or SMART. This greatly simplifies the list of hits to a number of sequence families instead of a clutter of single sequences. All major publicly available profile and alignment databases are available through HHpred. HHpred accepts a single query sequence or a multiple alignment as input. Within only a few minutes it returns the search results in an easy-to-read format similar to that of PSI-BLAST. Search options include local or global alignment and scoring secondary structure similarity, HHpred can produce pairwise query-template sequence alignments, merged query-template multiple alignments (e.g. for transitive searches), as well as 3D structural models calculated by the MODELLER software from HHpred alignments.

[00186] The term “nucleic acid-targeting system”, wherein nucleic acid is DNA or RNA, and in some aspects may also refer to DNA-RNA hybirds or derivatives thereof, refers collectively to transcripts and other elements involved in the expression of or directing the activity of DNA or RNA-targeting CRISPR-assoeiated (“Cas”) genes, which may include sequences encoding a DNA or RNA-targeting Cas protein and a DNA or RNA-targeting guide RNA comprising a CRISPR RNA (crRNA) sequence and (in CRISPR-Cas9 system but not all systems) a transactivating CRISPR-Cas system RNA (tracrRNA) sequence, or other sequences and transcripts from a DNA or RNA-targeting CRISPR locus. In the Cpfl DNA targeting RNA-guided endonuclease systems described herein, a tracrRNA sequence is not required. In general, a

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RNA-targeting system is characterized by elements that promote the formation of a RNAtargeting complex at the site of a target RNA sequence. In the context of formation of a DNA or RNA-targeting complex, “target sequence” refers to a DNA or RNA sequence to which a DNA or RNA-targeting guide RNA is designed to have complementarity, where hybridization between a target sequence and a RNA-targeting guide RNA promotes the formation of a RNAtargeting complex. In some embodiments, a target sequence is located in the nucleus or cytoplasm of a cell.

[00187] In an aspect of the invention, novel DNA targeting systems also referred to as DNAtargeting CRISPR-Cas or the CRISPR-Cas DNA-targeting system of the present application are based on identified Type V(e.g. subtype V-A and subtype V-B) Cas proteins which do not require the generation of customized proteins to target specific DNA sequences but rather a single effector protein or enzyme can be programmed by a RNA molecule to recognize a specific DNA target, in other words the enzyme can be recruited to a specific DNA target using said RNA molecule. Aspects of the invention particularly relate to DNA targeting RNA-guided Cpfl CRISPR systems.

[00188] In an aspect of the invention, novel RNA targeting systems also referred to as RNAor RNA-targeting CRISPR-Cas or the CRISPR-Cas system RNA-targeting system of the present application are based on identified Type VI Cas proteins which do not require the generation of customized proteins to target specific RNA sequences but rather a single enzyme can be programmed by a RNA molecule to recognize a specific RNA target, in other words the enzyme can be recruited to a specific RNA target using said RNA molecule.

[00189] The nucleic acids-targeting systems, the vector systems, the vectors and the compositions described herein may be used in various nucleic acids-targeting applications, altering or modifying synthesis of a gene product, such as a protein, nucleic acids cleavage, nucleic acids editing, nucleic acids splicing; trafficking of target nucleic acids, tracing of target nucleic acids, isolation of target nucleic acids, visualization of target nucleic acids, etc.

[00190] As used herein, a Cas protein or a CRISPR enzyme refers to any of the proteins presented in the new classification of CRISPR-Cas systems. In an advantageous embodiment, the present invention encompasses effector proteins identified in a Type V CRISPR-Cas loci, e.g. a Cpfl- encoding loci denoted as subtype V-A. Presently, the subtype V-A loci encompasses easl, cas2, a distinct gene denoted cpfl and a CRISPR array. Cpfl(CRISPR-associated protein Cpfl,

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PCT/US2016/038181 subtype PREFRAN) is a large protein (about 1300 amino acids) that contains a RuvC-like nuclease domain homologous to the corresponding domain of Cas9 along with a counterpart to the characteristic arginine-rich cluster of Cas9. However, Cpfl lacks the HNH nuclease domain that is present in all Cas9 proteins, and the RuvC-like domain is contiguous in the Cpfl sequence, in contrast to Cas9 where it contains long inserts including the HNH domain. Accordingly, in particular embodiments, the CRISPR-Cas enzyme comprises only a RuvC-like nuclease domain.

[00191] The Cpfl gene is found in several diverse bacterial genomes, typically in the same locus with cast, cas2, and cas4 genes and a CRISPR cassette (for example, FNFX1_1431FNFX1 1428 of Francisella cf. novicida Fxl). Thus, the layout of this putative novel CRISPRCas system appears to be similar to that of type II-B. Furthermore, similar to Cas9, the Cpfl protein contains a readily identifiable C-terminal region that is homologous to the transposon ORF-B and includes an active RuvC-like nuclease, an arginine-rich region, and a Zn finger (absent in Cas9). However, unlike Cas9, Cpfl is also present in several genomes without a CRISPR-Cas context and its relatively high similarity with ORF-B suggests that it might be a transposon component. It was suggested that if this was a genuine CRISPR-Cas system and Cpfl is a functional analog of Cas9 it would be a novel CRISPR-Cas type, namely type V (See Annotation and Classification of CRISPR-Cas Systems. Makarova KS, Koonin EV. Methods Mol Biol. 2015;1311:47-75). However, as described herein, Cpfl is denoted to be in subtype VA to distinguish it from C2clp which does not have an identical domain structure and is hence denoted to be in subtype V-B.

[00192] In an advantageous embodiment, the present invention encompasses compositions and systems comprising effector proteins identified in a Cpfl loci denoted as subtype V-A. [00193] Aspects of the invention also encompass methods and uses of the compositions and systems described herein in genome engineering, e.g. for altering or manipulating the expression of one or more genes or the one or more gene products, in prokaryotic or eukaryotic cells, in vitro, in vivo or ex vivo.

[00194] In embodiments of the invention the terms mature crRNA and guide RNA and single guide RNA are used interchangeably as in foregoing cited documents such as WO 2014/093622 (PCTZUS2013/074667). In general, a guide sequence is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target

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PCT/US2016/038181 sequence and direct sequence-specific binding of a CRISPR complex to the target sequence. In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g., the Burrows Wheeler Aligner), ClustalW, Clustal X, BEAT, Novoalign (Novocraft Technologies; available at www.novocraft.com), ELAND (Illumina, San Diego, CA), SOAP (available at soap.genornics.org.cn), and Maq (available at maq.sourceforge.net). In some embodiments, a guide sequence is about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In some embodiments, a guide sequence is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. Preferably the guide sequence is 10 - 30 nucleotides long. The ability of a guide sequence to direct sequence-specific binding of a CRISPR complex to a target sequence may be assessed by any suitable assay. For example, the components of a CRISPR system sufficient to form a CRISPR complex, including the guide sequence to be tested, may be provided to a host cell having the corresponding target sequence, such as by transfection with vectors encoding the components of the CRISPR sequence, followed by an assessment of preferential cleavage within the target sequence, such as by Surveyor assay as described herein. Similarly, cleavage of a target polynucleotide sequence may be evaluated in a test tube by providing the target sequence, components of a CRISPR complex, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at the target sequence between the test and control guide sequence reactions. Other assays are possible, and will occur to those skilled in the art. A guide sequence may be selected to target any target sequence. In some embodiments, the target sequence Is a sequence within a genome of a cell. Exemplary target sequences include those that are unique in the target genome.

[00195] In general, and throughout this specification, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. Vectors include, but are not limited to, nucleic acid molecules that are single-stranded, double-stranded,

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PCT/US2016/038181 or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g., circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art. One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments can be inserted, such as by standard molecular cloning techniques. Another type of vector is a viral vector, wherein virally-derived DNA or RNA sequences are present in the vector for packaging into a virus (e.g., retroviruses, replication defective retroviruses, adenoviruses, replication defective adenoviruses, and adeno-associated viruses). Viral vectors also include polynucleotides carried by a virus for transfection into a host cell. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g,, non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as “expression vectors.” Vectors for and that result in expression in a eukaryotic cell can be referred to herein as “eukaryotic expression vectors.” Common expression vectors of utility in recombinant DNA techniques are often in the form of plasmids, [00196] Recombinant expression vectors can comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory elements, which may be selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory element(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host ceil when the vector is introduced into the host cell).

[00197] The term “regulatory element” is intended to include promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly-U sequences). Such regulatory elements are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory elements include those that direct constitutive expression of a nucleotide sequence in many types

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PCT/US2016/038181 of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). A tissue-specific promoter may direct expression primarily in a desired tissue of interest, such as muscle, neuron, bone, skin, blood, specific organs (e.g., liver, pancreas), or particular cell types (e.g,, lymphocytes). Regulatory elements may also direct expression in a temporal-dependent manner, such as in a cell-cycle dependent or developmental stage-dependent manner, which may or may not also be tissue or cell-type specific. In some embodiments, a vector comprises one or more pol III promoter (e.g., 1, 2, 3, 4, 5, or more pol III promoters), one or more pol II promoters (e.g., 1, 2, 3, 4, 5, or more ροί II promoters), one or more pol I promoters (e.g., 1, 2, 3, 4, 5, or more pol I promoters), or combinations thereof. Examples of pol III promoters include, but are not limited to, L^T6 and Hl promoters. Examples of pol 11 promoters include, but are not limited to, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) [see, e.g., Boshart et al, Cell, 41;521 -530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EFla promoter. Also encompassed by the term “regulatory element” are enhancer elements, such as WERE; CMV enhancers; the R-U5’ segment in LTR of HTLV-I (Mol. Cell. Biol., Vol. 8(1), p. 466-472, 1988); SV40 enhancer; and the intron sequence between exons 2 and 3 of rabbit β-globin (Proc. Natl. Acad. Sci. USA., Vol. 78(3), p. 1527-31, 1981). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression desired, etc. A vector can be introduced into host cells to thereby produce transcripts, proteins, or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., clustered regularly interspersed short palindromic repeats (CRISPR) transcripts, proteins, enzymes, mutant forms thereof, fusion proteins thereof etc.).

[00198] Advantageous vectors include lentiviruses and adeno-associated viruses, and types of such vectors can also be selected for targeting particular types of cells.

[00199] As used herein, the term “crRNA” or “guide RNA” or “single guide RNA” or “sgRNA” or “one or more nucleic acid components” of a Type V CRISPR-Cas locus effector protein comprises any polynucleotide sequence having sufficient complementarity with a target nucleic acid sequence to hybridize with the target nucleic acid sequence and direct sequencespecific binding of a nucleic acid-targeting complex to the target nucleic acid sequence. In some

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PCT/US2016/038181 embodiments, the degree of complementarity, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g., the Burrows Wheeler Aligner), CiustalW, Clustal X, BEAT, Novoalign (Novocraft Technologies, available at www.novocraft.com), ELAND (Alumina, San Diego, CA), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). The ability of a guide sequence (within a nucleic acid-targeting guide RNA) to direct sequence-specific binding of a nucleic acid-targeting complex to a target nucleic acid sequence may be assessed by any suitable assay. For example, the components of a nucleic acid-targeting CR1SPR system sufficient to form a nucleic acid-targeting complex, including the guide sequence to be tested, may be provided to a host cell having the corresponding target nucleic acid sequence, such as by transfection with vectors encoding the components of the nucleic acid-targeting complex, followed by an assessment of preferential targeting (e.g., cleavage) within the target nucleic acid sequence, such as by Surveyor assay as described herein. Similarly, cleavage of a target nucleic acid sequence may be evaluated in a test tube by providing the target nucleic acid sequence, components of a nucleic acid-targeting complex, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at the target sequence between the test and control guide sequence reactions. Other assays are possible, and will occur to those skilled in the art. A guide sequence, and hence a nucleic acid-targeting guide RNA may be selected to target any target nucleic acid sequence. The target sequence may be DNA. The target sequence may be any RNA sequence. In some embodiments, the target sequence may be a sequence within a RNA molecule selected from the group consisting of messenger RNA (mRNA), pre-mRNA, ribosomaal RNA (rRNA), transfer RNA (tRNA), micro-RNA (miRNA), small interfering RNA (siRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), double stranded RNA (dsRNA), non coding RNA (ncRNA), long non-coding RNA (IncRNA), and small cytoplasmatic RNA (scRNA). In some preferred embodiments, the target sequence may be a sequence within a RNA molecule selected from the group consisting of mRNA, pre-mRNA, and rRNA. In some preferred embodiments, the target sequence may be a sequence within a RNA molecule selected from the group

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PCT/US2016/038181 consisting of ncRNA, and IncRNA. In some more preferred embodiments, the target sequence may be a sequence within an mRNA molecule or a pre-mRNA molecule.

[00200] In some embodiments, a nucleic acid-targeting guide RNA is selected to reduce the degree secondary structure within the RNA-targeting guide RNA, In some embodiments, about or less than about 75%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, or fewer of the nucleotides of the nucleic acid-targets ng guide RNA participate in self-complementary base pairing when optimally folded. Optimal folding may be determined by any suitable polynucleotide folding algorithm. Some programs are based on calculating the minimal Gibbs free energy. An example of one such algorithm is mFold, as described by Zuker and Stiegler (Nucleic Acids Res. 9 (1981), 133-148). Another example folding algorithm is the online webserver RNAfold, developed at Institute for Theoretical Chemistry at the University of Vienna, using the centroid structure prediction algorithm (see e.g., A.R. Gruber et al., 2008, Cell 106(1): 23-24, and PA Carr and GM Church, 2009, Nature Biotechnology 27(12): 1151-62). [00201] The “tracrRNA” sequence or analogous terms includes any polynucleotide sequence that has sufficient complementarity with a crRNA sequence to hybridize. As indicated herein above, in embodiments of the present invention, the tracrRNA is not required for cleavage activity of Cpf l effector protein complexes.

[00202] Applicants also perform a challenge experiment to verify the DNA targeting and cleaving capability of a Type V/Type VI protein such as Cpfl/C2cl/C2c2. This experiment closely parallels similar work in E. coli for the heterologous expression of StCas9 (Sapranauskas, R. et al. Nucleic Acids Res 39, 9275-9282 (2011)). Applicants introduce a plasmid containing both a PAM and a resistance gene into the heterologous E. coli, and then plate on the corresponding antibiotic. If there is DNA cleavage of the plasmid, Applicants observe no viable colonies.

[00203] In further detail, the assay is as follows for a DNA target. Two E.coli strains are used in this assay. One carries a plasmid that encodes the endogenous effector protein locus from the bacterial strain. The other strain carries an empty plasmid (e.g.pACYCl 84, control strain). All possible 7 or 8 bp PAM sequences are presented on an antibiotic resistance plasmid (pUC19 with ampiciilin resistance gene). The PAM] is located next to the sequence of proto-spacer 1 (the DNA target to the first spacer in the endogenous effector protein locus). Two PAM libraries were cloned. One has a 8 random bp 5’ of the proto-spacer (e.g. total of 65536 different PAM

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PCT/US2016/038181 sequences =^:: complexity). The other library has 7 random bp 3’ of the proto-spacer (e.g. total complexity is 16384 different PAMs). Both libraries were cloned to have in average 500 plasmids per possible PAM. Test strain and control strain were transformed with 5’PAM and 3’PAM library in separate transformations and transformed cells were plated separately on ampicillin plates. Recognition and subsequent cutting/interference with the plasmid renders a cell vulnerable to ampicillin and prevents growth. Approximately 12h after transformation, all colonies formed by the test and control strains where harvested and plasmid DNA was isolated. Plasmid DNA was used as template for PCR amplification and subsequent deep sequencing. Representation of all PAMs in the untransfomed libraries showed the expected representation of PAMs in transformed cells. Representation of all PAMs found in control strains showed the actual representation. Representation of all PAMs in test strain showed which PAMs are not recognized by the enzyme and comparison to the control strain allows extracting the sequence of the depleted PAM/ [00204] In some embodiments of CRISPR-Cas9 systems, the degree of complementarity between the tracrRNA sequence and crRNA sequence is along the length of the shorter of the two when optimally aligned. As described herein, in embodiments of the present invention, the tracrRNA is not required. In some embodiments of previously described CRISPR-Cas systems (e.g. CRISPR-Cas9 systems), chimeric synthetic guide RNAs (sgRNAs) designs may incorporate at least 12 bp of duplex structure between the crRNA and tracrRNA, however in the Cpfl CRISPR systems described herein such chimeric RNAs (chi-RNAs) are not possible as the system does not utilize a tracrRNA.

[00205] For minimization of toxicity and off-target effect, it will be important to control the concentration of nucleic acid-targeting guide RNA delivered. Optimal concentrations of nucleic acid-targeting guide RNA can be determined by testing different concentrations in a cellular or non-human eukaryote animal model and using deep sequencing the analyze the extent of modification at potential off-target genomic loci. The concentration that gives the highest level of on-target modification while minimizing the level of off-target modification should be chosen for in vivo deliver)'. The nucleic acid-targeting system is derived advantageously from a Type V/Type VI CRISPR system. In some embodiments, one or more elements of a nucleic acidtargeting system is derived from a particular organism comprising an endogenous RNA-targeting system. In preferred embodiments of the invention, the RNA-targeting system is a Type V/Type

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VI CRISPR system. In particular embodiments, the Type V/Type VI RNA-targeting Cas enzyme is Cpfl/C2cl/C2c2. Non-limiting examples of Cas proteins include Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csxl2), CaslO, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, CsrnS, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, CsxI7, Csxl4, CsxlO, CsxI6, CsaX, Csx3, Csxl, CsxI5, Csfl, Csf2, Csf3, Csf4, homologues thereof, or modified versions thereof.In embodiments, the Type V/Type VI protein such as Cpfl/C2cl/C2c2 as referred to herein also encompasses a homologue or an orthologue of a Type V/Type VI protein such as Cpfl/C2cl/C2c2. The terms “orthologue” (also referred to as “ortholog” herein) and “homologue” (also referred to as “homolog” herein) are well known in the art. By means of further guidance, a “homologue” of a protein as used herein is a protein of the same species which performs the same or a similar function as the protein it is a homologue of. Homologous proteins may but need not be structurally related, or are only partially structurally related. An “orthologue” of a protein as used herein is a protein of a different species which performs the same or a similar function as the protein it is an orthologue of. Orthologous proteins may but need not be structurally related, or are only partially structurally related. Homologs and orthologs may be identified by homology modelling (see, e.g., Greer, Science vol. 228 (1985) 1055, and Blundell et al. Eur J Biochem vol 172 (1988), 513) or structural BLAST (Dey F, Cliff Zhang Q, Petrey D, Honig B. Toward a structural BLAST: using structural relationships to infer function. Protein Sci. 2013 Apr;22(4):359-66. doi: 10.1002/pro.2225.). See also Shmakov et al. (2015) for application in the field of CRISPR-Cas loci. Homologous proteins may but need not be structurally related, or are only partially structurally related. In particular embodiments, the homologue or orthologue of Cpfl as referred to herein has a sequence homology or identity of at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with Cpfl. In further embodiments, the homologue or orthologue of Cpfl as referred to herein has a sequence identity of at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with the wild type Cpfl. Where the Cpfl has one or more mutations (mutated), the homologue or orthologue of said Cpfl as referred to herein has a sequence identity of at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with the mutated Cpfl, [00206] In an ambodiment, the type V Cas protein may be an ortholog of an organism of a genus which includes, but is not limited to Acidaminococcus sp, Lachnospiraceae bacterium or

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Moraxella bovocuJf in particular embodiments, the type V Cas protein may be an ortholog of an organism of a species which includes, but is not limited to Acidammococcus sp. BV3L6', Lachnospiraceae bacterium ND2006 (LbCpfl) or Moraxella bovoculi 237An particular embodiments, the homologue or orthologue of Cpfl as referred to herein has a sequence homology or identity of at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with one or more of the Cpfl sequences disclosed herein. In further embodiments, the homologue or orthologue of Cpf as referred to herein has a sequence identity of at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with the wild type FnCpfl, AsCpfl or LbCpfl.

[00207] In particular embodiments, the Cpfl protein of the invention has a sequence homology or identity of at least 60%, more particularly at least 70, such as at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with FnCpfl, AsCpfl or LbCpfl. In further embodiments, the Cpfl protein as referred to herein has a sequence identity of at least 60%, such as at least 70%, more particularly at least 80%, more preferably at least 85%, even more preferably at least 90%, such as for instance at least 95% with the wild type AsCpfl or LbCpfl. In particular embodiments, the Cpfl protein of the present invention has less than 60% sequence identity with FnCpfl. The skilled person will understand that this includes truncated forms of the Cpfl protein whereby the sequence identity is determined over the length of the truncated form.

[00208] Some methods of identifying orthologs of CRISPR-Cas system enzymes may involve identifying tracr sequences in genomes of interest. Identification of tracr sequences may relate to the following steps: Search for the direct repeats or tracr mate sequences in a database to identify a CRISPR region comprising a CRISPR enzyme. Search for homologous sequences in the CRISPR region flanking the CRISPR enzyme in both the sense and antisense directions. Look for transcriptional terminators and secondary structures. Identify any sequence that is not a direct repeat or a tracr mate sequence but has more than 50% identity to the direct repeat or tracr mate sequence as a potential tracr sequence. Take the potential tracr sequence and analyze for transcriptional terminator sequences associated therewith. In this system, RNA-sequencing data revealed that the potential tracrRNAs identified computationally were only lowly expressed suggesting possibility that tracrRNA may not be necessary for function of the present system. After further evaluation of the FnCpfl locus and addition of in vitro cleavage results, Applicants concluded that target DNA

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PCT/US2016/038181 cleavage by a Cpfl effector protein complex does not require a tracrRNA. Applicants determined that Cpfl effector protein complexes comprising only a Cpfl effector protein and a crRNA (guide RNA comprising a direct repeat sequence and a guide sequence) were sufficient to cleave target DNA., [00209] It will be appreciated that any of the functionalities described herein may be engineered into CRISPR enzymes from other orthologs, incuding chimeric enzymes comprising fragments from multiple orthologs. Examples of such orthologs are described elsewhere herein. Thus, chimeric enzymes may comprise fragments of CRISPR enzyme orthologs of organisms of a genus 'which includes but is not limited to Corynebacter, Sutterella, Legionella, Treponema, Filifactor, Eubacteriwn, Streptococcus, Lactobacillus, Mycoplasma, Bacteroides, Flaviivola, Ldavobacterium, Sphaerochaeta, Azospirillum, Gluconacetohacter, Neisseria, Roseburia, Parvibaculum, Staphylococcus, Nitratifractor, Mycoplasma and Campylobacter. A chimeric enzyme can comprise a first fragment and a second fragment, and the fragrments can be of CRISPR enzyme orthologs of organisms of genuses herein mentioned or of species herein mentioned; advantageously the fragments are from CRISPR enzyme orthologs of different species. [00210] In embodiments, the Type V/Type VI RNA-targeting effector protein, in particular the Cpfl/C2cl/C2c2 protein as referred to herein also encompasses a functional variant of Cpfl/C2cl/C2c2 or a homologue or an orthologue thereof. A “functional variant” of a protein as used herein refers to a variant of such protein which retains at least partially the activity of that protein. Functional variants may include mutants (which may be insertion, deletion, or replacement mutants), including polymorphs, etc. Also included within functional variants are fusion products of such protein with another, usually unrelated, nucleic acid, protein, polypeptide or peptide. Functional variants may be naturally occurring or may be man-made. Advantageous embodiments can involve engineered or non-naturally occurring Type V/Type VI RNA-targeting effector protein, e.g., Cpfl/C2cl/C2c2 or an ortholog or homolog thereof.

[00211] In an embodiment, nucleic acid molecule(s) encoding the Type V/Type VI RNAtargeting effector protein, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, may be codon-optimized for expression in an eukaryotic cell. A eukaryote can be as herein discussed. Nucleic acid molecule(s) can be engineered or non-naturally occurring.

[00212] In an embodiment, the Type V/Type VI RNA-targeting effector protein, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, may comprise one or more mutations (and

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PCT/US2016/038181 hence nucleic acid molecule(s) coding for same may have mutation(s)). The mutations may be artificially introduced mutations and may include but are not limited to one or more mutations in a catalytic domain. Examples of catalytic domains with reference to a Cas9 enzyme may include but are not limited to RuvC I, RuvC 11, RuvC Π1 and HNH domains.

[00213] In an embodiment, the Type V/'Type VI protein such as Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, may be used as a generic nucleic acid binding protein with fusion to or being operably linked to a functional domain. Exemplary functional domains may include but are not limited to translational initiator, translational activator, translational repressor, nucleases, in particular ribonucleases, a spliceosome, beads, a light inducible/controllable domain or a chemically inducible/controllable domain.

[00214] In some embodiments, the unmodified nucleic acid-targeting effector protein may have cleavage activity. In some embodiments, the RNA-targeting effector protein may direct cleavage of one or both nucleic acid (DNA or RNA) strands at the location of or near a target sequence, such as within the target sequence and/or within the complement of the target sequence or at sequences associated with the target sequence. In some embodiments, the nucleic acid-targeting effector protein may direct cleavage of one or both DNA or RNA strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. In some embodiments, the cleavage may be staggered, i.e. generating sticky ends, hr some embodiments, the cleavage is a staggered cut with a 5’ overhang. In some embodiments, the cleavage is a staggered cut with a 5’ overhang of 1 to 5 nucleotides, preferably of 4 or 5 nucleotides. In some embodiments, the cleavage site is distant from the PAM, e.g,, the cleavage occurs after the 18^tn nucleotide on the non-target strand and after the 23^rd nucleotide on the targeted strand (Figure 97A). In some embodiments, the cleavage site occurs after the 18^th nucleotide (counted from the PAM) on the non-target strand and after the 23^ld nucleotide (counted from the PAM) on the targeted strand (Figure 97A). In some embodiments, a vector encodes a nucleic acid-targeting effector protein that may be mutated with respect to a corresponding wild-type enzyme such that the mutated nucleic acid-targeting effector protein lacks the ability to cleave one or both DNA or RNA strands of a target polynucleotide containing a target sequence. As a further example, two or more catalytic domains of a Cas protein (e.g. RuvC I, RuvC II, and RuvC III or the HNH domain of a Cas9 protein) may be mutated to produce a mutated Cas protein substantially lacking all DNA

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PCT/US2016/038181 cleavage activity. As described herein, corresponding catalytic domains of a Cpfl effector protein may also he mutated to produce a mutated Cpfl effector protein lacking all DNA cleavage activity or having substantially reduced DNA cleavage activity. In some embodiments, a nucleic acid-targeting effector protein may be considered to substantially lack all RNA cleavage activity when the RNA cleavage activity of the mutated enzyme is about no more than 25%, 10%, 5%, 1%, 0.1%, 0.01%, or less of the nucleic acid cleavage activity of the nonmutated form of the enzyme; an example can be when the nucleic acid cleavage activity of the mutated form is nil or negligible as compared with the non-mutated form. An effector protein may he identified with reference to the general class of enzymes that share homology to the biggest nuclease with multiple nuclease domains from the Type V/Type VI CRISPR system. Most preferably, the effector protein is a Type V/Type VI protein such as Cpfl/C2cl/C2c2. In further embodiments, the effector protein is a Type V protein. By derived, Applicants mean that the derived enzyme is largely based, in the sense of having a high degree of sequence homology with, a wildtype enzyme, but that it has been mutated (modified) in some way as known in the art or as described herein .

[00215] Again, it will be appreciated that the terms Cas and CRISPR enzyme and CRISPR protein and Cas protein are generally used interchangeably and at all points of reference herein refer by analogy to novel CRISPR effector proteins further described in this application, unless otherwise apparent, such as by specific reference to Cas9. As mentioned above, many of the residue numberings used herein refer to the effector protein from the Type V/Type AT CRISPR locus. However, it will be appreciated that this invention includes many more effector proteins from other species of microbes. In certain embodiments, effector proteins may be const!tutively present or inducibly present or conditionally present or administered or delivered. Effector protein optimization may be used to enhance function or to develop new functions, one can generate chimeric effector proteins. And as described herein effector proteins may be modified to be used as a generic nucleic acid binding proteins.

[00216] Typically, in the context of a nucleic acid-targeting system, formation of a nucleic acid-targeting complex (comprising a guide RNA hybridized to a target sequence and complexed with one or more nucleic acid-targeting effector proteins) results in cleavage of one or both DNA or RNA strands in or near (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the target sequence. As used herein the term “sequence(s) associated with a target locus of

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PCT/US2016/038181 interest” refers to sequences near the vicinity of the target sequence (e.g. within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from the target sequence, wherein the target sequence is comprised within a target locus of interest).

[00217] An example of a codon optimized sequence, is in this instance a sequence optimized for expression in a eukaryote, e.g., humans (i.e. being optimized for expression in humans), or for another eukaryote, animal or mammal as herein discussed; see, e.g., SaCas9 human codon optimized sequence in WO 2014/093622 (PCT/US2013/074667) as an example of a codon optimized sequence (from knowledge in the art and this disclosure, codon optimizing coding nucleic acid molecule(s), especially as to effector protein (e.g., Cpfl) is within the ambit of the skilled artisan). Whilst this is preferred, it will be appreciated that other examples are possible and codon optimization for a host species other than human, or for codon optimization for specific organs is known. In some embodiments, an enzyme coding sequence encoding a DNA/RNA-targeting Cas protein is codon optimized for expression in particular cells, such as eukaryotic cells. The eukaryotic cells may be those of or derived from a particular organism, such as a plant or a mammal, including but not limited to human, or non-human eukaryote or animal or mammal as herein discussed, e.g., mouse, rat, rabbit, dog, livestock, or non-human mammal or primate. In some embodiments, processes for modifying the germ line genetic identity of human beings and/or processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes, may be excluded. In general, codon optimization refers to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing at least one codon (e.g., about or more than about 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more codons) of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit particular bias for certain codons of a particular amino acid. Codon bias (differences in codon usage between organisms) often correlates with the efficiency of translation of messenger RNA (mRNA), which is in turn believed to be dependent on, among other things, the properties of the codons being translated and the availability of particular transfer RNA (tRNA) molecules. The predominance of selected tRNAs in a cell is generally a reflection of the codons used most frequently in peptide synthesis. Accordingly, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon

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PCT/US2016/038181 usage tables are readily available, for example, at the “Codon Usage Database” available at www.kazusa.orjp/codon/ and these tables can be adapted in a number of ways. See Nakamura, Y., et al. “Codon usage tabulated from the international DNA sequence databases: status for the year 2000” Nucl, Acids Res. 28:292 (2000), Computer algorithms for codon optimizing a particular sequence for expression in a particular host cell are also available, such as Gene Forge (Aptagen; Jacobus, PA), are also available. In some embodiments, one or more codons (e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more, or ail codons) in a sequence encoding a DNA/RNAtargeting Cas protein corresponds to the most frequently used codon for a particular amino acid. As to codon usage in yeast, reference is made to the online Yeast Genome database available at http://www.yeastgenome.org/community/codon usage.shtml, or Codon selection in yeast, Bennetzen and Hall, J Biol Chem. 1982 Mar 25:257(6):3026-31, As to codon usage in plants including algae, reference is made to Codon usage in higher plants, green algae, and cyanobacteria, Campbell and Gowri, Plant Physiol. 1990 Jan; 92(1): 1--11,, as well as Codon usage in plant genes, Murray et al, Nucleic Acids Res. 1989 Jan 25;17(2):477-98; or Selection on the codon bias of chloroplast and cyanelle genes in different plant and algal lineages, Morton BR, J Mol Evol. 1998 Apr;46(4):449-59.

[00218] In some embodiments, a vector encodes a nucleic acid-targeting effector protein such as the Type V/Type VI RNA-targeting effector protein, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof comprising one or more nuclear localization sequences (NLSs), such as about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLSs. In some embodiments, the RNA-targeting effector protein comprises about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLSs at or near the amino-terminus, about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLSs at or near the carboxy-terminus, or a combination of these (e.g., zero or at least one or more NLS at the amino-terminus and zero or at one or more NLS at the carboxy terminus). W hen more than one NLS is present, each may be selected independently of the others, such that a single NLS may be present in more than one copy and/or in combination with one or more other NLSs present in one or more copies. In some embodiments, an NLS is considered near the N- or C-terminus when the nearest amino acid of the NLS is within about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 40, 50, or more amino acids along the polypeptide chain from the N- or C-terminus. Non-limiting examples of NLSs include an NLS sequence derived from: the NLS of the SV40 virus large T-antigen, having the amino acid sequence PKKKRKV (SEQ ID NO: 2); the NLS

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PCT/US2016/038181 from nucleoplasmin (e.g., the nucleoplasmin bipartite NLS with the sequence KRPAATKKAGQAKKKK (SEQ ID NO: 3)); the c-myc NLS having the amino acid sequence

PAAKRVKLD (SEQ ID NO: 4) or RQRRNELKRSP (SEQ ID NO: 5); the hRNPAI M9 NLS having the sequence NQSSNFGPMKGGNFGGRSSGPYGGGGQYF/ (SEQ ID

NO: 6); the sequence RMRIZFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV (SEQ ID NO: 7) of the IBB domain from importin-alpha; the sequences VSRKRPRP (SEQ ID

NO: 8) and PPKKARED (SEQ ID NO: 9) of the myoma T protein; the sequence PQPKKKPL (SEQ ID NO: 10) of human p53; the sequence SALIKKKKKMAP (SEQ ID NO: 11) of mouse c-abl IV; the sequences DRLRR (SEQ ID NO: 12) and PKQKKRK (SEQ ID NO: 13) of the influenza virus NS1; the sequence RKLKKKIKKL (SEQ ID NO: 14) of the Hepatitis virus delta antigen; the sequence REKKKFLKRR (SEQ ID NO: 15) of the mouse Mxl protein, the sequence KRKGDEVDGVDEVAKKKSKK (SEQ ID NO: 16) of the human poly(ADP-ribose) polymerase; and the sequence RKCLQAGMNLEARKTKK (SEQ ID NO: 17) of the steroid hormone receptors (human) glucocorticoid. In general, the one or more NLSs are of sufficient strength to drive accumulation of the DNA/RNA-targeting Cas protein in a detectable amount in the nucleus of a eukaryotic cell. In general, strength of nuclear localization activity may derive from the number of NLSs in the nucleic acid-targeting effector protein, the particular NLS(s) used, or a combination of these factors. Detection of accumulation in the nucleus may be performed by any suitable technique. For example, a detectable marker may be fused to the nucleic acid-targeting protein, such that location within a cell may be visualized, such as in combination with a means for detecting the location of the nucleus (e.g., a stain specific for the nucleus such as DAPI). Cell nuclei may also be isolated from cells, the contents of which may then be analyzed by any suitable process for detecting protein, such as immunohistochemistry, Western blot, or enzyme activity assay. Accumulation in the nucleus may also be determined indirectly, such as by an assay for the effect of nucleic acid-targeting complex formation (e.g., assay for DNA or RNA cleavage or mutation at the target sequence, or assay for altered gene expression activity affected by DNA or RNA-targeting complex formation and/or DNA or RNAtargeting Cas protein activity), as compared to a control not exposed to the nucleic acid-targeting Cas protein or nucleic acid-targeting complex, or exposed to a nucleic acid-targeting Cas protein lacking the one or more NLSs. In preferred embodiments of the herein described Cpfl effector protein complexes and systems the codon optimized Cpfl effector proteins comprise an NLS

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PCT/US2016/038181 attached to the C-terminal of the protein. In certain embodiments, other localization tags may be fused to the Cas protein, such as without limitation for localizing the Cas to particular sites in a cell, such as organells, such mitochondria, plastids, chloroplast, vesicles, golgi, (nuclear or cellular) membranes, ribosomes, nucleoluse, ER, cytoskeleton, vacuoles, eentrosome, nucleosome, granules, centrioles, etc [00219] In some embodiments, one or more vectors driving expression of one or more elements of a nucleic acid-targeting system are introduced into a host cell such that expression of the elements of the nucleic acid-targeting system direct formation of a nucleic acid-targeting complex at one or more target sites. For example, a nucleic acid-targeting effector enzyme and a nucleic acid-targeting guide RNA could each be operably linked to separate regulatory elements on separate vectors. RNA(s) of the nucleic acid-targeting system can be delivered to a transgenic nucleic acid-targeting effector protein animal or mammal, e.g., an animal or mammal that constitutively or inducibly or conditionally expresses nucleic acid-targeting effector protein, or an animal or mammal that is otherwise expressing nucleic acid-targeting effector proteins or has cells containing nucleic acid-targeting effector proteins, such as by way of prior administration thereto of a vector or vectors that code for and express in vivo nucleic acid-targeting effector proteins. Alternatively, two or more of the elements expressed from the same or different regulatory elements, may be combined in a single vector, with one or more additional vectors providing any components of the nucleic acid-targeting system not included in the first vector, nucleic acid-targeting system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5’ with respect to (“upstream” of) or 3’ with respect to (“downstream” of) a second element. The coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In some embodiments, a single promoter drives expression of a transcript encoding a nucleic acid-targeting effector protein and the nucleic acidtargeting guide RNA, embedded within one or more intron sequences (e.g., each in a different intron, two or more in at least one Intron, or all in a single intron). In some embodiments, the nucleic acid-targeting effector protein and the nucleic acid-targeting guide RNA may be operably linked to and expressed from the same promoter. Delivery vehicles, vectors, particles, nanoparticles, formulations and components thereof for expression of one or more elements of a nucleic acid-targeting system are as used in the foregoing documents, such as WO 2014/093622

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PCT/US2016/038181 (PCT/US2013/074667). In some embodiments, a vector comprises one or more insertion sites, such as a restriction endonuclease recognition sequence (also referred to as a “cloning site”). In some embodiments, one or more insertion sites (e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more insertion sites) are located upstream and/or downstream of one or more sequence elements of one or more vectors. When multiple different guide sequences are used, a single expression construct may be used to target nucleic acid-targeting activity to multiple different, corresponding target sequences within a cell. For example, a single vector may comprise about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more guide sequences. In some embodiments, about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more such guidesequence-containing vectors may be provided, and optionally delivered to a cell. In some embodiments, a vector comprises a regulatory element operably linked to an enzyme-coding sequence encoding a a nucleic acid-targeting effector protein. Nucleic acid-targeting effector protein or nucleic acid-targeting guide RNA or RNA(s) can be delivered separately, and advantageously at least one of these is delivered via a particle complex, nucleic acid-targeting effector protein mRNA can be delivered prior to the nucleic acid-targeting guide RNA to give time for nucleic acid-targeting effector protein to be expressed. Nucleic acid-targeting effector protein mRNA might be administered 1-12 hours (preferably around 2-6 hours) prior to the administration of nucleic acid-targeting guide RNA. Alternatively, nucleic acid-targeting effector protein mRNA and nucleic acid-targeting guide RNA can be administered together. Advantageously, a second booster dose of guide RNA can be administered 1-12 hours (preferably around 2-6 hours) after the initial administration of nucleic acid-targeting effector protein mRNA + guide RNA. Additional administrations of nucleic acid-targeting effector protein mRNA and/or guide RNA might be useful to achieve the most efficient levels of genome modification.

[00220] In one aspect, the invention provides methods for using one or more elements of a nucleic acid-targeting system. The nucleic acid-targeting complex of the invention provides an effective means for modifying a target DNA or RNA (single or double stranded, linear or supercoiled). The nucleic acid-targeting complex of the invention has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target DNA or RNA in a multiplicity of cell types. As such the nucleic acid-targeting complex of the invention has a broad spectrum of applications in, e.g., gene therapy, diug screening, disease

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PCT/US2016/038181 diagnosis, and prognosis. An exemplary nucleic acid-targeting complex comprises a DNA or RNA-targeting effector protein complexed with a guide RNA hybridized to a target sequence within the target locus of interest.

[00221] In one embodiment, this invention provides a method of cleaving a target RNA. The method may comprise modifying a target RNA using a nucleic acid-targeting complex that binds to the target RNA and effect cleavage of said target RNA. In an embodiment, the nucleic acidtargeting complex of the invention, when introduced into a cell, may create a break (e.g., a single or a double strand break) in the RNA sequence. For example, the method can be used to cleave a disease RNA in a cell. For example, an exogenous RNA template comprising a sequence to be integrated flanked by an upstream sequence and a downstream sequence may be introduced into a cell. The upstream and downstream sequences share sequence similarity with either side of the site of integration in the RNA. Where desired, a donor RNA can be mRNA. The exogenous RNA template comprises a sequence to be integrated (e.g., a mutated RNA), The sequence for integration may be a sequence endogenous or exogenous to the cell. Examples of a sequence to be integrated include RNA encoding a protein or a non-coding RNA (e.g., a microRNA). Thus, the sequence for integration may be operably linked to an appropriate control sequence or sequences. Alternatively, the sequence to be Integrated may provide a regulatory function. The upstream and downstream sequences in the exogenous RNA template are selected to promote recombination between the RNA sequence of interest and the donor RNA. The upstream sequence is a RNA sequence that shares sequence similarity with the RNA sequence upstream of the targeted site for integration. Similarly, the downstream sequence is a RNA sequence that shares sequence similarity with the RNA sequence downstream of the targeted site of integration. The upstream and downstream sequences in the exogenous RNA template can have 75%, 80%, 85%, 90%, 95%, or 100% sequence Identity with the targeted RNA sequence. Preferably, the upstream and downstream sequences in the exogenous RNA template have about 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the targeted RNA sequence. In some methods, the upstream and downstream sequences in the exogenous RNA template have about 99% or 100% sequence identity with the targeted RNA sequence. An upstream or downstream sequence may comprise from about 20 bp to about 2500 bp, for example, about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500 bp. In some methods, the exemplary upstream or downstream

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PCT/US2016/038181 sequence have about 200 bp to about 2000 bp, about 600 bp to about 1000 bp, or more particularly about 700 bp to about 1000 bp. In some methods, the exogenous RNA template may further comprise a marker. Such a marker may make it easy to screen for targeted integrations. Examples of suitable markers include restriction sites, fluorescent proteins, or selectable markers. The exogenous RNA template of the invention can be constructed using recombinant techniques (see, for example, Sambrook et al., 2001 and Ausubel et al., 1996). In a method for modifying a target RNA by integrating an exogenous RNA template, a break (e.g., double or single stranded break in double or single stranded DNA or RNA) is introduced into the DNA or RNA sequence by the nucleic acid-targeting complex, the break is repaired via homologous recombination with an exogenous RNA template such that the template is integrated into the RNA target. The presence of a double-stranded break facilitates integration of the template. In other embodiments, this invention provides a method of modifying expression of a RNA in a eukaryotic cell. The method comprises increasing or decreasing expression of a target polynucleotide by using a nucleic acid-targeting complex that binds to the DNA or RNA (e.g., mRNA or pre-mRNA). In some methods, a target RNA can be inactivated to effect the modification of the expression in a cell. For example, upon the binding of a RNA-targeting complex to a target sequence in a cell, the target RNA is inactivated such that the sequence is not translated, the coded protein is not produced, or the sequence does not function as the wild-type sequence does. For example, a protein or microRNA coding sequence may be inactivated such that the protein or microRNA or pre-microRNA transcript is not produced. The target 1<NA of a RNA-targeting complex can be any RNA endogenous or exogenous to the eukaryotic cell. For example, the target RNA can be a RNA residing in the nucleus of the eukaryotic cell. The target RNA can be a sequence (e.g., mRNA or pre-mRNA) coding a gene product (e.g., a protein) or a non-coding sequence (e.g., ncRNA, IncRNA, tRNA, or rRNA). Examples of target RNA include a sequence associated with a signaling biochemical pathway, e.g., a signaling biochemical pathway-associated RNA. Examples of target RNA include a disease associated RNA. A “disease-associated” RNA refers to any RNA which is yielding translation products at an abnormal level or in an abnormal form in cells derived from a disease-affected tissues compared with tissues or cells of a non disease control. It may be a RNA transcribed from a gene that becomes expressed at an abnormally high level; it may be a RNA transcribed from a gene that becomes expressed at an abnormally low level, where the altered expression correlates with the

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PCT/US2016/038181 occurrence and/or progression of the disease. A disease-associated RNA also refers to a RNA transcribed from a gene possessing mutation(s) or genetic variation that is directly responsible or is in linkage disequilibrium with a gene(s) that is responsible for the etiology of a disease. The translated products may be known or unknown, and may be at a normal or abnormal level. The target RNA of a RNA-targeting complex can be any RNA endogenous or exogenous to the eukaryotic cell. For example, the target RNA can be a RNA residing in the nucleus of the eukaryotic cell. The target RNA can be a sequence (e.g., mRNA or pre-mRNA) coding a gene product (e.g., a protein) or a non-coding sequence (e.g., ncRNA, IncRNA, tRNA, or rRNA). [00222] In some embodiments, the method may comprise allowing a nucleic acid-targeting complex to bind to the target DNA or RNA to effect cleavage of said target DNA or RNA thereby modifying the target DNA or RNA, wherein the nucleic acid-targeting complex comprises a nucleic acid-targeting effector protein complexed with a guide RNA hybridized to a target sequence within said target DNA or RNA, In one aspect, the invention provides a method of modifying expression of DNA or RNA in a eukaryotic cell. In some embodiments, the method comprises allowing a nucleic acid-targeting complex to bind to the DNA or RNA such that said binding results in increased or decreased expression of said DNA or RNA; wherein the nucleic acid-targeting complex comprises a nucleic acid-targeting effector protein complexed with a guide RNA. Similar considerations and conditions apply as above for methods of modifying a target DNA or RNA. In fact, these sampling, culturing and re-introduction options apply across the aspects of the present invention. In one aspect, the invention provides for methods of modifying a target DNA or RNA in a eukaryotic cell, which may be in vivo, ex vivo or in vitro. In some embodiments, the method comprises sampling a cell or population of cells from a human or non-human animal, and modifying the cell or cells. Culturing may occur at any stage ex vivo. The cell or cells may even be re-introduced into the non-human animal or plant. For re-introduced cells it is particularly preferred that the cells are stem cells.

[00223] Indeed, in any aspect of the invention, the nucleic acid-targeting complex may comprise a nucleic acid-targeting effector protein complexed with a guide RNA hybridized to a target sequence.

[00224] The invention relates to the engineering and optimization of systems, methods and compositions used for the control of gene expression involving DNA or RNA sequence targeting, that relate to the nucleic acid-targeting system and components thereof. In

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PCT/US2016/038181 advantageous embodiments, the effector enzyme is a Type V/Type VI protein such as Cpfl/C2cl/C2c2. An advantage of the present methods is that the CRISPR system minimizes or avoids off-target binding and its resulting side effects. This is achieved using systems arranged to have a high degree of sequence specificity for the target DNA or RNA.

[00225] In relation to a nucleic acid-targeting complex or system preferably, the crRNA sequence has one or more stem loops or hairpins and is 30 or more nucleotides in length, 40 or more nucleotides in length, or 50 or more nucleotides in length; the crRNA sequence is between 10 to 30 nucleotides in length, the nucleic acid-targeting effector protein is a Type V/Type VI Cas enzyme. In certain embodiments, the crRNA sequence is between 42 and 44 nucleotides in length, and the nucleic acid-targeting Cas protein is Cpfl of Francisella lularensis subsp.novocida U112. In certain embodiments, the crRNA comprises, consists essentialy of, or consists of 19 nucleotides of a direct repeat and between 23 and 25 nucleotides of spacer sequence, and the nucleic acid-targeting Cas protein is Cpfl of Francisella tularensis subsp.novocida U112.

[00226] The use of two different aptamers (each associated with a distinct nucleic acidtargeting guide RNAs) allows an activator-adaptor protein fusion and a repressor-adaptor protein fusion to be used, with different nucleic acid-targeting guide RNAs, to activate expression of one DNA or RNA, whilst repressing another. They, along with their different guide RNAs can be administered together, or substantially together, in a multiplexed approach. A large number of such modified nucleic acid-targeting guide RNAs can be used all at the same time, for example 10 or 20 or 30 and so forth, whilst only one (or at least a minimal number) of effector protein molecules need to be delivered, as a comparatively small number of effector protein molecules can be used with a large number modified guides. The adaptor protein may be associated (preferably linked or fused to) one or more activators or one or more repressors. For example, the adaptor protein may be associated with a first activator and a second activator. The first and second activators may be the same, but they are preferably different activators. Three or more or even four or more activators (or repressors) may be used, but package size may limit the number being higher than 5 different functional domains. Linkers are preferably used, over a direct fusion to the adaptor protein, where two or more functional domains are associated with the adaptor protein. Suitable linkers might include the GlySer linker.

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PCT/US2016/038181 [00227] It is also envisaged that the nucleic acid-targeting effector protein-guide RNA complex as a whole may be associated with two or more functional domains. For example, there may be two or more functional domains associated with the nucleic acid-targeting effector protein, or there may be two or more functional domains associated with the guide RNA (via one or more adaptor proteins), or there may be one or more functional domains associated with the nucleic acid-targeting effector protein and one or more functional domains associated with the guide RNA (via one or more adaptor proteins).

[00228] The fusion between the adaptor protein and the activator or repressor may include a linker. For example, GlySer linkers GGGS (SEQ ID NO: 18) can be used. They can be used in repeats of 3 ((GGGGS), (SEQ ID NO: 19)) or 6 (SEQ ID NO: 20), 9 (SEQ ID NO: 21) or even 12 (SEQ ID NO: 22) or more, to provide suitable lengths, as required. Linkers can be used between the guide RNAs and the functional domain (activator or repressor), or between the nucleic acid-targeting Cas protein (Cas) and the functional domain (activator or repressor). The linkers the user to engineer appropriate amounts of “mechanical flexibility”.

[00229] The invention comprehends a nucleic acid-targeting complex comprising a nucleic acid-targeting effector protein and a guide RNA, wherein the nucleic acid-targeting effector protein comprises at least one mutation, such that the nucleic acid-targeting effector protein has no more than 5% of the activity of the nucleic acid-targeting effector protein not having the at least one mutation and, optional, at least one or more nuclear localization sequences; the guide RNA comprises a guide sequence capable of hybridizing to a target sequence in a RNA of interest in a cell; and wherein: the nucleic acid-targeting effector protein is associated with two or more functional domains; or at least one loop of the guide RNA is modified by the insertion of distinct RNA sequence(s) that hind to one or more adaptor proteins, and wherein the adaptor protein is associated with two or more functional domains; or the nucleic acid-targeting Cas protein is associated with one or more functional domains and at least one loop of the guide RNA is modified by the insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins, and wherein the adaptor protein is associated with one or more functional domains. [00230] In one aspect, the invention provides a method of generating a model eukaryotic cell comprising a mutated disease gene. In some embodiments, a disease gene is any gene associated an increase in the risk of having or developing a disease. In some embodiments, the method comprises (a) introducing one or more vectors into a eukaryotic cell, wherein the one or more

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PCT/US2016/038181 vectors drive expression of one or more of: a Cpfl enzyme and a protected guide RNA comprising a guide sequence linked to a direct repeat sequence; and (b) allowing a CRISPR complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said disease gene, wherein the CRISPR complex comprises the Cpfl enzyme complexed with the guide RNA comprising the sequence that is hybridized to the target sequence within the target polynucleotide, thereby generating a model eukaryotic cell comprising a mutated disease gene. In some embodiments, said cleavage comprises cleaving one or two strands at the location of the target sequence by said Cpfl enzyme. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by non-homologous end joining (NHEJ)-based gene insertion mechanisms with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expression from a gene comprising the target sequence.

[00231] In an aspect the invention provides methods as herein discussed wherein the host is a eukaryotic cell. In an aspect the invention provides a method as herein discussed wherein the host is a mammalian cell. In an aspect the invention provides a method as herein discussed, wherein the host is a non-human eukaryote cell. In an aspect the invention provides a method as herein discussed, wherein the non-human eukaryote cell is a non-human mammal cell. In an aspect the invention provides a method as herein discussed, wherein the non-human mammal cell may be including, but not limited to, primate bovine, ovine, procine, canine, rodent, Leporidae such as monkey, cow, sheep, pig, dog, rabbit rat or mouse cell. In an aspect the invention provides a method as herein discussed, the ceil may be a a non-mammalian eukaryotic cell such as poultry bird (e.g., chicken), vertebrate fish (e.g., salmon) or shellfish (e.g., oyster, claim, lobster, shrimp) cell. In an aspect the invention provides a method as herein discussed, the nonhuman eukaryote cell is a plant cell. The plant cell may be of a monocot or dicot or of a crop or grain plant such as cassava, corn, sorghum, soybean, wheat, oat or rice. The plant cell may also be of an algae, tree or production plant, fruit or vegetable (e.g., trees such as citrus trees, e.g., orange, grapefruit or lemon trees; peach or nectarine trees, apple or pear trees; nut trees such as almond or walnut or pistachio trees; nightshade plants; plants of the genus Brassica, plants of the genus Lactuca. plants of the genus Spinacia', plants of the genus Capsicum', cotton, tobacco,

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PCT/US2016/038181 asparagus, carrot, cabbage, broccoli, cauliflower, tomato, eggplant, pepper, lettuce, spinach, strawberry, blueberry, raspberry, blackberry, grape, coffee, cocoa, etc).

[00232] In one aspect, the invention provides a method for developing a biologically active agent that modulates a cell signaling event associated with a disease gene. In some embodiments, a disease gene is any gene associated an increase in the risk of having or developing a disease. In some embodiments, the method comprises (a) contacting a test compound with a model cell of any one of the above-described embodiments; and (b ) detecting a change in a readout that is indicative of a reduction or an augmentation of a cell signaling event associated with said mutation in said disease gene, thereby developing said biologically active agent that modulates said cell signaling event associated with said disease gene.

[00233] In one aspect the invention provides for a method of selecting one or more cell(s) by introducing one or more mutations in a gene in the one or more cell (s), the method comprising: introducing one or more vectors into the cell (s), wherein the one or more vectors drive expression of one or more of: Cpfl, a guide sequence linked to a direct repeat sequence, and an editing template; wherein the editing template comprises the one or more mutations that abolish Cpfl cleavage; allowing homologous recombination of the editing template with the target polynucleotide in the cell(s) to be selected; allowing a Cpfl CRISPR-Cas complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said gene, wherein the Cpfl CRISPR-Cas complex comprises the Cpfl complexed with (1) the guide sequence that is hybridized to the target sequence within the target polynucleotide, and (2) the direct repeat sequence, wherein binding of the Cpfl CRISPR-Cas complex to the target polynucleotide induces cell death, thereby allowing one or more cell(s) in which one or more mutations have been introduced to be selected; this includes the present split Cpfl. In another preferred embodiment of the invention the cell to be selected may be a eukaryotic cell. Aspects of the invention allow for selection of specific cells without requiring a selection marker or a two-step process that may include a counter-selection system. In particular embodiments, the model eukaryotic cell is comprised within a model eukaryotic organism.

[00234] In one aspect, the invention provides a recombinant polynucleotide comprising a guide sequence downstream of a direct repeat sequence, wherein the guide sequence when expressed directs sequence-specific binding of a Cpfl CRISPR-Cas complex to a corresponding target sequence present in a eukaryotic cell. In some embodiments, the target sequence is a viral

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PCT/US2016/038181 sequence present in a eukaryotic cell. In some embodiments, the target sequence is a protooncogene or an oncogene.

[00235] In one aspect, the invention provides a vector system or eukaryotic host cell comprising (a) a first regulatory element operably linked to a direct repeat sequence and one or more insertion sites for inserting one or more guide sequences (including any of the modified guide sequences as described herein) downstream of the DR sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a Cpfl CRISPR-Cas complex to a target sequence in a eukaryotic cell, wherein the Cpfl CRISPR-Cas complex comprises Cpfl (including any of the modified enzymes as described herein) complexed with the guide sequence that is hybridized to the target sequence (and optionally the DR sequence); and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme comprising a nuclear localization sequence and/or NES. In some embodiments, the host cell comprises components (a) and (b). In some embodiments, component (a), component (b), or components (a) and (b) are stably integrated into a genome of the host eukaryotic cell. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a Cpfl CRISPR-Cas complex to a different target sequence in a eukaryotic cell. . In some embodiments, the CRISPR enzyme comprises one or more nuclear localization sequences and/or nuclear export sequences or NES of sufficient strength to drive accumulation of said CRISPR. enzyme in a detectable amount in and/or out of the nucleus of a eukaryotic cell. In some embodiments, the Cpfl enzyme is derived from Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC20I7 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011_GWA2_33_10, Parcubacteria bacterium GW2011 GWC2 44 17, Smithella sp. SC ADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2Q20, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, or Porphyromonas macacae Cpfl, including any of the modified enzymes as described herein, and may include further alteration or mutation of the Cpfl, and can be a chimeric Cpfl. . In some embodiments, the CRISPR enzyme is codon-optimized for expression in a eukaryotic cell. In some embodiments, the CRISPR enzyme directs cleavage of one or two strands at the location of the target sequence. In a

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PCT/US2016/038181 preferred embodiment, the strand break is a staggered cut with a 5’ overhang. In some embodiments, the Cpfl lacks DNA strand cleavage activity (e.g., no more than 5% nuclease activity as compared with a wild type enzyme or enzyme not having the mutation or alteration that decreases nuclease activity). In some embodiments, the first regulatory element is a polymerase III promoter. In some embodiments, the second regulatory' element is a polymerase II promoter. In some embodiments, the direct repeat has a minimum length of 16 nts and a single stem loop. In further embodiments the direct repeat has a length longer than 16 nts, preferably more than 17 nts, and has more than one stem loop or optimized secondary structures. In some embodiments, the guide sequence is at least 16, 17, 18, 19, 20, 25 nucleotides, or between 16-30, or between 16-25, or between 16-20 nucleotides in length.

[00236] In one aspect, the invention provides a kit comprising one or more of the components described herein. In some embodiments, the kit comprises a vector system or host cell as described herein and instructions for using the kit.

Modified Cpfl enzymes [00237] Computational analysis of the primary structure of Cpfl nucleases reveals three distinct regions (Figure 1). First a C-terminal RuvC like domain, which is the only functional characterized domain. Second a N-terminal alpha-helical region and thirst a mixed alpha and beta region, located between the RuvC like domain and the alpha-helical region.

[00238] Several small stretches of unstructured regions are predicted within the Cpfl primary' structure. Unstructured regions, which are exposed to the solvent and not conserved within different Cpfl orthologs, are preferred sides for splits and insertions of small protein sequences (Figure 2 and 3). In addition, these sides can be used to generate chimeric proteins between Cpfl orthologs.

[00239] Based on the above information, mutants can be generated which lead to inactivation of the enzyme or which modify the double strand nuclease to nickase activity. In alternative embodiments, this information is used to develop enzymes with reduced off-target effects (described elsewhere herein) [00240] In certain of the above-described Cpfl enzymes, the enzyme is modified by mutation of one or more residues including but not limited to positions D917, El006, E1028, D1227, D1255A, N1257, according to FnCpfl protein or any corresponding ortholog. In an aspect the invention provides a herein-discussed composition wherein the Cpfl enzyme is an inactivated enzyme which comprises one or more mutations selected from the group consisting of D917A,

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El006A, E1028A, DI227A, D1255A, N1257A, D917A, El006A, E1028A, DI227A, D1255A and N1257A according to FnCpfl protein or corresponding positions in a Cpfl ortholog. In an aspect the invention provides a herein-discussed composition, wherein the CRISPR enzyme comprises D917, or E1006 and D917, or D917 and DI255, according to FnCpfl protein or a corresponding position in a Cpfl ortholog.

[00241] In certain of the above-described Cpfl enzymes, the enzyme is modified by mutation of one or more residues (in the RuvC domain) including but not limited to positions R909, R912, R930, R947, K949, R951, R955, K965, K968, K1000, K1002, R1003, K1009, K1017, K1022, K1029, K1035, K1054, K1072, K1086, R1094, K1095, K1109, K1118, K1142, K1150, K 1 I 58, K1159, R1220, R1226, R1242, and/or R1252 with reference to amino acid position numbering of AsCpfl ( Acidaminococcus sp, BV3L6), [00242] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of one or more residues (in the RAD50) domain including but not limited positions K324, K335, K337, R331, K369, K370, R386, R392, R393, K400, K404, K406, K408, K414, K429, K436, K438, K459, K460, K464, R670, K675, R681, K686, K689, R699, K705, R725, K729, K739, K748, and/or K752 with reference to amino acid position numbering of AsCpfl (Aci daminococcus sp. BV3L6).

[00243] In certain of the Cpfl enzymes, the enzyme is modified by mutation of one or more residues including but not limited positions R912, T923, R947, K949, R951, R955, K965, K968, K1000, R1003, K1009, K1017, K1022, K1029, K1072, K1086, F1103, RI226, and/or R1252 with reference to amino acid position numbering of AsCpfl (Acidaminococcus sp. BV3L6). [00244] In certain embodiments, the Cpfl enzyme is modified by mutation of one or more residues including but not limited positions R833, R836, K847, K879, K881, R883, R887, K897, K900, K932, R935, K940, K948, K953, K960, K984, K1003, K1017, R1033, R1138, RI165, and/or R1252 with reference to amino acid position numbering of LbCpfl (Lachnospiraceae bacterium ND2006).

[00245] In certain embodiments, the Cpfl enzyme is modified by mutation of one or more residues including but not limited positions K15, R18, K26, Q34, R43, K48, K51, R56, R84, K85, K87, N93, RI03, N104, T118, K123, K134, R176, K177, R192, K200, K226, K273, K275, T29I, R301, K307, K369, S404, V409, K4I4, K436, K438, K468, D482, K516, R5I8, K524, K530, K532, K548, K559, K570, R574, K592, D596, K603, K607, K613, C647, R681, K686,

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H720, K739, K748, K757, T766, K780, R790, P791, K796, K809, K815, T816, K860, R862, R863, K868, K897, R909, R912, T923, R947, K949, R951, R955, K965, K968, K1000, R1003, K1009, K1017, K1022, K1029, A1053, KI072, K1086, FI 103, Si209. R1226, R1252, K1273, K1282, and/or K1288 with reference to amino acid position numbering of AsCpfl (Acidaminococcus sp. BV3L6).

[00246] In certain embodiments, the enzyme is modified by mutation of one or more residues including but not limited positions K15, R18, K26, R34, R43, K48, K51, K56, K87, K88, D90, K96, K106, K107, K120, Q125, K143, R186, K187, R202, K210, K235, K296, K298, K314,

K320, K326, K397, K444, K449, E454, A483, E491, K527, K541, K581, R583, K589, K595,

K597, K613, K624, K635, K639, K656, K660, K667, K671, K677, K719, K725, K730, K763,

K782, K791, R800, K809, K823, R833, K834, K839, K852, K858, K859, K869, K871, R872,

K877, K905, R918, R921, K932, I960, K962, R964, R968, K978, K981, K1013, R1016, K102I, K1029, K1034, K1041, K1065, K1084, and/or K1098 with reference to amino acid position numbering of FnCpfi (Francisella novicida 1,4 12 ).

[00247] In certain embodiments, the enzyme is modified by mutation of one or more residues including but not limited positions K15, R18, K26, K34, R43, K48, K51, R56, K83, K84, R86, K92, R102, K103, K116, K121, R.158, Cl59, R174, R182, K206, K251, K253, K269, K271, K278, P342, K380, R385, K390, K415, K421, K457, K471, A506, R508, K514, K520, K522,

K538, Y548, K560, K564, K580, K584, K591, K595, K601, K634, K640, R645, K679, K689,

K707, T716, K725, R737, R747, R748, K753, K768, K774, K775, K785, K787, R788, Q793,

K821, R833, R836, K847, K879, K881, R883, R887, K897, K900, K932, R935, K940, K948,

K953, K960, K984, K1003, K1017, R1033, K1121, R1138, R1165, K1190, KI199, and/or K1208 with reference to amino acid position numbering of LbCpfl (Lachnospiraceae bacterium ND2006).

[00248] In certain embodiments, the enzyme is modified by mutation of one or more residues including but not limited positions K14, R17, R25, K33, M42, Q47, K50, D55, K85, N86, K88, K94, R104, K105, K118, K123, K131, R174, K175, R190, R198, 1221, K267, Q269, K285,

K291, K297, K357, K403, K409, K4I4, K448, K460, K501, K515, K550, R552, K558, K564,

K566, K582, K593, K604, K608, K623, K627, K633, K637, E643, K780, Y787, K792, K830,

Q846, K858, K867, K876, K890, R900, K901, M906, K921, K927, K928, K937, K939, R940,

K945, Q975, R987, R990, K1001, R1034,11036, R1038, R1042, K1052, K1055, K1087, R1090,

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K1095, N1103, K1108, K1115, K1139, K1158, R1172, K1188, K1276, R1293, A1319, K1340, K1349, and/or K1356 with reference to amino acid position numbering of MbCpfl (Moraxella bovoculi 237).

[00249] Where the Cpfl protein has nuclease activity, the Cpfl protein may be modified to have diminished nuclease activity e.g., nuclease inactivation of at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or 100% as compared with the wild type enzyme; or to put in another way, a Cpfl enzyme having advantageously about 0% of the nuclease activity of the non-mutated or wild type Cpfl enzyme or CRISPR enzyme, or no more than about 3% or about 5% or about 10% of the nuclease activity of the non-mutated or wild type Cpfl enzyme, e.g. of the non-mutated or wild type Francisella novicida U112 (FnCpfl), Acidammococcus sp. BV3L6 (AsCpfl), Lachnospiraceae bacterium ND2006 (LbCpfl) or Moraxella bovoculi 237 (MbCpfl Cpfl enzyme or CRISPR enzyme. This is possible by introducing mutations into the nuclease domains of the Cpfl and orthologs thereof.

[00250] More particularly, the inactivated Cpfl enzymes include enzymes mutated in amino acid positions As908, As993, Asl263 of AsCpfl or corresponding positions in Cpfl orthologs. Additionally, the inactivated Cpfl enzymes include enzymes mutated in amino acid position Lb832, 925, 947 or 1180 of LbCpfl or corresponding positions in Cpfl orthologs. More particularly, the inactivated Cpfl enzymes include enzymes comprising one or more of mutations AsD908A, AsE993A, AsD1263A of AsCpfl or corresponding mutations in Cpfl orthologs. Additionally, the inactivated Cpfl enzymes include enzymes comprising one or more of mutations LbD832A, E925A, D947A or D1I80A of LbCpfl or corresponding mutations in Cpfl orthologs.

[00251] The inactivated Cpfl CRISPR enzyme may have associated (e.g., via fusion protein) one or more functional domains, including for example, one or more domains from the group comprising, consisting essentially of or consisting of methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, RNA cleavage activity, DNA cleavage activity, nucleic acid binding activity, and molecular switches (e.g., light inducible). Preferred domains are FokI, VP64, P65, HSF1, MyoDl. In the event that FokI is provided, it is advantageous that multiple Fokl functional domains are provided to allow for a functional dimer and that gRNAs are

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PCT/US2016/038181 designed to provide proper spacing for functional use (Fokl) as specifically described in Tsai et al. Nature Biotechnology, Vol. 32, Number 6, June 2014). The adaptor protein may utlilize known linkers to attach such functional domains. In some cases it is advantageous that additionally at least one NLS is provided. In some instances, it is advantageous to position the NLS at the N terminus. When more than one functional domain is included, the functional domains may be the same or different.

[00252] In general, the positioning of the one or more functional domain on the inactivated Cpfl enzyme is one which allows for correct spatial orientation for the functional domain to affect the target with the attributed functional effect. For example, if the functional domain is a transcription activator (e.g., VP64 or p65), the transcription activator is placed in a spatial orientation which allows it to affect the transcription of the target. Likewise, a transcription repressor will be advantageously positioned to affect the transcription of the target, and a nuclease (e.g,, Fokl) will be advantageously positioned to cleave or partaliy cleave the target. This may include positions other than the N- / C- terminus of the CRISPR enzyme.

[00253] In certain embodiments, the effector protein (CRISPR enzyme; Cpfl) according to the invention as described herein is associated with or fused to a destabilization domain (DD). In some embodiments, the DD is ER50. A corresponding stabilizing ligand for this DD is, in some embodiments, 4HT. As such, in some embodiments, one of the at least one DDs is ER50 and. a stabilizing ligand therefor is 4HT or CMP8. In some embodiments, the DD is DHFR50. A corresponding stabilizing ligand for this DD is, in some embodiments, TMP. As such, in some embodiments, one of the at least one DDs is DHFR50 and a stabilizing ligand therefor is TMP. In some embodiments, the DD is ER50. A corresponding stabilizing ligand for this DD is, in some embodiments, CMP8. CMP8 may therefore be an alternative stabilizing ligand to 4HT in the ER50 system. While it may be possible that CMP8 and 4HT can/should be used in a competitive matter, some cell types may be more susceptible to one or the other of these two ligands, and from this disclosure and the knowledge in the art the skilled person can use CMP8 and/or 4HT.

[00254] In some embodiments, one or two DDs may be fused to the N- terminal end of the CRISPR enzyme with one or two DDs fused to the C- terminal of the CRISPR enzyme. In some embodiments, the at least two DDs are associated with the CRISPR enzyme and the DDs are the same DD, i.e. the DDs are homologous. Thus, both (or two or more) of the DDs could be ER50 DDs. This is preferred in some embodiments. Alternatively, both (or two or more) of the DDs could be DHFR50 DDs. This is also

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PCT/US2016/038181 preferred in some embodiments. In some embodiments, the at least two DDs are associated with the CRISPR enzyme and the DDs are different DDs, i.e. the DDs are heterologous. Thus, one of the DDS could be ER50 while one or more of the DDs or any other DDs could be DHFR50. Having two or more DDs which are heterologous may be advantageous as it would provide a greater level of degradation control. A tandem fusion of more than one DD at the N or C-tenn may enhance degradation; and such a tandem, fusion can be, for example ER50-ER50-C2c2 or DHFR-DHFR-Cpfl. It is envisaged that high levels of degradation would occur in the absence of either stabilizing ligand, intermediate levels of degradation would occur in the absence of one stabilizing ligand and the presence of the other (or another) stabilizing ligand, while low levels of degradation wouW occur in the presence of both (or two of more) of the stabilizing ligands. Control may also be imparted by having an N-terminal ER50 DD and a C-terminal DHFR50 DD.

[00255] In some embodiments, the fusion of the CRISPR enzyme with the DD comprises a linker between the DD and the CRISPR enzyme, hi some embodiments, the linker is a GlySer linker. In some embodiments, the DD-CRISPR enzyme further comprises at least one Nuclear Export Signal (NES). In some embodiments, the DD-CRISPR enzyme comprises two or more NESs. In some embodiments, the DD-CRISPR enzyme comprises at least one Nuclear Localization Signal (NLS). This may be in addition to an NES. In some embodiments, the CRISPR enzyme comprises or consists essentially of or consists of a. localization (nuclear import or export) signal as, or as part of, the linker between the CRISPR enzyme and the DD. HA or Flag tags are also within the ambit of the invention as linkers. Applicants use NLS and/or NES as linker and also use Glycine Serine linkers as short as GS up to (GGGGS)3.

[00256] Destabilizing domains have general utility to confer instability to a wade range of proteins; see, e.g., Miyazaki, J Am Chem Soc. Mar 7, 2012; 134(9): 3942-3945, incorporated herein by reference. CMP8 or 4-hydroxyta.moxifen can be destabilizing domains. More generally, A temperature-sensitive mutant of mammalian DHFR (DHFRts), a destabilizing residue by the N-end rule, was found to be stable at a permissive temperature but unstable at 37 °C. The addition of methotrexate, a high-affinity ligand for mammalian DHFR, to cells expressing DHFRts inhibited degradation of the protein partially. This was an important demonstration that a small molecule ligand can stabilize a protein otherwise targeted for degradation in cells. A rapamycin derivative was used to stabilize an unstable mutant of the FRB domain of mTOR (FRB*) and restore the function of the fused kinase, GSK-3f.6,7 This system demonstrated that ligand-dependent stability represented an attractive strategy to regulate the function of a specific protein in a complex biological environment. A system to control protein activity can involve the DD becoming functional when the ubiquitin complementation occurs by rapamycin induced dimerization of FK506binding protein and FKBP12. Mutants of human FKBP12 or ecDHFR protein can be engineered to be metabolically unstable in the absence of their high-affinity ligands, Shield-1 or trimethoprim (TMP),

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PCT/US2016/038181 respectively. These mutants are some of the possible destabilizing domains (DDs) useful in the practice of the invention and instability of a DD as a fusion with a CRISPR enzyme confers to the CRISPR protein degradation of the entire fusion protein by the proteasome. Shield-1 and TMP bind to and stabilize the DD in a dose-dependent manner. The estrogen receptor ligand binding domain (ERLBD, residues 305549 of ERS1) can also be engineered as a destabilizing domain. Since the estrogen receptor signaling pathway is involved in a variety of diseases such as breast cancer, the pathway has been widely studied and numerous agonist and antagonists of estrogen receptor have been developed. Thus, compatible pairs of ERLBD and drugs are known. There are ligands that bind to mutant but not wild-type forms of the ERLBD. By using one of these mutant domains encoding three mutations (L384M, M421G, G521R)12, it is possible to regulate the stability of an ERLBD-derived DD using a ligand that does not perturb endogenous estrogen-sensitive networks. An additional mutation (Y537S) can be introduced to further destabilize the ERLBD and to configure it as a potential DD candidate. This tetra-mutant is au advantageous DD development. The mutant ERLBD can be fused to a CRISPR enzyme and its stability can be regulated or perturbed using a ligand, whereby the CRISPR enzyme has a DD. Another DD can be a 12-kDa (107-amino-acid) tag based on a mutated FKBP protein, stabilized by Shieldl ligand; see, e.g., Nature Methods 5, (2008). For instance a DD can be a modified FK506 binding protein 12 (FKBP12) that binds to and is reversibly stabilized by a synthetic, biologically inert small molecule, Shield-1: see, e.g., Banaszynski LA, Chen LC, Maynard-Smith LA, Ooi AG, Wandless TJ. A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell. 2006:126:9951004; Banaszynski LA, Sellmyer MA, Contag CH, Wandless TJ, Thome SFI. Chemical control of protein stability and function m living mice. Nat Med. 2008;14:1123-1127; Maynard-Smith LA, Chen LC, Banaszynski LA, Ooi AG, Wandless TJ. A directed approach for engineering conditional protein stability using biologically silent small molecules. The Journal of biological chemistry. 2007;282:24866-24872; and Rodriguez, Chem Biol. Mar 23, 2012; 19(3): 391-398—all of which are incorporated herein byreference and may be employed in the practice of the invention in selected a DD to associate with a CRISPR enzyme in the practice of this invention. As can be seen, the knowledge in the art includes a number of DDs, and the DD can be associated with, e.g., fused to, advantageously with a linker, to a CRISPR enzyme, whereby the DD can be stabilized in the presence of a ligand and when there is the absence thereof the DD can become destabilized, whereby the CRISPR enzyme is entirely destabilized, or the DD can be stabilized in the absence of a ligand and when the ligand is present the DD can become destabilized; the DD allows the CRISPR enzyme and hence the CRISPR-Cas complex or system to be regulated or controlled—turned on or off so to speak, to thereby provide means for regulation or control of the system, e.g., in an in vivo or in vitro environment. For instance, when a protein of interest is expressed as a fusion with the DD tag, it is destabilized and rapidly degraded in the ceil, e.g., by

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PCT/US2016/038181 proteasomes. Thus, absence of stabilizing ligand leads to a D associated Cas being degraded. When a new DD is fused to a protein of interest, its instability is conferred to the protein of interest, resulting in the rapid degradation of the entire fusion protein. Peak activity for Cas is sometimes beneficial to reduce off-target effects. Thus, short bursts of high activity are preferred. The present invention is able to provide such peaks. In some senses the system is inducible. In some other senses, the system repressed in the absence of stabilizing ligand and de-repressed in the presence of stabilizing ligand.

Enzyme mutations reducing off-target effects [00257] In one aspect, the invention provides a non-naturally occurring or engineered CRISPR enzyme, preferably a class 2 CRISPR enzyme, preferably a Type V or VI CRISPR enzyme as described herein, such as preferably, but without limitation Cpfl as described herein elsewhere, having one or more mutations resulting in reduced off-target effects, i.e. improved CRISPR enzymes for use in effecting modifications to target loci but winch reduce or eliminate activity towards off-targets, such as when complexed to guide RNAs, as well as improved improved CRISPR enzymes for increasing the activity of CRISPR enzymes, such as when complexed with guide RNAs. It is to be understood that mutated enzymes as described herein below may he used in any of the methods according to the invention as described herein elsewhere. Any of the methods, products, compositions and uses as described herein elsewhere are equally applicable with the mutated CRISPR enzymes as further detailed below. It is to he understood, that in the aspects and embodiments as described herein, when referring to or reading on Cpfl as the CRISPR enzyme, reconstitution of a functional CRISPR-Cas system preferably does not require or is not dependent on a tracr sequence and/or direct repeat is 5’ (upstream) of the guide (target or spacer) sequence.

[00258] By means of further guidance, the following particular aspects and embodiments are provided.

[00259] The inventors have surprisingly determined that modifications may be made to CRISPR enzymes which confer reduced off-target activity compared to unmodified CRISPR enzymes and/or increased target activity compared to unmodified CRISPR enzymes. Thus, in certain aspects of the invention provided herein are improved CRISPR enzymes which may have utility in a wide range of gene modifying applications. Also provided herein are CRISPR complexes, compositions and systems, as well as methods and uses, all comprising the herein disclosed modified CRISPR enzymes.

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PCT/US2016/038181 [00260] In this disclosure, the term “Cas” can mean “Cpfl” or a CRISPR enzyme. In the context of this aspect of the invention, a Cpfl or CRISPR enzyme is mutated or modified, “whereby the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme” (or like expressions); and, when reading this specification, the terms “Cpfl” or “Cas” or “CRISPR enzyme and the like are meant to include mutated or modified Cpfl or Cas or CRISPR. enzyme in accordance with the invention,

1. e., “whereby the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme” (or like expressions).

[00261] In an aspect, there is provided an engineered Cpfl protein as defined herein, such as Cpfl, wherein the protein complexes with a nucleic acid molecule comprising RNA to form a CRISPR complex, wherein when in the CRISPR complex, the nucleic acid molecule targets one or more target polynucleotide loci, the protein comprises at least one modification compared to unmodified Cpfl protein, and wherein the CRISPR complex comprising the modified protein has altered activity as compared to the complex comprising the unmodified Cpfl protein. It is to be understood that when referring herein to CRISPR “protein”, the Cpfl protein preferably is a modified CRISPR enzyme (e.g. having increased or decreased (or no) enzymatic activity, such as without limitation including Cpfl. The term “CRISPR protein” may be used interchangeably with “CRISPR enzyme”, irrespective of whether the CRISPR protein has altered, such as increased or decreased (or no) enzymatic activity, compared to the wild type CRISPR protein. [00262] In an aspect, the altered activity of the engineered CRISPR protein comprises an altered binding property as to the nucleic acid molecule comprising RNA or the target polynucleotide loci, altered binding kinetics as to the nucleic acid molecule comprising RNA or the target polynucleotide loci, or altered binding specificity as to the nucleic acid molecule comprising RNA or the target polynucleotide loci compared to off-target polynucleotide loci. [00263] In some embodiments, the unmodified Cas has DNA cleavage activity, such as Cpfl. In some embodiments, the Cas directs cleavage of one or both strands at the location of a target sequence, such as within the target sequence and/or within the complement of the target sequence. In some embodiments, the Cas directs cleavage of one or both strands within about 1,

2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. In some embodiments, a vector encodes a Cas that is mutated to with respect to a corresponding wild-type enzyme such that the mutated Cas lacks the ability to

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PCT/US2016/038181 cleave one or both strands of a target polynucleotide containing a target sequence. In some embodiments, a Cas is considered to substantially lack all DNA cleavage activity when the DNA cleavage activity of the mutated enzyme is about no more than 25%, 10%, 5%, 1%, 0.1%, 0,01%, or less of the DNA cleavage activity of the non-mutated form of the enzyme, an example can be when the DNA cleavage activity of the mutated form is nil or negligible as compared with the non-mutated form. Thus, the Cas may comprise one or more mutations and may be used as a generic DNA binding protein with or without fusion to a functional domain. The mutations may be artificially introduced mutations or gain- or loss-of-function mutations. In one aspect of the invention, the Cas enzyme may be fused to a protein, e.g., a TAG, and/or an inducible/controllable domain such as a chemically inducible/controllable domain. The Cas in the invention may be a chimeric Cas proteins; e.g,, a Cas having enhanced function by being a chimera. Chimeric Cas proteins may be new Cas containing fragments from more than one naturally occurring Cas. These may comprise fusions of N-terminal fragment(s) of one Cas9 homolog with C-terminal fragment(s) of another Cas homolog. The Cas can be delivered into the cell in the form of mRNA. The expression of Cas can be under the control of an inducible promoter. It is explicitly an object of the invention to avoid reading on known mutations. Indeed, the phrase “whereby the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme” (or like expressions) is not intended to read upon mutations that only result in a nickase or dead Cas or known Cas9 mutations. HOWEVER, this is not to say that the instant invention modification(s) or mutation(s) “whereby the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme” (or like expressions) cannot be combined with mutations that result in the enzyme being a nickase or dead. Such a dead enzyme can be an enhanced nucleic acid molecule binder. And such a nickase can be an enhanced nickase. For instance, changing neutral amino acid(s) in and/or near the groove and/or other charged residues in other locations in Cas that are in close proximity to a nucleic acid (e.g., DNA, cDNA, RNA, gRNA to positive charged amino acid(s) may result in “whereby the enzyme in the CRISPR complex has reduced capability of modifying one or more

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PCT/US2016/038181 off-target loci as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme”, e.g., more cutting. As this can be both enhanced on- and off-target cutting (a super cutting Cpfl), using such with what is known in the art as a tru-guide or tru-sgRNAs (see, e.g., Fu et al., “Improving CRISPR-Cas nuclease specificity using truncated guide RNAs,” Nature Biotechnology 32, 279-284 (2014) doi:10.1038/nbt,2808 Received 17 November 2013 Accepted 06 January 2014 Published online 26 January 2014 Corrected online 29 January 2014) to have enhanced on target activity without higher off target cutting or for making super cutting nickases, or for combination with a mutation that renders the Cas dead for a super binder. [00264] In certain embodiments, the altered activity of the engineered Cpfl protein comprises increased targeting efficiency or decreased off-target binding. In certain embodiments, the altered activity of the engineered Cpf l protein comprises modified cleavage activity.

[00265] In certain embodiments, the altered activity comprises altered binding property as to the nucleic acid molecule comprising RNA or the target polynucleotide loci, altered binding kinetics as to the nucleic acid molecule comprising RNA or the target polynucleotide loci, or altered binding specificity as to the nucleic acid molecule comprising RNA or the target polynucleotide loci compared to off-target polynucleotide loci.

[00266] In certain embodiments, the altered activity comprises increased targeting efficiency or decreased off-target binding. In certain embodiments, the altered activity comprises modified cleavage activity. In certain embodiments, the altered activity comprises increased cleavage activity as to the target polynucleotide loci. In certain embodiments, the altered activity comprises decreased cleavage activity as to the target polynucleotide loci. In certain embodiments, the altered activity comprises decreased cleavage activity as to off-target polynucleotide loci. In certain embodiments, the altered activity comprises increased cleavage activity as to off-target polynucleotide loci.

[00267] Accordingly, in certain embodiments, there is increased specificity for target polynucleotide loci as compared to off-target polynucleotide loci. In other embodiments, there is reduced specificity for target polynucleotide loci as compared to off-target polynucleotide loci. [00268] In an aspect of the invention, the altered activity of the engineered Cpfl protein comprises altered helicase kinetics.

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PCT/US2016/038181 [00269] In an aspect of the invention, the engineered Cpfl protein comprises a modification that alters association of the protein with the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. In an aspect of the invention, the engineered Cpfl protein comprises a modification that alters formation of the CRISPR complex.

[00270] In certain embodiments, the modified Cpfl protein comprises a modification that alters targeting of the nucleic acid molecule to the polynucleotide loci. In certain embodiments, the modification comprises a mutation in a region of the protein that associates with the nucleic acid molecule. In certain embodiments, the modification comprises a mutation in a region of the protein that associates with a strand of the target polynucleotide loci. In certain embodiments, the modification comprises a mutation in a region of the protein that associates with a strand of the off-target polynucleotide loci. In certain embodiments, the modification or mutation comprises decreased positive charge in a region of the protein that associates with the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. In certain embodiments, the modification or mutation comprises decreased negative charge in a region of the protein that associates with the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. In certain embodiments, the modification or mutation comprises increased positive charge in a region of the protein that associates with the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. In certain embodiments, the modification or mutation comprises increased negative charge in a region of the protein that associates with the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. In certain embodiments, the modification or mutation increases steric hindrance between the protein and the nucleic acid molecule comprising RNA, or a strand of the target polynucleotide loci, or a strand of off-target polynucleotide loci. In certain embodiments, the modification or mutation comprises a substitution of Lys, His, Arg, Glu, Asp, Ser, Gly, or Thr. In certain embodiments, the modification or mutation comprises a substitution with Gly, Ala, lie, Glu, or Asp. In certain embodiments, the modification or mutation comprises an amino acid substitution in a binding groove.

[00271 ] In as aspect, the present invention provides:

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PCT/US2016/038181 a non-naturally-occurring CRISPR enzyme as defined herein, such as Cpfl, wherein:

the enzyme complexes with guide RNA to form a CRISPR complex, when in the CRISPR complex, the guide RNA targets one or more target polynucleotide loci and the enzyme alters the polynucleotide loci, and the enzyme comprises at least one modification, whereby the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme, and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme.

[00272] In any such non-naturally-occurring CRISPR enzyme, the modification may comprise modification of one or more amino acid residues of the enzyme.

[00273] In any such non-naturally-occurring CRISPR enzyme, the modification may comprise modification of one or more amino acid residues located in a region which comprises residues which are positively charged in the unmodified enzyme.

[00274] In any such non-naturally-occurring CRISPR enzyme, the modification may comprise modification of one or more amino acid residues which are positively charged in the unmodified enzyme.

[00275] In any such non-naturally-occurring CRISPR enzyme, the modification may comprise modification of one or more amino acid residues which are not positively charged In the unmodified enzyme.

[00276] The modification may comprise modification of one or more amino acid residues which are uncharged in the unmodified enzyme.

[00277] The modification may comprise modification of one or more amino acid residues which are negatively charged in the unmodified enzyme.

[00278] The modification may comprise modification of one or more amino acid residues which are are hydrophobic in the unmodified enzyme.

[00279] The modification may comprise modification of one or more anrino acid residues which are polar in the unmodified enzyme.

[00280] In certain of the above-described non-naturally-occurring CRISPR enzymes, the modification may compri se modification of one or more residues located in a groove.

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PCT/US2016/038181 [00281] In certain of the above-described non-naturally-occurring CRISPR enzymes, the modification may comprise modification of one or more residues located outside of a groove. [00282] In certain of the above-described non-naturally-occurring CRISPR enzymes, the modification comprises a modification of one or more residues wherein the one or more residues comprises arginine, histidine or lysine.

[00283] In any of the above-described non-naturally-occurring CRISPR enzymes, the enzyme may be modified by mutation of said one or more residues.

[00284] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with an alanine residue.

[00285] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with aspartic acid or glutamic acid. [00286] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with serine, threonine, asparagine or glutamine.

[00287] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with alanine, glycine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine or valine.

[00288] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with a polar amino acid residue. [00289] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with an amino acid residue which is not a polar amino acid residue.

[00290] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation

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PCT/US2016/038181 comprises substitution of a residue in the unmodified enzyme with a negatively charged amino acid residue.

[00291] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with an amino acid residue which is not a negatively charged amino acid residue, [00292] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with an uncharged amino acid residue [00293] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with with an amino acid residue which is not an uncharged amino acid residue.

[00294] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with a hydrophobic amino acid residue [00295] In certain of the above-described non-naturally-occurring CRISPR enzymes, the enzyme is modified by mutation of said one or more residues, and wherein the mutation comprises substitution of a residue in the unmodified enzyme with an amino acid residue which is not a hydrophobic amino acid residue.

[00296] In some embodiments, the CRISPR enzyme, such as preferably Cpfl enzyme is derived Francisella tularensis I, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011 GWA2 33 10, Parcubacteria bacterium GW2011 GWC2 44 17, Smithella sp. SCADC, Acidaminococcus sp, BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, or Porphyromonas macacae Cpfl(e.g., a Cpfl of one of these organisms modified as described herein), and may include further mutations or alterations or be a chimeric Cpfl.

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PCT/US2016/038181 [00297] In certain embodiments, the Cpfl protein comprises one or more nuclear localization signal (NLS) domains. In certain embodiments, the Cpfl protein comprises at least two or more NLSs.

[00298] In certain embodiments, the Cpfl protein comprises a chimeric CRISPR protein, comprising a first fragment from a first CRISPR orthologue and a second fragment from a second CIRSPR orthologue, and the first and second CRISPR orthologues are different.

[00299] In certain embodiments, the enzyme is modified by or comprises modification, e.g., comprises, consists essentially of or consists of modification by mutation of any one of the residues listed herein or a corresponding residue in the respective orthologue; or the enzyme comprises, consists essentially of or consists of modification in any one (single), two (double), three (triple), four (quadruple) or more position(s) in accordance with the disclosure throughout this application, or a corresponding residue or position in the CRISPR enzyme orthologue, e.g., an enzyme comprising, consisting essentially of or consisting of modification in any one of the Cpfl residues recited herein, or a corresponding residue or position in the CRISPR enzyme orthologue. In such an enzyme, each residue may be modified by substitution with an alanine residue.

[00300] Applicants recently described a method for the generation of Cas9 orthologues with enhanced specificity (Slaymaker et al. 2015 “Rationally engineered Cas9 nucleases with improved specificity”). This strategy can be used to enhance the specificity of Cpfl orthologues. Primary’ residues for mutagenesis are preferably all positive charges residues within the RuvC domain. Additional residues are positive charged residues that are conserved between different orthologues.

[00301] In certain embodiments, specificity of Cpfl may be improved by mutating residues that stabilize the non-targeted DNA strand.

[00302] In certain of the above-described non-naturally-occurring Cpfl enzymes, the enzyme is modified by mutation of one or more residues (in the RuvC domain) including but not limited positions R909, R912, R930, R947, K949, R951, R955, K965, K968, K1000, K1002, R1003, K1009, KI017, K1022, K1029, K1035, K1054, K1072, K1086, R1094, K1095, K1109, K1118, Ki 142. K1150, Kl 158, Kl 159, R1220, R1226, R1242, and/or R1252 with reference to amino acid position numbering of AsCpfl (Acidaminococcus sp. BV3L6).

[00303] In certain of the above-described non-naturally-occurring Cpfl enzymes, the enzyme is modified by mutation of one or more residues (in the RAD50) domain including but not

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PCT/US2016/038181 limited positions K324, K.335, K337, R331, K369, K370, R386, R392, R393, K400, K404, K406, K408, K414, K429, K436, K438, K459, K460, K464, R670, K675, R681, K686, K689, R699, K705, R725, K729, K739, K748, and/or K752 with reference to amino acid position numbering of AsCpfl (Acidaminococcus sp. BV3L6), [00304] In certain of the above-described non-naturally-occurring Cpfl enzymes, the enzyme is modified by mutation of one or more residues including but not limited positions R912, T923, R947, K949, R951, R955, K965, K968, K1000, R1003, K1009, K1017, K1022, K1029, K1072, K.1086, FI 103, R1226, and/or R1252 with reference to amino acid position numbering of AsCpfl (Acidaminococcus sp. BV3L6).

[00305] In certain embodiments, the enzyme is modified by mutation of one or more residues including but not limited positions R833, R836, K847, K879, K881, R883, R887, K897, K900, K932, R935, K940, K948, K953, K960, K984, K1003, K1017, R1033, R1138, R1165, and/or R1252 with reference to amino acid position numbering of LbCpfl (Lachnospiraceae bacterium ND2006).

[00306] In certain embodiments, the Cpfl enzyme is modified by mutation of one or more residues including but not limited positions K15, R18, K26, Q34, R43, K48, K51, R56, R84, K.85, K.87, N93, R103, N104, T118, K123, K134, R176, K. 177, R192, K200, K226, K.273, K275, T291, R301, K307, K369, S404, V409, K414, K436, K438, K468, D482, K516, R518, K524, K530, K532, K548, K559, K570, R574, K592, D596, K603, K607, K6I3, C647, R681, K686, H720, K739, K748, K757, T766, K780, R790, P791, K796, K809, K815, T816, K860, R862, R863, K868, K897, R909, R912, T923, R947, K949, R951, R955, K965, K968, K1000, R1003, KI009, K10I7, KJ 022, K1029, A1053, K1072, K1086, FI 103, S1209, R1226, R1252, K1273, K1282, and/or K1288 with reference to amino acid position numbering of AsCpfl (Acidaminococcus sp. BV3L6).

[00307] In certain embodiments, the Cpfl enzyme is modified by mutation of one or more residues including but not limited positions K15, R18, K26, R34, R43, K48, K51, K56, K87, K88, D90, K96, K106, K107, K120, Q125, K143, R186, K187, R202, K210, K235, K296, K298, K3I4, K320, K326, K397, K444, K449, E454, A483, E491, K527, K541, K581, R583, K589,

K595, K597, K613, K624, K635, K639, K656, K660, K667, K671, K677, K719, K725, K730,

K763, K782, K791, R800, K809, K823, R833, K834, K839, K852, K858, K859, K869, K871,

R872, K877, K905, R918, R921, K932, I960, K962, R964, R968, K.978, K981, K1013, R1016,

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K1021, ΚΙ029, K1034, K1041, K1065, K1084, and/or K1098 with reference to amino acid position numbering of FnCpfl (Francisella novicida U112).

[00308] In certain embodiments, the Cpfl enzyme is modified by mutation of one or more residues including but not limited positions K15, R18, K26, K34, R43, K48, K51, R56, K83, K84, R86, K92, R102, K103, K116, K12I, R158, EI59, R174, R182, K206, K25I, K253, K269, K271, K278, P342, K380, R385, K390, K415, K421, K457, K471, A506, R508, K514, K520,

K522, K538, Y548, K560, K564, K580, K584, K591, K595, K601, K634, K640, R645, K679,

K689, K707, T716, K725, R737, R747, R748, K753, K768, K774, K775, K785, K787, R788,

Q793, K821, R833, R836, K847, K879, K881, R883, R887, K897, K900, K932, R935, K940,

K948, K953, K960, K984, K1003, K1017, R1033, K1I21, R1138, R1165, K1190, KI199, and/or K1208 with reference to amino acid position numbering of Lb Cpfl (Lachnospiraceae bacterium ND2006).

[00309] In certain embodiments, the enzyme is modified by mutation of one or more residues including but not limited positions K14, RI7, R25, K33, M42, Q47, K50, D55, K85, N86, K88, K94, R104, K105, K118, K123, K13L R174, K175, R190, R198, 1221, K267, Q269, K285,

K291, K297, K357, K403, K409, K414, K448, K460, K501, K515, K550, R552, K558, K564,

K566, K582, K593, K604, K608, K623, K627, K633, K637, E643, K780, Y787, K792, K830,

Q846, K858, K867, K876, K890, R900, K901, M906, K921, K927, K928, K937, K939, R940,

K945, Q975, R987, R990, K1001, R1034, Γ1036, R1038, R1042, KI052, KIO55, K1087, RI090, K1095, Nil03, K1108, Kill5, K1139, K1158, R1172, K1188, K1276, R1293, A1319, K1340, K1349, and/or K1356 with reference to amino acid position numbering of MbCpfl (Moraxella bovoculi 237).

[00310] In any of the non-naturally-occurring CRISPR enzymes:

a single mismatch may exist between the target and a corresponding sequence of the one or more off-target loci; and/or two, three or four or more mismatches may exist between the target and a corresponding sequence of the one or more off-target loci, and/or wherein in (ii) said two, three or four or more mismatches are contiguous.

[00311] In any of the non-naturally-occurring CRISPR enzymes the enzyme In the CRISPR complex may have reduced capability of modifying one or more off-target loci as compared to

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PCT/US2016/038181 an unmodified enzyme and wherein the enzyme in the CRISPR complex has increased capability of modifying the said target loci as compared to an unmodified enzyme.

[00312] In any of the non-naturally-occurring CRISPR enzymes, when in the CRISPR complex the relative difference of the modifying capability of the enzyme as between target and at least one off-target locus may be increased compared to the relative difference of an unmodified enzyme.

[00313] In any of the non-naturally-occurring CRISPR enzymes, the CRISPR enzyme may comprise one or more additional mutations, wherein the one or more additional mutations are in one or more catalytically active domains.

[00314] In such non-naturally-occurring CRISPR enzymes, the CRISPR enzyme may have reduced or abolished nuclease activity compared with an enzyme lacking said one or more additional mutations.

[00315] In some such non-naturally-occurring CRISPR enzymes, the CRISPR enzyme does not direct cleavage of one or other DNA strand at the location of the target sequence.

[00316] Where the CRISPR enzyme comprises one or more additional mutations in one or more catalytically active domains, the one or more additional mutations may be in a catalytically active domain of the CRISPR enzyme compri sing RuvCI, RuvCII or RuvCIII.

[00317] Without being bound by theory, in an aspect of the invention, the methods and mutations described provide for enhancing conformational rearrangement of CRISPR enzyme domains (e.g. Cpfl domains) to positions that results in cleavage at on-target sits and avoidance of those conformational states at off-target sites. CRISPR enzymes cleave target DNA in a series of coordinated steps. First, the PAM-interacting domain recognizes the PAM sequence 5’ of the target DNA. After PAM binding, the first 10-12 nucleotides of the target sequence (seed sequence) are sampled for gRNA:DNA complementarity, a process dependent on DNA duplex separation. If the seed sequence nucleotides complement the gRNA, the remainder of DNA is unwound and the full length of gRNA hybridizes with the target DNA strand, nt-grooves may stabilize the non-targeted DNA strand and facilitate unwinding through non-specific interactions with positive charges of the DNA phosphate backbone. RNA:cDNA and CRISPR enzymemcDNA interactions drive DNA unwinding in competition against cDNAmcDNA rehybridization. Other CRISPR enzyme domains may affect the conformation of nuclease domains as well, for example linkers connecting different domains. Accordingly, the methods

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PCT/US2016/038181 and mutations provided encompass, without limitation, RuvCI, RuvCIII, RuvCIII and linkers. Conformational changes in for instance Cpfl brought about by target DNA binding, including seed sequence interaction, and interactions with the target and non-target DNA strand determine whether the domains are positioned to trigger nuclease activity. Thus, the mutations and methods provided herein demonstrate and enable modifications that go beyond PAM recognition and RNA-DNA. base pairing, [00318] In an aspect, the invention provides CRISPR nucleases as defined herein, such as Cpfl, that comprise an improved equilibrium towards conformations associated with cleavage activity when involved in on-target interactions and/or improved equilibrium away from conformations associated with cleavage activity when involved in off-target interactions. In one aspect, the invention provides Cas (e.g. Cpfl) nucleases with improved proof-reading function, i.e. a Cas (e.g. Cpfl) nuclease which adopts a conformation comprising nuclease activity at an on-target site, and which conformation has increased unfavorability at an off-target site, Sternberg et al., Nature 527(7576):110-3, doi: 10.1038/natureI5544, published online 28 October 2015. Epub 2015 Oct 28, used Forster resonance energy transfer FRET) experiments to detect relative orientations of the Cas (e.g. Cpfl) catalytic domains when associated with on- and off-target DNA, and which may be extrapolated to the CRISPR enzymes of the present invention (e.g. Cpfl).

[00319] The invention further provides methods and mutations for modulating nuclease activity and/or specificity using modified guide RNAs, As discussed, on-target nuclease activity can be increased or decreased. Also, off-target nuclease activity can be increased or decreased. Further, there can be increased or decreased specificity as to on-target activity vs. off-target activity. Modified guide RNAs include, without limitation, truncated guide RNAs, dead guide RNAs, chemically modified guide RNAs, guide RNAs associated with functional domains, modified guide RNAs comprising functional domains, modified guide RNAs comprising aptamers, modified guide RNAs comprising adapter proteins, and guide RNAs comprising added or modified loops. In some embodiments, one or more functional domains are associated with an dead gRNA (dRNA). In some embodiments, a dRNA complex with the CRISPR enzyme directs gene regulation by a functional domain at on gene locus while an gRNA directs DNA cleavage by the CRISPR enzyme at another locus. In some embodiments, dRNAs are selected to maximize selectivity of regulation for a gene locus of interest compared to off-target regulation.

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In some embodiments, dRNAs are selected to maximize target gene regulation and minimize target cleavage.

[00320] For the purposes of the following discussion, reference to a functional domain could be a functional domain associated with the CRISPR enzyme or a functional domain associated with the adaptor protein.

[00321] In the practice of the invention, loops of the gRNA may be extended, without colliding with the Cas (e.g. Cpfl) protein by the insertion of distinct RNA loop(s) or disctinct sequence(s) that may recruit adaptor proteins that can bind to the distinct RNA loop(s) or distinct sequence(s). The adaptor proteins may include but are not limited to orthogonal RNA-binding protein / aptamer combinations that exist within the diversity of bacteriophage coat proteins. A list of such coat proteins includes, but is not limited to: Qp, F2, GA, fr, JP501, M12, R17, BZ13, JP34, JP500, KUI, Mil, MX1, TW18, VK, SP, FI, ID2, NL95, TW19, AP205, φθ>5, 4>Cb8r, 4>Cbl2r, (|)Cb23r, 7s and PRR1. These adaptor proteins or orthogonal RNA binding proteins can further recruit effector proteins or fusions which comprise one or more functional domains. In some embodiments, the functional domain may be selected from the group consisting of: transposase domain, integrase domain, recombinase domain, resolvase domain, invertase domain, protease domain, DNA methyltransferase domain, DNA hydroxylmethylase domain, DNA demethylase domain, histone acetylase domain, histone deacetylases domain, nuclease domain, repressor domain, activator domain, nuclear-localization signal domains, transcriptionregulatory protein (or transcription complex recruiting) domain, cellular uptake activity associated domain, nucleic acid binding domain, antibody presentation domain, histone modifying enzymes, recruiter of histone modifying enzymes; inhibitor of histone modifying enzymes, histone methyl transferase, histone demethylase, histone kinase, histone phosphatase, histone ribosylase, histone deribosylase, histone ubiquitinase, histone deubiquitinase, histone biotinase and histone tail protease. In some preferred embodiments, the functional domain is a transcriptional activation domain, such as, without limitation, VP64, p65, MyoDl, 11ST’ i, RTA, SET7/9 or a histone acetyltransferase. In some embodiments, the functional domain is a transcription repression domain, preferably KRAB. In some embodiments, the transcription repression domain is SID, or concatemers of SID (eg SID4X). In some embodiments, the functional domain is an epigenetic modifying domain, such that an epigenetic modifying enzyme is provided. In some embodiments, the functional domain is an activation domain, which may be

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PCT/US2016/038181 the P65 activation domain. In some embodiments, the functional domain is a deaminase, such as a cytidine deaminase. Cytidine deaminese may be directed to a target nucleic acid to where it directs conversion of cytidine to uridine, resulting in C to T substitutions (G to A on the complementary strand). In such an embodiment, nucleotide substitutions can be effected without DNA cleavage.

[00322] In an aspect, the invention also provides methods and mutations for modulating Cas (e.g. Cpfl) binding activity and/or binding specificity. In certain embodiments Cas (e.g. Cpfl) proteins lacking nuclease activity are used. In certain embodiments, modified guide RNAs are employed that promote binding but not nuclease activity of a Cas (e.g. Cpfl) nuclease. In such embodiments, on-target binding can be increased or decreased. Also, in such embodiments offtarget binding can be increased or decreased. Moreover, there can be increased or decreased specificity as to on-target binding vs. off-target binding.

[00323] In particular embodiments, a reduction of off-target cleavage is ensured by destabilizing strand separation, more particularly by introducing mutations in the Cpfl enzyme decreasing the positive charge in the DNA interacting regions (as described herein and further exemplified for Cas9 by Slaymaker et al. 2016 (Science, 1;351(6268):84-8). In further embodiments, a reduction of off-target cleavage is ensured by introducing mutations into Cpfl enzyme which affect the interaction between the target strand and the guide RNA sequence, more particularly disrupting interactions between Cpfl and the phosphate backbone of the target DNA strand in such a way as to retain target specific activity but reduce off-target activity (as described for Cas9 by Kleinstiver et al. 2016, Nature, 28;529(7587):490-5). In particular embodiments, the off-target activity is reduced by way of a modified Cpfl wherein both interaction with target strand and non-target strand are modified compared to wild-type Cpfl. [00324] The methods and mutations which can be employed in various combinations to increase or decrease activity and/or specificity of on-target vs. off-target activity, or increase or decrease binding and/or specificity of on-target vs. off-target binding, can be used to compensate or enhance mutations or modifications made to promote other effects. Such mutations or modifications made to promote other effects include mutations or modification to the Cas (e.g. Cpfl) and or mutation or modification made to a guide RNA. In certain embodiments, the methods and mutations are used with chemically modified guide RNAs. Examples of guide RNA chemical modifications include, without limitation, incorporation of 2'-O-methyI (M), 2-087

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PCT/US2016/038181 methyl 3'phosphorothioate (MS), or 2'-O-methyl 3'thioPACE (MSP) at one or more terminal nucleotides. Such chemically modified guide RNAs can comprise increased stability and increased activity as compared to unmodified guide RNAs, though on-target vs. off-target specificity is not predictable, (See, Hendel, 2015, Nat Biotechnol. 33(9):985-9, doi: 10.1038/nbt.3290, published online 29 June 2015). Chemically modified guide RNAs futher include, without limitation, RNAs with phosphorothioate linkages and locked nucleic acid (ENA) nucleotides comprising a methylene bridge between the 2' and 4' carbons of the ribose ring. The methods and mutations of the invention are used to modulate Cas (e.g. Cpfl) nuclease activity and/or binding with chemically modified guide RNAs.

[00325] In an aspect, the invention provides methods and mutations for modulating binding and/or binding specificity of Cas (e.g. Cpfl) proteins according to the invention as defined herein comprising functional domains such as nucleases, transcriptional activators, transcriptional repressors, and the like. For example, a Cas (e.g. Cpfl) protein can be made nuclease-null, or having altered or reduced nuclease activity by introducing mutations such as for instance Cpfl mutations described herein elsewhere, and include for instance D917A, El006A, El028A, D1227A, D1255A, N1257A, D917A, E1006A, E1028A, D1227A, D1255A and N1257A with reference to the amino acid positions in the FnCpflp RuvC domain, or for instance N580A, N584A, T587A, W609A, D610A, K613A, E614A, D616A, K624A, D625A, K627A and Y629A with reference to the putative second nuclease domain as described herein elsewhere. Nuclease deficient Cas (e.g. Cpfl) proteins are useful for RNA-guided target sequence dependent delivery of functional domains. The invention provides methods and mutations for modulating binding of Cas (e.g. Cpfl) proteins. In one embodiment, the functional domain comprises VP64, providing an RNA-guided transcription factor. In another embodiment, the functional domain comprises Fok I, providing an RNA-guided nuclease activity. Mention is made of U.S. Pat. Pub. 2014/0356959, U.S. Pat. Pub. 2014/0342456, U.S. Pat. Pub. 2015/0031132, and Mali, P. et al., 2013, Science 339(6121):823-6, doi: 10.1126/seienee. 1232033, published online 3 January 2013 and through the teachings herein the invention comprehends methods and materials of these documents applied in conjunction with the teachings herein. In certain embodiments, on-target binding is increased. In certain embodiments, off-target binding is decreased. In certain embodiments, on-target binding is decreased. In certain embodiments, off-target binding is

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PCT/US2016/038181 increased. Accordingly, the invention also provides for increasing or decreasing specificity of on-target binding vs. off-target binding of functionalized Cas (e.g. Cpfl) binding proteins.

[00326] The use of Cas (e.g. Cpfl) as an RNA-guided binding protein is not limited to nuclease-null Cas (e.g, Cpfl). Cas (e.g, Cpfl) enzymes comprising nuclease activity can also function as RNA-guided binding proteins when used with certain guide RNAs. For example short guide RNAs and guide RNAs comprising nucleotides mismatched to the target can promote RNA directed Cas (e.g. Cpfl) binding to a target sequence with little or no target cleavage. (See, e.g., Dahlman, 2015, Nat Biotechnol. 33(11):1159-1161, doi: 10.1038/nbt.3390, published online 05 October 2015). In an aspect, the invention provides methods and mutations for modulating binding of Cas (e.g. Cpfl) proteins that comprise nuclease activity. In certain embodiments, on-target binding is increased. In certain embodiments, off-target binding is decreased. In certain embodiments, on-target binding is decreased. In certain embodiments, offtarget binding is increased. In certain embodiments, there is increased or decreased specificity of on-target binding vs. off-target binding. In certain embodiments, nuclease activity of guide RNA-Cas (e.g. Cpfl) enzyme is also modulated.

[00327] RNA-DNA heteroduplex formation is important for cleavage activity and specificity throughout the target region, not only the seed region sequence closest to the PAM. Thus, truncated guide RNAs show reduced cleavage activity and specificity. In an aspect, the invention provides method and mutations for increasing activity and specificity of cleavage using altered guide RNAs, [00328] The invention also demonstrates that modifications of Cas (e.g. Cpfl) nuclease specificity can be made in concert with modifications to targeting range. Cas (e.g. Cpfl) mutants can be designed that have increased target specificity as well as accommodating modifications in PAM recognition, for example by choosing mutations that alter PAM specificity and combining those mutations with nt-groove mutations that increase (or if desired, decrease) specificity for on-target sequences vs. off-target sequences. In one such embodiment, a PI domain residue is mutated to accommodate recognition of a desired PAM sequence while one or more nt-groove amino acids is mutated to alter target specificity. The Cas (e.g. Cpfl) methods and modifications described herein can be used to counter loss of specificity resulting from alteration of PAM recognition, enhance gain of specificity resulting from alteration of PAM recognition, counter

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PCT/US2016/038181 gain of specificity resulting from alteration of PAM recognition, or enhance loss of specificity resulting from alteration of PAM recognition.

[00329] The methods and mutations can be used with any Cas (e.g. Cpfl) enzyme with altered PAM recognition. Non-limiting examples of PAMs included are as described herein elsewhere. [00330] In further embodiments, the methods and mutations are used modified proteins. [00331] In any of the non-naturally-occurring CRISPR. enzymes, the CRISPR enzyme may comprise one or more heterologous functional domains.

[00332] The one or more heterologous functional domains may comprise one or more nuclear localization signal (NTS) domains. The one or more heterologous functional domains may comprise at least two or more NLSs.

[00333] The one or more heterologous functional domains may comprise one or more transcriptional activation domains. A transcriptional activation domain may comprise VP64. [00334] The one or more heterologous functional domains may comprise one or more transcriptional repression domains. A transcriptional repression domain may comprise a KRAB domain or a SID domain.

[00335] The one or more heterologous functional domain may comprise one or more nuclease domains. The one or more nuclease domains may comprise Foki.

[00336] The one or more heterologous functional domains may have one or more of the following activities: methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, nuclease activity, single-strand RNA cleavage activity, double-strand RNA cleavage activity, single-strand DNA cleavage activity, double-strand DNA cleavage activity and nucleic acid binding activity.

[00337] The at least one or more heterologous functional domains may be at or near the amino-terminus of the enzyme and/or at or near the carboxy-terminus of the enzyme.

[00338] The one or more heterologous functional domains may be fused to the CRISPR enzyme, or tethered to the CRISPR. enzyme, or linked to the CRISPR enzyme by a linker moiety. [00339] In any of the non-naturally-occurring CRISPR enzymes, the CRISPR enzyme may comprise a CRISPR enzyme from an organism from a genus comprising Francisella iuiarensis 1, Francisella tuiarensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclaslicus, Peregrinibacteria bacterium GW2011 GWA2 33 10,

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Parcubacteria bacterium GW2011 GWC2 44 17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, or Porphyromonas macacae (e.g., a Cpfl of one of these organisms modified as described herein), and may include further mutations or alterations or be a chimeric Cas (e.g. Cpfl), [00340] In any of the non-naturally-occurring CRISPR enzymes, the CRISPR enzyme may comprise a chimeric Cas (e.g. Cpfl) enzyme comprising a first fragment from a first Cas (e.g. Cpfl) ortholog and a second fragment from a second Cas (e.g. Cpfl) ortholog, and the first and second Cas (e.g. Cpfl) orthologs are different. At least one of the first and second Cas (e.g. Cpfl) orthologs may comprise a Cas (e.g. Cpfl) from an organism comprising Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium

GW2011 GWA2 33 10, Parcubacteria bacterium GW2011 GWC2 44 17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, or Porphyromonas macacae.

[00341] In any of the non-naturally-occurring CRISPR enzymes, a nucleotide sequence encoding the CRISPR enzyme may be codon optimized for expression in a eukaryote.

[00342] In any of the non-naturally-occurring CRISPR enzymes, the cell may be a eukaryotic cell or a prokaryotic cell; wherein the CRISPR complex is operable in the cell, and whereby the enzyme of the CRISPR complex has reduced capability of modifying one or more off-target loci of the ceil as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme.

[00343] Accordingly, in an aspect, the invention provides a eukaryotic cell comprising the engineered CRISPR protein or the system as defined herein.

[00344] In certain embodiments, the methods as described herein may comprise providing a Cas (e.g. Cpfl) transgenic cell in which one or more nucleic acids encoding one or more guide RNAs are provided or introduced operably connected in the cell with a regulatory' element

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PCT/US2016/038181 comprising a promoter of one or more gene of interest. As used herein, the term “Cas transgenic cell” refers to a cell, such as a eukaryotic ceil, in which a Cas gene has been genomically integrated. The nature, type, or origin of the cell are not particularly limiting according to the present invention. Also the way how the Cas transgene is introduced in the cell is may vary and can be any method as is known in the art. In certain embodiments, the Cas transgenic cell is obtained by introducing the Cas transgene in an isolated cell. In certain other embodiments, the Cas transgenic cell is obtained by isolating cells from a Cas transgenic organism. By means of example, and without limitation, the Cas transgenic cell as referred to herein may be derived from a Cas transgenic eukaryote, such as a Cas knock-in eukaryote. Reference is made to WO 2014/093622 (PCT/US13/74667), incorporated herein by reference. Methods of US Patent Publication Nos. 20120017290 and 20110265198 assigned to Sangamo BioSciences, Inc. directed to targeting the Rosa locus may be modified to utilize the CRISPR Cas system of the present invention. Methods of US Patent Publication No. 20130236946 assigned to Cellectis directed to targeting the Rosa locus may also be modified to utilize the CRISPR Cas system of the present invention. By means of further example reference is made to Platt et. al. (Cell; 159(2):440-455 (2014)), describing a Cas9 knock-in mouse, which is incorporated herein by reference, and which can be extrapolated to the CRISPR enzymes of the present invention as defined herein. The Cas transgene can further comprise a Lox-Stop-polyA-Lox(LSL) cassette thereby rendering Cas expression inducible by Cre recombinase. Alternatively, the Cas transgenic cell may be obtained by introducing the Cas transgene in an isolated cell. Delivery systems for transgenes are well known in the art. By means of example, the Cas transgene maybe delivered in for instance eukaryotic cell by means of vector (e.g,, AAV, adenovirus, lentivirus) and/or particle and/or nanoparticle delivery-, as also described herein elsewhere. [00345] It will be understood by the skilled person that the cell, such as the Cas transgenic cell, as referred to herein may comprise further genomic alterations besides having an integrated Cas gene or the mutations arising from the sequence specific action of Cas when complexed with RNA capable of guiding Cas to a target locus, such as for Instance one or more oncogenic mutations, as for instance and without limitation described in Platt et al. (2014), Chen et al., (2014) or Kumar et al.. (2009).

[00346] The invention also provides a composition comprising the engineered CRISPR protein as described herein, such as described in this section.

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PCT/US2016/038181 [00347] The invention also provides a non-naturally-occurring, engineered composition comprising a CRISPR-Cas complex comprising any the non-naturally-occurring CRISPR enzyme described above.

[00348] In an aspect, the invention provides in a vector system comprising one or more vectors, wherein the one or more vectors comprises:

a) a first regulatory⁷ element operably linked to a nucleotide sequence encoding the engineered CRISPR protein as defined herein; and optionally

b) a second regulatory element operably linked to one or more nucleotide sequences encoding one or more nucleic acid molecules comprising a guide RNA comprising a guide sequence, a direct repeat sequence , optionally wherein components (a) and (b) are located on same or different vectors.

[00349] The invention also provides a non-naturally-occurring, engineered composition comprising:

a delivery system operably configured to deliver CRISPR-Cas complex components or one or more polynucleotide sequences comprising or encoding said components into a cell, and wherein said CRISPR-Cas complex is operable in the cell,

CRISPR-Cas complex components or one or more polynucleotide sequences encoding for transcription and/or translation in the cell the CRISPR-Cas complex components, comprising:

(I) the non-naturally-occumng CRISPR enzyme (e.g. engineered Cpfl) as described herein;

(Π) CRISPR-Cas guide RNA comprising: the guide sequence, and a direct repeat sequence, wherein the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme.

[00350] In an aspect, the invention also provides in a system comprising the engineered CRISPR protein as described herein, such as described in this section.

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PCT/US2016/038181 [00351] In any such compositions, the delivery system may comprise a yeast system, a lipofection system, a microinjection system, a biolistic system, virosomes, liposomes, immunoliposomes, polycations, lipidmucleic acid conjugates or artificial virions, as defined herein elsewhere, [00352] In any such compositions, the delivery system may comprise a vector system comprising one or more vectors, and wherein component (II) comprises a first regulatory element operably linked to a polynucleotide sequence which comprises the guide sequence, the direct repeat sequence and optionally, and wherein component (I) comprises a second regulatory element operably linked to a polynucleotide sequence encoding the CRISPR enzyme.

[00353] In any such compositions, the delivery system may comprise a vector system comprising one or more vectors, and wherein component (II) comprises a first regulatory element operably linked to the guide sequence and the direct repeat sequence, and wherein component (I) comprises a second regulator)/ element operably linked to a polynucleotide sequence encoding the CRISPR enzyme.

[00354] In any such compositions, the composition may comprise more than one guide RNA, and each guide RNA has a different target whereby there is multiplexing.

[00355] In any such compositions, the polynucleotide sequence(s) may be on one vector. [00356] The invention also provides an engineered, non-naturally occurring Clustered Regularly Interspersed Short Palindromic Repeats (CRISPRj-CRISPR associated (Cas) (CRISPR-Cas) vector system comprising one or more vectors comprising:

a) a first regulatory element operably linked to a nucleotide sequence encoding a non-naturallyoccurring CRISPR enzyme of any one of the inventive constructs herein; and

b) a second regulatory element operably linked to one or more nucleotide sequences encoding one or more of the guide RNAs, the guide RNA comprising a guide sequence, a direct repeat sequence, wherein:

components (a) and (b) are located on same or different vectors, the CRISPR complex is formed;

the guide RNA targets the target polynucleotide loci and the enzyme alters the polynucleotide loci, and

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PCT/US2016/038181 the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme.

[00357] In such a system, component (II) may comprise a first regulatory element operably linked to a polynucleotide sequence which comprises the guide sequence, the direct repeat sequence, and wherein component (II) may comprise a second regulatory' element operably linked to a polynucleotide sequence encoding the CRISPR enzyme. In such a system, where applicable the guide RNA may comprise a chimeric RNA.

[00358] In such a system, component (I) may comprise a first regulatory element operably linked to the guide sequence and the direct repeat sequence, and wherein component (II) may comprise a second regulatory' element operably linked to a polynucleotide sequence encoding the CRISPR enzyme. Such a system may comprise more than one guide RNA, and each guide RNA has a different target whereby there is multiplexing. Components (a) and (b) may be on the same vector.

[00359] In any such systems comprising vectors, the one or more vectors may comprise one or more viral vectors, such as one or more retrovirus, lentivirus, adenovirus, adeno-associated virus or herpes simplex virus.

[00360] In any such systems comprising regulatory elements, at least one of said regulatory elements may comprise a tissue-specific promoter. The tissue-specific promoter may direct expression in a mammalian blood cell, in a mammalian liver cell or in a mammalian eye.

[00361] In any of the above-described compositions or systems the direct repeat sequence, may comprise one or more protein-interacting RNA aptamers. The one or more aptamers may be located in the tetraloop. The one or more aptamers may be capable of binding MS2 bacteriophage coat protein.

[00362] In any of the above-described compositions or systems the cell may a eukaryotic cell or a prokaryotic cell, wherein the CRISPR complex is operable in the cell, and whereby the enzyme of the CRISPR complex has reduced capability of modifying one or more off-target loci of the cell as compared to an unmodified enzyme and/or whereby the enzyme in the CRISPR complex has increased capability of modifying the one or more target loci as compared to an unmodified enzyme.

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PCT/US2016/038181 [00363] The invention also provides a CRISPR complex of any of the above-described compositions or from any of the above-described systems.

[00364] The invention also provides a method of modifying a locus of interest in a cell comprising contacting the cell with any of the herein-described engineered CRISPR enzymes (e.g. engineered Cpfl), compositions or any of the herein-described systems or vector systems, or wherein the cell comprises any of the herein-described CRISPR complexes present within the cell. In such methods the cell may be a prokaryotic or eukaryotic cell, preferably a eukaryotic cell. In such methods, an organism may comprise the cell. In such methods the organism may not be a human or other animal.

[00365] Any such method may be ex vivo or in vitro.

[00366] In certain embodiments, a nucleotide sequence encoding at least one of said guide RNA or Cas protein is operably connected in the cell with a regulatory element comprising a promoter of a gene of interest, whereby expression of at least one CRISPR-Cas system component is driven by the promoter of the gene of interest, “operably connected” is intended to mean that the nucleotide sequence encoding the guide RNA and/or the Cas is linked to the regulatory element(s) in a manner that allows for expression of the nucleotide sequence, as also referred to herein elsewhere. The term “regulatory element” is also described herein elsewhere. According to the invention, the regulatory element comprises a promoter of a gene of interest, such as preferably a promoter of an endogenous gene of interest. In certain embodiments, the promoter is at its endogenous genomic location. In such embodiments, the nucleic acid encoding the CRISPR and/or Cas is under transcriptional control of the promoter of the gene of interest at its native genomic location. In certain other embodiments, the promoter is provided on a (separate) nucleic acid molecule, such as a vector or plasmid, or other extrachromosomal nucleic acid, i.e. the promoter is not provided at its native genomic location. In certain embodiments, the promoter is genomically integrated at a non-native genomic location.

[00367] Any such method, said modifying may comprise modulating gene expression. Said modulating gene expression may comprise activating gene expression and/or repressing gene expression. Accordingly, in an aspect, the invention provides in a method of modulating gene expression, wherein the method comprises introducing the engineered CRISPR protein or system as described herein into a cell.

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PCT/US2016/038181 [00368] The invention also provides a method of treating a disease, disorder or infection in an individual in need thereof comprising administering an effective amount of any of the engineered CRISPR enzymes (e.g. engineered Cpfl), compositions, systems or CRISPR complexes described herein. The disease, disorder or infection may comprise a viral infection. The viral infection may be HBV.

[00369] The invention also provides the use of any of the engineered CRISPR enzymes (e.g. engineered Cpfl), compositions, systems or CRISPR complexes described above for gene or genome editing.

[00370] The invention also provides a method of altering the expression of a genomic locus of interest in a mammalian cell comprising contacting the cell with the engineered CRISPR enzymes (e.g. engineered Cpfl), compositions, systems or CRISPR complexes described herein and thereby delivering the CRISPR-Cas (vector) and allowing the CRISPR-Cas complex to form and bind to target, and determining if the expression of the genomic locus has been altered, such as increased or decreased expression, or modification of a gene product.

[00371] The invention also provides any of the engineered CRISPR enzymes (e.g. engineered Cpfl), compositions, systems or CRISPR complexes described above for use as a therapeutic. The therapeutic may be for gene or genome editing, or gene therapy.

[00372] In certain embodiments the activity of engineered CRISPR enzymes (e.g. engineered Cpfl) as described herein comprises genomic DNA cleavage, optionally resulting in decreased transcription of a gene.

[00373] In an aspect, the invention provides in an isolated cell having altered expression of a genomic locus from the method s as described herein, wherein the altered expression is in comparison with a cell that has not been subjected to the method of altering the expression of the genomic locus. In a related aspect, the invention provides in a cell line established from such cell.

[00374] In one aspect, the invention provides a method of modifying an organism or a nonhuman organism by manipulation of a target sequence in a genomic locus of interest of for instance an HSC(hematopoietic stem cell), e.g., wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, comprising:

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PCT/US2016/038181 delivering to an HSC, e.g., via contacting an HSC with a particle containing, a nonnaturally occurring or engineered composition comprising:

I. a CRISPR-Cas system guide RNA (gRNA) polynucleotide sequence, comprising:

(a) a guide sequence capable of hybridizing to a target sequence in a HSC, (b) a direct repeat sequence, and

II. a CRISPR enzyme, optionally comprising at least one or more nuclear localization sequences, wherein, the guide sequence directs sequence-specific binding of a CRISPR complex, to the target sequence, and wherein the CRISPR complex comprises the CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence,, and the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the method may include isolating or obtaining HSC from the organism or nonhuman organism, optionally expanding the HSC population, performing contacting of the particle(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally administering modified HSCs to the organism or non-human organism.

[00375] In one aspect, the invention provides a method of modifying an organism or a nonhuman organism by manipulation of a target sequence in a genomic locus of interest of for instance a HSC, e.g., wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, comprising: delivering to an HSC, e.g., via contacting an HSC with a particle containing, a non-naturally occurring or engineered composition comprising: I. (a) a guide sequence capable of hybridizing to a target sequence in a HSC, and (b) at least one or more direct repeat sequences, and II. a CRISPR enzyme optionally having one or more NLSs,, and the guide sequence directs sequence98

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PCT/US2016/038181 specific binding of a CRISPR complex to the target sequence, and wherein the CRISPR complex comprises the CRISPR enzyme complexed with the guide sequence that is hybridized to the target sequence,; and the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the method may include isolating or obtaining HSC from the organism or nonhuman organism, optionally expanding the HSC population, performing contacting of the particle(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally administering modified HSCs to the organism or non-human organism.

[00376] The delivery can be of one or more polynucleotides encoding any one or more or all of the CRISPR-complex, advantageously linked to one or more regulatory elements for in vivo expression, e.g. via particle(s), containing a vector containing the polynucleotide(s) operably linked to the regulatory element(s). Any or all of the polynucleotide sequence encoding a CRISPR enzyme, guide sequence, direct repeat sequence, may be RNA. It will be appreciated that where reference is made to a polynucleotide, which is RNA and is said to ‘comprise’ a feature such a direct repeat sequence, the RNA sequence includes the feature. Where the polynucleotide is DNA and is said to comprise a feature such a direct repeat sequence, the DNA sequence is or can be transcribed into the RNA including the feature at issue. Where the feature is a protein, such as the CRISPR enzyme, the DNA or RNA sequence referred to is, or can be, translated (and in the case of DNA transcribed first), [00377] In certain embodiments the invention provides a method of modifying an organism, e.g., mammal including human or a non-human mammal or organism by manipulation of a target sequence in a genomic locus of interest of an HSC e.g., wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, comprising delivering, e.g., via contacting of a non-naturally occurring or engineered composition with the HSC, wherein the composition comprises one or more particles comprising viral, plasmid or nucleic acid molecule vector(s) (e.g. RNA) operably encoding a

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PCT/US2016/038181 composition for expression thereof, wherein the composition comprises: (A) I. a first regulatory element operably linked to a CRISPR-Cas system RNA polynucleotide sequence, wherein the polynucleotide sequence comprises (a) a guide sequence capable of hybridizing to a target sequence in a eukaryotic cell, (b) a direct repeat sequence and II. a second regulatory element operably linked to an enzyme-coding sequence encoding a CRISPR enzyme comprising at least one or more nuclear localization sequences (or optionally at least one or more nuclear localization sequences as some embodiments can involve no NLS), wherein (a), (h) and (c) are arranged in a 5’ to 3’ orientation, wherein components I and II are located on the same or different vectors of the system, wherein when transcribed and the guide sequence directs sequence-specific binding of a CRISPR complex to the target sequence, and wherein the CRISPR complex comprises the CRISPR enzyme complexed with the guide sequence that is hybridized to the target sequence, or (B) a non-naturally occurring or engineered composition comprising a vector system comprising one or more vectors comprising I, a first regulator)/ element operably linked to (a) a guide sequence capable of hybridizing to a target sequence in a eukaryotic cell, and (b) at least one or more direct repeat sequences, II. a second regulatory element operably linked to an enzyme-coding sequence encoding a CRISPR enzyme, and optionally, where applicable, wherein components I, and II are located on the same or different vectors of the system, wherein when transcribed and the guide sequence directs sequencespecific binding of a CRISPR complex to the target sequence, and wherein the CRISPR complex comprises the CRISPR enzyme complexed with the guide sequence that is hybridized to the target sequence; the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the method may include isolating or obtaining HSC from the organism or non-human organism, optionally expanding the HSC population, performing contacting of the particle(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally administering modified HSCs to the organism or non-human organism. In some embodiments, components I, II and III are located on the same vector. In other embodiments, components I and II are located on the same vector, while component III is located on another vector. In other embodiments,

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PCT/US2016/038181 components I and III are located on the same vector, while component II is located on another vector. In other embodiments, components II and III are located on the same vector, while component I is located on another vector. In other embodiments, each of components I, II and III is located on different vectors. The invention also provides a viral or plasmid vector system as described herein.

[00378] By manipulation of a target sequence. Applicants also mean the epigenetic manipulation of a target sequence. This may be f the chromatin state of a target sequence, such as by modification of the methylation state of the target sequence (i.e. addition or removal of methylation or methylation patterns or CpG islands), histone modification, increasing or reducing accessibility to the target sequence, or by promoting 3D folding. It will be appreciated that where reference is made to a method of modifying an organism or mammal including human or a non-human mammal or organism by manipulation of a target sequence in a genomic locus of interest, this may apply to the organism (or mammal) as a whole or just a single cell or population of cells from that organism (if the organism is multicellular). In the case of humans, for instance, Applicants envisage, inter alia, a single cell or a population of cells and these may preferably be modified ex vivo and then re-introduced. In this case, a biopsy or other tissue or biological fluid sample may be necessary. Stem cells are also particularly preferred in this regard. But, of course, in vivo embodiments are also envisaged. And the invention is especially advantageous as to HSCs.

[00379] The invention in some embodiments comprehends a method of modifying an organism or a non-human organism by manipulation of a first and a second target sequence on opposite strands of a DNA duplex in a genomic locus of interest in a HSC e.g., wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, comprising delivering, e.g., by contacting HSCs with particle(s) comprising a non-naturally occurring or engineered composition comprising :

I. a first CRISPR-Cas (e.g. Cpfl) system RNA polynucleotide sequence, wherein the first polynucleotide sequence comprises:

(a) a first guide sequence capable of hybridizing to the first target sequence, (b) a first direct repeat sequence, and

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II. a second CRISPR-Cas (e.g. Cpfl) system guide RNA polynucleotide sequence, wherein the second polynucleotide sequence comprises:

(a) a second guide sequence capable of hybridizing to the second target sequence, (b) a second direct repeat sequence, and

III. a polynucleotide sequence encoding a CRISPR enzyme comprising at least one or more nuclear localization sequences and comprising one or more mutations, wherein (a), (b) and (c) are arranged in a 5’ to 3’ orientation; or

IV. expression product(s) of one or more of I. to III., e.g., the the first and the second direct repeat sequence, the CRISPR enzyme, wherein when transcribed, the first and the second guide sequence directs sequencespecific binding of a first and a second CRISPR complex to the first and second target sequences respectively, wherein the first CRISPR complex comprises the CRISPR enzyme complexed with (1) the first guide sequence that is hybridized to the first target sequence, wherein the second CRISPR complex comprises the CRISPR enzyme complexed with (1) the second guide sequence that is hybridized to the second target sequence, wherein the polynucleotide sequence encoding a CRISPR enzyme is DNA or RNA, and wherein the first guide sequence directs cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directs cleavage of the other strand near the second target sequence inducing a double strand break, thereby modifying the organism or the non-human organism; and the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the method may include isolating or obtaining HSC from the organism or non-human organism, optionally expanding the HSC population, performing contacting of the particle(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally administering modified HSCs to the organism or non-human organism. In some methods of the invention any or all of the polynucleotide sequence encoding the CRISPR enzyme, the first and the second guide sequence, the first and the second direct repeat sequence. In further embodiments of the invention the

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PCT/US2016/038181 polynucleotides encoding the sequence encoding the CRISPR enzyme, the first and the second guide sequence, the first and the second direct repeat sequence, is/are RNA and are delivered via liposomes, nanoparticles, exosomes, microvesicles, or a gene-gun; but, it is advantageous that the delivery is via a particle. In certain embodiments of the invention, the first and second direct repeat sequence share 100% identity. In some embodiments, the polynucleotides may be comprised within a vector system comprising one or more vectors. In preferred embodiments, the first CRISPR enzyme has one or more mutations such that the enzyme is a complementary strand nicking enzyme, and the second CRISPR enzyme has one or more mutations such that the enzyme is a non-complementary strand nicking enzyme. Alternatively the first enzyme may be a non-complementary strand nicking enzyme, and the second enzyme may be a complementary strand nicking enzyme. In preferred methods of the invention the first guide sequence directing cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directing cleavage of the other strand near the second target sequence results in a. 5’ overhang. In embodiments of the invention the 5’ overhang is at most 200 base pairs, preferably at most 100 base pairs, or more preferably at most 50 base pairs. In embodiments of the invention the 5’ overhang is at least 26 base pairs, preferably at least 30 base pairs or more preferably 34-50 base pairs, [00380] The invention in some embodiments comprehends a method of modifying an organism or a non-human organism by manipulation of a first and a second target sequence on opposite strands of a DNA duplex in a genomic locus of interest in for instance a HSC e.g,, wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, comprising delivering, e.g., by contacting HSCs with particle(s) comprising a non-naturally occurring or engineered composition comprising :

I. a first regulatory' element operably linked to (a) a first guide sequence capable of hybridizing to the first target sequence, and (b) at least one or more direct repeat sequences,

Π. a. second regulatory element operably linked to (a) a second guide sequence capable of hybridizing to the second target sequence, and

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PCT/US2016/038181 (b) at least one or more direct repeat sequences,

III. a third regulatory element operably linked to an enzyme-coding sequence encoding a CRISPR enzyme (e.g. Cpfl), and

V. expression product(s) of one or more of I. to IV., e.g., the the first and the second direct repeat sequence, the CRISPR enzyme; wherein components I, Π, III and IV are located on the same or different vectors of the system, when transcribed, and the first and the second guide sequence direct sequence-specific binding of a first and a second CRISPR complex to the first and second target sequences respectively, wherein the first CRISPR complex comprises the CRISPR enzyme complexed with (1) the first guide sequence that is hybridized to the first target sequence, wherein the second CRISPR complex comprises the CRISPR enzyme complexed with the second guide sequence that is hybridized to the second target sequence, wherein the polynucleotide sequence encoding a CRISPR enzyme is DNA or RNA, and wherein the first guide sequence directs cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directs cleavage of the other strand near the second target sequence inducing a double strand break, thereby modifying the organism or the non-human organism; and the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the method may include isolating or obtaining HSC from the organism or non-human organism, optionally expanding the HSC population, performing contacting of the particle(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally admini stering modified HSCs to the organism or non-human organism.

[00381] The invention also provides a vector system as described herein. The system may comprise one, two, three or four different vectors. Components I, II, III and IV may thus be located on one, two, three or four different vectors, and all combinations for possible locations of the components are herein envisaged, for example: components I, II, III and IV can be located on the same vector; components I, II, III and IV can each be located on different vectors; components I, II, III and IV may be located on a total of two or three different vectors, with all

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PCT/US2016/038181 combinations of locations envisaged, etc. In some methods of the invention any or all of the polynucleotide sequence encoding the CRISPR enzyme, the first and the second guide sequence, the first and the second direct repeat sequence is/are RNA. In further embodiments of the invention the first and second direct repeat sequence share 100% identity. In preferred embodiments, the first CRISPR enzyme has one or more mutations such that the enzyme is a complementary strand nicking enzyme, and the second CRISPR enzyme has one or more mutations such that the enzyme is a non-complementary strand nicking enzyme. Alternatively the first enzyme may be a non-complementary strand nicking enzyme, and the second enzyme may be a complementary strand nicking enzyme. In a further embodiment of the invention, one or more of the viral vectors are delivered via liposomes, nanoparticles, exosomes, microvesicles, or a gene-gun; but, particle delivery is advantageous.

[00382] In preferred methods of the invention the first guide sequence directing cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directing cleavage of other strand near the second target sequence results in a 5’ overhang. In embodiments of the invention the 5’ overhang is at most 200 base pairs, preferably at most 100 base pairs, or more preferably at most 50 base pairs. In embodiments of the invention the 5’ overhang is at least 26 base pairs, preferably at least 30 base pairs or more preferably 34-50 base pairs.

[00383] The invention in some embodiments comprehends a method of modifying a genomic locus of interest in for instance HSC e.g., wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, by introducing into the HSC, e.g., by contacting HSCs with particle(s) comprising, a Cas protein having one or more mutations and two guide RNAs that target a first strand and a second strand of the DNA molecule respectively in the HSC, whereby the guide RNAs target the DNA molecule and the Cas protein nicks each of the first strand and the second strand of the DNA molecule, whereby a target in the HSC is altered; and, wherein the Cas protein and the two guide RNAs do not naturally occur together and the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the

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PCT/US2016/038181 method may include isolating or obtaining HSC from the organism or non-human organism, optionally expanding the HSC population, performing contacting of the particle(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally administering modified HSCs to the organism or non-human organism. In preferred methods of the invention the Cas protein nicking each of the first strand and the second strand of the DNA molecule results in a 5’ overhang. In embodiments of the invention the 5’ overhang is at most 200 base pairs, preferably at most 100 base pairs, or more preferably at most 50 base pairs. In embodiments of the invention the 5’ overhang is at least 26 base pairs, preferably at least 30 base pairs or more preferably 34-50 base pairs. In an aspect of the invention the Cas protein is codon optimized for expression in a eukaryotic cell, preferably a mammalian ceil or a human cell. Aspects of the invention relate to the expression of a gene product being decreased or a template polynucleotide being further introduced into the DNA molecule encoding the gene product or an intervening sequence being excised precisely by allowing the two 5’ overhangs to reanneal and ligate or the activity or function of the gene product being altered or the expression of the gene product being increased. In an embodiment of the invention, the gene product is a protein.

[00384] The invention in some embodiments comprehends a method of modifying a genomic locus of interest in for instance HSC e.g., wherein the genomic locus of interest is associated with a mutation associated with an aberrant protein expression or with a disease condition or state, by introducing into the HSC, e.g., by contacting HSCs with particie(s) comprising,

a) a first regulatory element operably linked to each of two CRISPR-Cas system guide RNAs that target a first strand and a second strand respectively of a double stranded DN A molecule of the HSC, and

b) a second regulatory element operably linked to a Cas (e.g. Cpfl) protein, or

c) expression product(s) of a) or b), wherein components (a) and (b) are located on same or different vectors of the system, whereby the guide RNAs target the DNA molecule of the HSC and the Cas protein nicks each of the first strand and the second strand of the DNA molecule of the HSC; and, wherein the Cas protein and the two guide RNAs do not naturally occur together; and the method may optionally include also delivering a HDR template, e.g., via the particle contacting the HSC containing or contacting the HSC with another particle containing, the HDR template wherein the HDR template provides

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PCT/US2016/038181 expression of a normal or less aberrant form of the protein; wherein “normal” is as to wild type, and “aberrant” can be a protein expression that gives rise to a condition or disease state; and optionally the method may include isolating or obtaining HSC from the organism or non-human organism, optionally expanding the HSC population, performing contacting of the particie(s) with the HSC to obtain a modified HSC population, optionally expanding the population of modified HSCs, and optionally administering modified HSCs to the organism or non-human organism. In aspects of the invention the guide RNAs may comprise a guide sequence fused to a direct repeat sequence. Aspects of the invention relate to the expression of a gene product being decreased or a template polynucleotide being further introduced into the DNA molecule encoding the gene product or an intervening sequence being excised precisely by allowing the two 5’ overhangs to reanneal and ligate or the activity or function of the gene product being altered or the expression of the gene product being increased . In an embodiment of the invention, the gene product is a protein. In preferred embodiments of the invention the vectors of the system are viral vectors. In a further embodiment, the vectors of the system are delivered via liposomes, nanoparticles, exosomes, microvesicles, or a gene-gun; and particles are preferred. In one aspect, the invention provides a method of modifying a target polynucleotide in a HSC. In some embodiments, the method comprises allowing a CRISPR complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized to a target sequence within said target polynucleotide, wherein said guide sequence is linked to a direct repeat sequence. In some embodiments, said cleavage comprises cleaving one or two strands at the location of the target sequence by said CRISPR enzyme. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expressed from a gene comprising the target sequence. In some embodiments, the method further comprises delivering one or more vectors or expression product(s) thereof, e.g., via particle(s), to for instance said HSC, wherein the one or more vectors drive expression of one or more of: the CRISPR enzyme, the guide sequence linked to the direct

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PCT/US2016/038181 repeat sequence. In some embodiments, said vectors are delivered to for instance the HSC in a subject. In some embodiments, said modifying takes place in said HSC in a cell culture. In some embodiments, the method further comprises isolating said HSC from a subject prior to said modifying. In some embodiments, the method further comprises returning said HSC and/or cells derived therefrom to said subject.

[00385] In one aspect, the invention provides a method of generating for instance a HSC comprising a mutated disease gene. In some embodiments, a disease gene is any gene associated with an increase in the risk of having or developing a di sease. In some embodiments, the method comprises (a) introducing one or more vectors or expression product(s) thereof, e.g., via particle(s), into a HSC, wherein the one or more vectors drive expression of one or more of: a CRISPR enzyme, a guide sequence linked to a direct repeat sequence; and (b) allowing a CRISPR complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said disease gene, wherein the CRISPR complex comprises the CRISPR enzyme complexed with the guide sequence that is hybridized to the target sequence within the target polynucleotide, and optionally, where applicable, thereby generating a HSC comprising a mutated disease gene. In some embodiments, said cleavage comprises cleaving one or two strands at the location of the target sequence by said CRISPR enzyme. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expression from a gene comprising the target sequence. In some embodiments the modified HSC is administered to an animal to thereby generate an animal model.

[00386] In one aspect, the invention provides for methods of modifying a target polynucleotide in for instance a HSC. In some embodiments, the method comprises allowing a CRISPR complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized to a target sequence within said target polynucleotide, wherein said guide sequence is linked to a direct repeat

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PCT/US2016/038181 sequence. In other embodiments, this invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell that arises from for instance an HSC. The method comprises increasing or decreasing expression of a target polynucleotide by using a CRISPR complex that binds to the polynucleotide in the HSC; advantageously the CRISPR complex is delivered via particle(s).

[00387] In some methods, a target polynucleotide can be inactivated to effect the modification of the expression in for instance an HSC. For example, upon the binding of a CRISPR complex to a target sequence in a cell, the target polynucleotide is inactivated such that the sequence is not transcribed, the coded protein is not produced, or the sequence does not function as the wild-type sequence does.

[00388] In some embodiments the RNA of the CRISPR-Cas system, e.g., the guide or gRNA, can be modified; for instance to include an aptamer or a functional domain. An aptamer is a synthetic oligonucleotide that binds to a specific target molecule, for instance a nucleic acid molecule that has been engineered through repeated rounds of in vitro selection or SELEX (systematic evolution of ligands by exponential enrichment) to bind to various molecular targets such as small molecules, proteins, nucleic acids, and even cells, tissues and organisms. Aptamers are useful in that they offer molecular recognition properties that rival that of antibodies. In addition to their discriminate recognition, aptamers offer advantages over antibodies including that they elicit little or no immunogenicity in therapeutic applications. Accordingly, in the practice of the invention, either or both of the enzyme or the RNA can include a functional domain.

[00389] In some embodiments, the functional domain is a transcriptional activation domain, preferably VP64. In some embodiments, the functional domain is a transcription repression domain, preferably KRAB. In some embodiments, the transcription repression domain is SID, or concatemers of SID (eg S1D4X). In some embodiments, the functional domain is an epigenetic modifying domain, such that an epigenetic modifying enzyme is provided. In some embodiments, the functional domain is an activation domain, which may be the P65 activation domain. In some embodiments, the functional domain comprises nuclease activity. In one such embodiment, the functional domain comprises Fokl..

[00390] The invention also provides an in vitro or ex vivo cell comprising any of the modified CRISPR enzymes, compositions, systems or complexes described above, or from any of the

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PCT/US2016/038181 methods described above. The cell may be a eukaryotic cell or a prokaryotic cell. The invention also provides progeny of such cells. The invention also provides a product of any such cell or of any such progeny, wherein the product is a product of the said one or more target loci as modified by the modified CRISPR enzyme of the CRISPR complex. The product may be a peptide, polypeptide or protein. Some such products may be modified by the modified CRISPR enzyme of the CRISPR complex. In some such modified products, the product of the target locus is physically distinct from the product of the said target locus which has not been modified by the said modified CRISPR enzyme.

[00391] The invention also provides a polynucleotide molecule comprising a polynucleotide sequence encoding any of the non-naturally-occurring CRISPR enzymes described above.

[00392] Any such polynucleotide may further comprise one or more regulator}' elements which are operably linked to the polynucleotide sequence encoding the non-naturally-occurring CRI SPR enzyme.

[00393] In any such polynucleotide which comprises one or more regulator}’ elements, the one or more regulatory elements may be operably configured for expression of the non-naturallyoccurring CRISPR enzyme in a eukaryotic cell. The eukaryotic cell may be a human cell. The eukaryotic cell may be a rodent cell, optionally a mouse cell. The eukaryotic cell may be a yeast cell. The eukaryotic cell may be a Chinese hamster ovary (CHO) cell. The eukaryotic cell may be an insect cell.

[00394] In any such polynucleotide which comprises one or more regulatory elements, the one or more regulatory elements may be operably configured for expression of the non-naturallyoccurring CRISPR enzyme in a prokaryotic cell.

[00395] In any such polynucleotide which comprises one or more regulatory elements, the one or more regulatory elements may operably configured for expression of the non-naturallyoccurring CRISPR enzyme in an in vitro system.

[00396] The invention also provides an expression vector comprising any of the abovedescribed polynucleotide molecules. The invention also provides such polynucleotide molecule(s), for instance such polynucleotide molecules operably configured to express the protein and/or the nucleic acid component(s), as well as such vector/s).

[00397] The invention further provides for a method of making muations to a Cas (e.g. Cpfl) or a mutated or modified Cas (e.g. Cpfl) that is an ortholog of the CRISPR enzymes according

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PCT/US2016/038181 to the invention as described herein, comprising ascertaining amino acid(s) in that ortholog may be in close proximity or may touch a nucleic acid molecule, e.g., DNA, RNA, gRNA, etc., and/or amino acid(s) analogous or corresponding to herein-identified amino acid(s) in CRISPR enzymes according to the invention as described herein for modification and/or mutation, and synthesizing or preparing or expressing the orthologue comprising, consisting of or consisting essentially of modification(s) and/or mutation(s) or mutating as herein-discussed, e.g., modifying, e.g,, changing or mutating, a neutral amino acid to a charged, e.g., positively charged, amino acid, e.g., from alanine to, e.g., lysine. The so modified ortholog can be used in CRISPR-Cas systems; and nucleic acid molecule(s) expressing it may be used in vector or other delivery systems that deliver molecules or or encoding CRISPR-Cas system components as herein-discussed.

[00398] In an aspect, the invention provides efficient on-target activity and minimizes off target activity. In an aspect, the invention provides efficient on-target cleavage by a CRISPR protein and minimizes off-target cleavage by the CRISPR protein. In an aspect, the invention provides guide specific binding of a CRISPR protein at a gene locus without DNA cleavage. In an aspect, the invention provides efficient guide directed on-target binding of a CRISPR protein at a gene locus and minimizes off-target binding of the CRISPR protein. Accordingly, in an aspect, the invention provides target-specific gene regulation. In an aspect, the invention provides guide specific binding of a CRISPR enzyme at a gene locus without DNA cleavage. Accordingly, in an aspect, the invention provides for cleavage at one gene locus and gene regulation at a different gene locus using a single CRISPR enzyme. In an aspect the invention provides orthogonal activation and/or inhibition and/or cleavage of multiple targets using one or more CRISPR protein and/or enzyme.

[00399] In another aspect, the present invention provides for a method of functional screening of genes in a genome in a pool of cells ex vivo or in vivo comprising the administration or expression of a library comprising a plurality of CRISPR-Cas system guide RNAs (gRNAs) and wherein the screening further comprises use of a CRISPR enzyme, wherein the CRISPR complex is modified to comprise a heterologous functional domain. In an aspect the invention provides a method for screening a genome comprising the administration to a host or expression in a host in vivo of a library. In an aspect the invention provides a method as herein discussed further comprising an activator administered to the host or expressed in the host. In an aspect the invention provides a method as herein discussed wherein the activator is attached to a CRISPR

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PCT/US2016/038181 protein. In an aspect the invention provides a method as herein discussed wherein the activator is attached to the N terminus or the C terminus of the CRISPR protein. In an aspect the invention provides a method as herein discussed wherein the activator is attached to a gRNA loop. In an aspect the invention provides a method as herein discussed further comprising a repressor administered to the host or expressed in the host. In an aspect the invention provides a method as herein discussed wherein the screening comprises affecting and detecting gene activation, gene inhibition, or cleavage in the locus.

[00400] In an aspect the invention provides a method as herein discussed wherein the host is a eukaryotic cell. In an aspect the invention provides a method as herein discussed wherein the host is a mammalian cell. In an aspect the invention provides a method as herein discussed, wherein the host is a non-human eukaryote cell. In an aspect the invention provides a method as herein discussed, wherein the non-human eukaryote cell is a non-hunran mammal cell. In an aspect the invention provides a method as herein discussed, wherein the non-human mammal cell may be including, but not limited to, primate bovine, ovine, procine, canine, rodent, Leporidae such as monkey, cow, sheep, pig, dog, rabbit, rat or mouse cell. In an aspect the invention provides a method as herein discussed, the cell may be a a non-mammalian eukaryotic ceil such as poultry bird (e.g., chicken), vertebrate fish (e.g., salmon) or shellfish (e.g., oyster, claim, lobster, shrimp) cell. In an aspect the invention provides a method as herein discussed, the nonhuman eukaryote cell is a plant cell. The plant cell may be of a monocot or dicot or of a crop or grain plant such as cassava, corn, sorghum, soybean, wheat, oat or rice. The plant cell may also be of an algae, tree or production plant, fruit or vegetable (e.g., trees such as citrus trees, e.g., orange, grapefruit or lemon trees; peach or nectarine trees; apple or pear trees; nut trees such as almond or walnut or pistachio trees; nightshade plants; plants of the genus Brassica, plants of the genus Lactuca, plants of the genus Spinacia, plants of the genus Capsicum·, cotton, tobacco, asparagus, carrot, cabbage, broccoli, cauliflower, tomato, eggplant, pepper, lettuce, spinach, strawberry, blueberry, raspberry, blackberry, grape, coffee, cocoa, etc).

[00401] In an aspect the invention provides a method as herein discussed comprising the delivery of the CRISPR-Cas complexes or conrponent(s) thereof or nucleic acid molecule(s) coding therefor, wherein said nucleic acid molecule(s) are operatively linked to regulatory sequence(s) and expressed in vivo. In an aspect the invention provides a method as herein discussed wherein the expressing in vivo is via a lentivirus, an adenovirus, or an AAV. In an

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PCT/US2016/038181 aspect the invention provides a method as herein discussed wherein the delivery is via a particle, a nanoparticle, a lipid or a cell penetrating peptide (CPP).

[00402] In particular embodiments it can be of interest to target the CRISPR-Cas complex to the chloroplast. In many cases, this targeting may be achieved by the presence of an N -terminal extension, called a chloroplast transit peptide (CTP) or plastid transit peptide. Chromosomal transgenes from bacterial sources must have a sequence encoding a CTP sequence fused to a sequence encoding an expressed polypeptide if the expressed polypeptide is to be compartmentalized in the plant plastid (e.g. chloroplast). Accordingly, localization of an exogenous polypeptide to a chloroplast is often 1 accomplished by means of operably linking a polynucleotide sequence encoding a CTP sequence to the 5' region of a polynucleotide encoding the exogenous polypeptide. The CTP is removed in a processing step during translocation into the plastid. Processing efficiency may, however, be affected by the amino acid sequence of the CTP and nearby sequences at the NH 2 terminus of the peptide. Other options for targeting to the chloroplast which have been described are the maize cab-m7 signal sequence (Li. S. Patent 7,022,896, WO 97/41228) a pea glutathione reductase signal sequence (WO 97/41228) and the CTP described in IJS2009029861.

[00403] In an aspect the invention provides a pair of CRISPR-Cas complexes, each comprising a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell, wherein at least one loop of each sgRNA is modified by the insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins, and wherein the adaptor protein is associated with one or more functional domains, wherein each gRNA of each CRISPR-Cas comprises a functional domain having a DNA cleavage activity. In an aspect the invention provides a paired CRISPR-Cas complexes as herein-discussed, wherein the DNA cleavage activity is due to a Foki nuclease.

[00404] In an aspect the invention provides a method for cutting a target sequence in a genomic locus of interest comprising delivery to a cell of the CRISPR-Cas complexes or component(s) thereof or nucleic acid molecule(s) coding therefor, wherein said nucleic acid molecule(s) are operatively linked to regulatory sequence(s) and expressed in vivo. In an aspect the invention provides a method as herein-discussed wherein the delivery is via a lentivirus, an adenovirus, or an AAV. In an aspect the invention provides a method as herein-discussed or paired CRISPR-Cas complexes as herein-discussed wherein the target sequence for a first

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PCT/US2016/038181 complex of the pair is on a first strand of double stranded DNA and the target sequence for a second complex of the pair is on a second strand of double stranded DNA. In an aspect the invention provides a method as herein-discussed or paired CRISPR-Cas complexes as hereindiscussed wherein the target sequences of the first and second complexes are in proximity to each other such that the DNA is cut in a manner that facilitates homology directed repair. In an aspect a herein method can further include introducing into the cell template DNA. In an aspect a herein method or herein paired CRISPR-Cas complexes can involve wherein each CRISPR-Cas complex has a CRISPR enzyme that is mutated such that it has no more than about 5% of the nuclease activity of the CRISPR enzyme that is not mutated.

[00405] In an aspect the invention provides a library, method or complex as herein-discussed wherein the gRNA is modified to have at least one non-coding functional loop, e.g., wherein the at least one non-coding functional loop is repressive; for instance, wherein the at least one noncoding functional loop comprises Alu.

[00406] In one aspect, the invention provides a method for altering or modifying expression of a gene product. The said method may comprise introducing into a cell containing and expressing a DNA molecule encoding the gene product an engineered, non-naturally occurring CRISPR-Cas system comprising a Cas protein and guide RNA that targets the DNA molecule, whereby the guide RNA targets the DNA molecule encoding the gene product and the Cas protein cleaves the DNA molecule encoding the gene product, whereby expression of the gene product is altered; and, wherein the Cas protein and the guide RNA do not naturally occur together. The invention further comprehends the Cas protein being codon optimized for expression in a Eukaryotic cell. In a preferred embodiment the Eukaryotic cell is a mammalian cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of the gene product is decreased.

[00407] In an aspect, the invention provides altered cells and progeny of those cells, as well as products made by the cells. CRISPR-Cas (e.g. Cpfl) proteins and systems of the invention are used to produce cells comprising a modified target locus. In some embodiments, the method may comprise allowing a nucleic acid-targeting complex to bind to the target DNA or RNA to effect cleavage of said target DNA or RNA thereby modifying the target DNA or RNA, wherein the nucleic acid-targeting complex comprises a nucleic acid-targeting effector protein complexed with a guide RNA hybridized to a target sequence within said target DNA or RNA. In one

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PCT/US2016/038181 aspect, the invention provides a method of repairing a genetic locus in a cell. In another aspect, the invention provides a method of modifying expression of DNA or RNA in a eukaryotic cell. In some embodiments, the method comprises allowing a nucleic acid-targeting complex to bind to the DNA or RNA such that said binding results in increased or decreased expression of said DNA or RNA; wherein the nucleic acid-targeting complex comprises a nucleic acid-targeting effector protein complexed with a guide RNA. Similar considerations and conditions apply as above for methods of modifying a target DNA or RNA. In fact, these sampling, culturing and reintroduction options apply across the aspects of the present invention. In an aspect, the invention provides for methods of modifying a target DNA or RNA in a eukaryotic cell, which may be in vivo, ex vivo or in vilro. In some embodiments, the method comprises sampling a cell or population of cells from a human or non-human animal, and modifying the cell or cells. Culturing may occur at any stage ex vivo. Such cells can be, without limitation, plant cells, animal cells, particular cell types of any organism, including stem cells, immune cells, T cell, B cells, dendritic cells, cardiovascular cells, epithelial cells, stem cells and the like. The cells can be modified according to the invention to produce gene products, for example in controlled amounts, which may be increased or decreased, depending on use, and/or mutated. In certain embodiments, a genetic locus of the cell is repaired. The cell or cells may even be re-introduced into the non-human animal or plant. For re-introduced cells it may be preferred that the cells are stem cells.

[00408] In an aspect, the invention provides cells which transiently comprise CRISPR. systems, or components. For example, CRISPR proteins or enzymes and nucleic acids are transiently provided to a cell and a genetic locus is altered, followed by a decline in the amount of one or more components of the CRISPR system. Subsequently, the cells, progeny of the cells, and organisms which comprise the cells, having acquired a CRISPR mediated genetic alteration, comprise a diminished amount of one or more CRISPR system components, or no longer contain the one or more CRISPR system components. One non-limiting example is a self-inactivating CRISPR-Cas system such as further described herein. Thus, the invention provides cells, and organisms, and progeny of the cells and organisms which comprise one or more CRISPR-Cas system-altered genetic loci, but essentially lack one or more CRISPR. system component. In certain embodiments, the CRISPR system components are substantially absent. Such cells, tissues and organisms advantageously comprise a desired or selected genetic alteration but have

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PCT/US2016/038181 lost CRISPR-Cas components or remnants thereof that potentially might act non-specifically, lead to questions of safety, or hinder regulatory approval. As well, the invention provides products made by the cells, organisms, and progeny of the cells and organisms.

Inducible

[00409] In an aspect the invention provides a non-naturally occurring or engineered inducible Cpfl CRISPR-Cas system, comprising:

a first Cpfl fusion construct attached to a first half of an inducible dimer and a second Cpfl fusion construct attached to a second half of the inducible dimer, wherein the first Cpfl fusion construct is operably linked to one or more nuclear localization signals, wherein the second Cpfl fusion construct is operably linked to one or more nuclear export signals, wherein contact with an inducer energy source brings the first and second halves of the inducible dimer together, wherein bringing the first and second halves of the inducible dimer together allows the first and second Cpfl fusion constructs to constitute a functional Cpfl CRISPR-Cas system, wherein the Cpfl CRISPR-Cas system comprises a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell, and wherein the functional Cpfl CRISPR-Cas system binds to the target sequence and, optionally, edits the genomic locus to alter gene expression.

[00410] In an aspect of the invention in the inducible Cpfl CRISPR-Cas system, the inducible dimer is or comprises or consists essentially of or consists of an inducible heterodimer. In an aspect, in inducible Cpfl CRISPR-Cas system, the first half or a first portion or a first fragment of the inducible heterodimer is or comprises or consists of or consists essentially of an FKBP, optionally FKBP 12. In an aspect of the invention, in the inducible Cpfl CRISPR-Cas system, the second half or a second portion or a second fragment of the inducible heterodimer is or comprises or consists of or consists essentially of FRB. In an aspect of the invention, in the inducible Cpfl CRISPR-Cas system, the arrangement of the first Cpfl fusion construct is or comprises or consists of or consists essentially of N’ terminal Cpfl part-FRB-NES. In an aspect of the invention, in the inducible Cpfl CRISPR-Cas system, the arrangement of the first Cpfl

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PCT/US2016/038181 fusion construct is or comprises or consists of or consists essentially of NES-N’ terminal Cpfl part-FRB-NES. In an aspect of the invention, in the inducible Cpfl CRISPR-Cas system, the arrangement of the second Cpfl fusion construct is or comprises or consists essentially of or consists of C’ terminal Cpfl part-FKBP-NLS. In an aspect the invention provides in the inducible Cpfl CRISPR-Cas system, the arrangement of the second Cpfl fusion construct is or comprises or consists of or consists essentially of NLS-C’ terminal Cpfl part-FKBP-NLS. In an aspect, in inducible Cpfl CRISPR-Cas system there can be a linker that separates the Cpfl part from the half or portion or fragment of the inducible dimer. In an aspect, in the inducible Cpfl CRISPR-Cas system, the inducer energy source is or comprises or consists essentially of or consists of rapamycin. In an aspect, in inducible Cpfl CRISPR-Cas system, the inducible dimer is an inducible homodimer. In an aspect, in inducible Cpfl CRISPR-Cas system, the Cpfl is FnCpfl. In an aspect, in the inducible Cpfl CRISPR-Cas system, one or more functional domains are associated with one or both parts of the Cpfl, e.g., the functional domains optionally including a transcriptional activator, a transcriptional or a nuclease such as a Fokl nuclease. In an aspect, In the inducible Cpfl CRISPR-Cas system, the functional Cpfl CRISPR-Cas system binds to the target sequence and the enzyme is a dead-Cpfl, optionally having a diminished nuclease activity of at least 97%, or 100% (or no more than 3% and advantageously 0% nuclease activity) as compared with the Cpfl not having the at least one mutation. The invention further comprehends and an aspect of the invention provides, a polynucleotide encoding the inducible Cpfl CRISPR-Cas system as herein discussed.

[00411] In an aspect, the invention provides a vector for delivery of the first Cpfl fusion construct, attached to a first half or portion or fragment of an inducible dimer and operably linked to one or more nuclear localization signals, according as herein discussed. In an aspect, the invention provides a vector for delivery of the second Cpfl fusion construct, attached to a second half or portion or fragment of an inducible dimer and operably linked to one or more nuclear export signals.

[00412] In an aspect, the invention provides a vector for delivery of both; the first Cpfl fusion construct, attached to a first half or portion or fragment of an inducible dimer and operably linked to one or more nuclear localization signals, as herein discussed; and the second Cpfl fusion construct, attached to a second half or portion or fragment of an inducible dimer and operably linked to one or more nuclear export signals, as herein discussed.

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PCT/US2016/038181 [00413] In an aspect, the vector can be single plasmid or expression cassette.

[00414] The invention, in an aspect, provides a eukaryotic host cell or cell line transformed with any of the vectors herein discussed or expressing the inducible Cpfl CRISPR-Cas system as herein discussed, [00415] The invention, in an aspect provides, a transgenic organism transformed with any of the vectors herein discussed or expressing the inducible Cpfl CRISPR-Cas system herein discussed, or the progeny thereof. In an aspect, the invention provides a model organism which constitutively expresses the inducible Cpfl CRISPR-Cas system as herein discussed.

[00416] In an aspect, the invention provides non-naturally occurring or engineered inducible Cpfl CRISPR-Cas system, comprising:

a first Cpfl fusion construct attached to a first half of an inducible heterodimer and a second Cpfl fusion construct attached to a second half of the inducible heterodimer, wherein the first Cpfl fusion construct is operably linked to one or more nuclear localization signals, wherein the second CPfl fusion construct is operably linked to a nuclear export signal, wherein contact with an inducer energy source brings the first and second halves of the inducible heterodimer together, wherein bringing the first and second halves of the inducible heterodimer together allows the first and second Cpfl fusion constructs to constitute a functional Cpfl CRISPR-Cas system, wherein the Cpfl CRISPR-Cas system comprises a guide RNA. (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell, and wherein the functional Cpfl CRISPR-Cas system edits the genomic locus to alter gene expression.

[00417] In an aspect, the invention provides a method of treating a subject in need thereof, comprising inducing gene editing by transforming the subject with the polynucleotide as herein discussed or any of the vectors herein discussed and administering an inducer energy source to the subject. The invention comprehends uses of such a polynucleotide or vector in the manufacture of a medicament, e.g., such a medicament for treating a subject or for such a method of treating a subject. The invention comprehends the polynucleotide as herein discussed or any of the vectors herein discussed for use in a method of treating a subject in need thereof

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PCT/US2016/038181 comprising inducing gene editing, wherein the method further comprises administering an inducer energy source to the subject. In an aspect, in the method, a repair template is also provided, for example delivered by a vector comprising said repair template.

[00418] The invention also provides a method of treating a subject in need thereof, comprising inducing transcriptional activation or repression by transforming the subject with the polynucleotide herein discussed or any of the vectors herein discussed, wherein said polynucleotide or vector encodes or comprises the catalytically inactive Cpfl and one or more associated functional domains as herein discussed, the method further comprising administering an inducer energy source to the subject. The invention also provides the polynucleotide herein discussed or any of the vectors herein discussed for use in a method of treating a subject in need thereof comprising inducing transcriptional activation or repression, wherein the method further comprises administering an inducer energy source to the subject.

[00419] Accordingly, the invention comprehends inter alia homodimers as well as heterodimers, dead-Cpfl or Cpfl having essentially no nuclease activity, e.g., through mutation, systems or complexes wherein there is one or more NLS and/or one or more NES; functional domain(s) linked to split Cpfl; methods, including methods of treatment, and uses.

[00420] It will be appreciated that where reference is made herein to Cpfl, Cpfl protein or Cpfl enzyme, this includes the present split Cpfl. In one aspect, the invention provides a method for altering or modifying expression of a gene product. The said method may comprise introducing into a cell containing and expressing a DNA molecule encoding the gene product an engineered, non-naturally occurring Cpfl CRISPR-Cas system comprising a Cpfl protein and guide RNA that targets the DNA molecule, whereby the guide RNA targets the DNA molecule encoding the gene product and the Cpfl protein cleaves the DNA molecule encoding the gene product, whereby expression of the gene product is altered; and, wherein the Cpfl protein and the guide RNA do not naturally occur together. The invention comprehends the guide RNA comprising a guide sequence linked to a direct repeat (DR) sequence. The invention further comprehends the Cpfl protein being codon optimized for expression in a eukaryotic cell. In a preferred embodiment the eukaryotic cell is a mammalian cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of the gene product is decreased.

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PCT/US2016/038181 [00421] In one aspect, the invention provides an engineered, non-naturally occurring Cpfl CRISPR-Cas system comprising a Cpfl protein and a guide RNA that targets a DNA molecule encoding a gene product in a cell, whereby the guide RNA targets the DNA molecule encoding the gene product and the Cpfl protein cleaves the DNA molecule encoding the gene product, whereby expression of the gene product is altered; and, wherein the Cpfl protein and the guide RNA do not naturally occur together, this including the present split Cpfl. The invention comprehends the guide RNA comprising a guide sequence linked to a DR sequence. The invention further comprehends the Cpfl protein being codon optimized for expression in a eukaryotic ceil. In a preferred embodiment the eukaryotic cell is a mammalian cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of the gene product is decreased.

[00422] In another aspect, the invention provides an engineered, non-naturally occurring vector system comprising one or more vectors comprising a first regulatory element operably linked to a Cpfl CRISPR-Cas system guide RNA that targets a DNA molecule encoding a gene product and a second regulatory element operably linked to a Cpfl protein; this includes the present split Cpfl. Components (a) and (b) may be located on same or different vectors of the system. The guide RNA targets the DNA molecule encoding the gene product in a cell and the Cpfl protein cleaves the DNA molecule encoding the gene product, whereby expression of the gene product is altered; and, wherein the Cpfl protein and the guide RNA do not naturally occur together. The invention comprehends the guide RNA comprising a guide sequence linked to a DR sequence. The invention further comprehends the Cpfl protein being codon optimized for expression in a eukaryotic cell. In a preferred embodiment the eukaryotic cell is a mammalian cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of the gene product is decreased.

[00423] In one aspect, the invention provides a vector system comprising one or more vectors. In some embodiments, the system comprises: (a) a first regulatory element operably linked to a DR sequence and one or more insertion sites for inserting one or more guide sequences downstream of the DR sequence, wherein when expressed, the guide sequence directs sequencespecific binding of a Cpfl CRISPR-Cas complex to a target sequence in a eukaryotic cell, wherein the Cpfl CRISPR-Cas complex comprises Cpfl complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the DR sequence; and (b) a second regulatory

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PCT/US2016/038181 element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme comprising a nuclear localization sequence; wherein components (a) and (b) are located on the same or different vectors of the system; this includes the present split Cpfl. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a Cpfl CRISPR-Cas complex to a different target sequence in a eukaryotic cell.

[00424] In some embodiments, the Cpfl CRISPR-Cas complex comprises one or more nuclear localization sequences of sufficient strength to drive accumulation of said Cpfl CRISPRCas complex in a detectable amount in the nucleus of a eukaryotic cell. Without wishing to be bound by theory, it is believed that a nuclear localization sequence is not necessary for Cpfl CRISPR-Cas complex activity in eukaryotes, but that including such sequences enhances activity of the system, especially as to targeting nucleic acid molecules in the nucleus, [00425] In some embodiments, the Cpfl enzyme is Cpfl of a bacterial species selected from the group consisting of Francisella tularensis I, Franci sella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibaeteria bacterium GW2011 GW^TA2 33 JO, Parcubacteria bacterium GW2011 GW^TC2 44 17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidates Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, and Porphyromonas macacae, and may include mutated CPfl derived from these organisms. The enzyme may be a Cpfl homolog or ortholog. In some embodiments, the Cpfl is codon-optimized for expression in a eukaryotic cell. In some embodiments, the Cpfl directs cleavage of one or two strands at the location of the target sequence. In a preferred embodiment, the strand break is a staggered cut with a 5’ overhang. In some embodiments, the first regulatory⁷ element is a polymerase III promoter. In some embodiments, the second regulatory element is a polymerase II promoter. In some embodiments, the direct repeat has a minimum length of 16 nts and a single stem loop. In further embodiments the direct repeat has a length longer than 16 nts, preferably more than 17 nts, and has more than one stem loop or optimized secondary⁷ structures.

[00426] In one aspect, the invention provides a eukaryotic host cell comprising (a) a first regulatory element operably linked to a direct repeat sequence and one or more insertion sites for

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PCT/US2016/038181 inserting one or more guide sequences downstream of the DR sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a Cpfl CRISPR-Cas complex to a target sequence in a eukaryotic cell, wherein the Cpfl CRISPR-Cas complex comprises Cpfl complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the DR sequence; and/or (b) a second regulatory' element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme comprising a nuclear localization sequence. In some embodiments, the host cell comprises components (a) and (b); this includes the present split Cpf l. In some embodiments, component (a), component (b), or components (a) and (b) are stably integrated into a genome of the host eukaryotic cell. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a Cpfl CRISPR-Cas complex to a different target sequence in a eukaryotic cell. In some embodiments, the CPfl is codon-optimized for expression in a eukaryotic cell. In some embodiments, the Cpfl directs cleavage of one or two strands at the location of the target sequence. In a preferred embodiment, the strand break is a staggered cut with a 5’ overhang. In some embodiments, the Cpfl lacks DNA strand cleavage activity. In some embodiments, the first regulatory element is a polymerase III promoter. In some embodiments, the direct repeat has a minimum length of 16 nts and a single stem loop. In further embodiments the direct repeat has a length longer than 16 nts, preferably more than 17 nts, and has more than one stem loop or optimized secondary structures. In an aspect, the invention provides a non-human eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments. In other aspects, the invention provides a eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments. The organism in some embodiments of these aspects may be an animal; for example a mammal. Also, the organism may be an arthropod such as an insect. The organism also may be a plant. Further, the organism may be a fungus. [00427] In one aspect, the invention provides a. kit comprising one or more of the components described herein. In some embodiments, the kit comprises a vector system and instructions for using the kit. In some embodiments, the vector system comprises (a) a first regulatory element operably linked to a direct repeat sequence and one or more insertion sites for inserting one or more guide sequences downstream of the DR sequence, wherein when expressed, the guide

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PCT/US2016/038181 sequence directs sequence-specific binding of a Cpf l CRISPR-Cas complex to a target sequence in a eukaryotic cell, wherein the Cpfl CRISPR-Cas complex comprises Cpfl complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the DR sequence; and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme comprising a nuclear localization sequence and advantageously this includes the present split Cpfl. In some embodiments, the kit comprises components (a) and (b) located on the same or different vectors of the system. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a Cpfl CRISPR-Cas complex to a different target sequence in a eukaryotic cell. In some embodiments, the Cpfl comprises one or more nuclear localization sequences of sufficient strength to drive accumulation of said Cpfl in a detectable amount in the nucleus of a eukaryotic cell. In some embodiments, the Cpfl enzyme is Cpfl of a bacterial species selected from the group consisting of Francisella tularensis I, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclastieus, Peregrinibacteria bacterium GW2Q11_GWA2_33_1O, Parcubacteria bacterium GW2011_GWC2_44_17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, and Porphyromonas macacae, and may include mutated CPfl derived from these organisms. The enzyme may be a Cpfl homolog or ortholog. In some embodiments, the Cpfl is codon-optimized for expression in a eukaryotic cell. In some embodiments, the Cpfl directs cleavage of one or two strands at the location of the target sequence. In a preferred embodiment, the strand break is a staggered cut with a 5’ overhang. In some embodiments, the CRISPR enzyme lacks DNA strand cleavage activity. In some embodiments, the direct repeat has a minimum length of 16 nts and a single stem loop. In further embodiments the direct repeat has a length longer than 16 nts, preferably more than 17 nts, and has more than one stem loop or optimized secondary structures. [00428] In one aspect, the invention provides a method of modifying a target polynucleotide in a eukaryotic cell. In some embodiments, the method comprises allowing a Cpfl CRISPR-Cas complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the Cpfl CRISPR-Cas complex comprises

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PCT/US2016/038181

Cpfl complexed with a guide sequence hybridized to a target sequence within said target polynucleotide, wherein said guide sequence is linked to a direct repeat sequence. In some embodiments, said cleavage comprises cleaving one or two strands at the location of the target sequence by said Cpfl; this includes the present split Cpfl. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expressed from a gene comprising the target sequence. In some embodiments, the method further comprises delivering one or more vectors to said eukaryotic cell, wherein the one or more vectors drive expression of one or more of: the Cpfl, and the guide sequence linked to the DR sequence. In some embodiments, said vectors are delivered to the eukaryotic cell in a subject. In some embodiments, said modifying takes place in said eukaryotic cell in a cell culture. In some embodiments, the method further comprises isolating said eukaryotic cell from a subject prior to said modifying. In some embodiments, the method further comprises returning said eukaryotic cell and/or cells derived therefrom to said subject.

[00429] In one aspect, the invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell. In some embodiments, the method comprises allowing a Cpfl CRISPR-Cas complex to bind to the polynucleotide such that said binding results in increased or decreased expression of said polynucleotide; wherein the Cpfl CRISPR-Cas complex comprises Cpfl complexed with a guide sequence hybridized to a target sequence within said polynucleotide, wherein said guide sequence is linked to a direct repeat sequence; this includes the present split Cpfl. In some embodiments, the method further comprises delivering one or more vectors to said eukaryotic ceils, wherein the one or more vectors drive expression of one or more of: the Cpfl, and the guide sequence linked to the DR sequence. [00430] In one aspect, the invention provides a method of generating a model eukaryotic cell comprising a mutated disease gene. In some embodiments, a disease gene is any gene associated an increase in the risk of having or developing a disease. In some embodiments, the method comprises (a) introducing one or more vectors into a eukaryotic cell, wherein the one or more vectors drive expression of one or more of: Cpfl, and a guide sequence linked to a direct repeat

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PCT/US2016/038181 sequence; and (b) allowing a Cpfl CRISPR-Cas complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said disease gene, wherein the Cpfl CRISPRCas complex comprises the Cpfl complexed with (1) the guide sequence that is hybridized to the target sequence within the target polynucleotide, and (2) the DR sequence, thereby generating a model eukaryotic cell comprising a mutated disease gene; this includes the present split Cpfl. In some embodiments, said cleavage comprises cleaving one or two strands at the location of the target sequence by said Cpfl. In a preferred embodiment, the strand break is a staggered cut with a 5’ overhang. In some embodiments, said cleavage results in decreased transcription of a target gene. In some embodiments, the method further comprises repairing said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of said target polynucleotide. In some embodiments, said mutation results in one or more amino acid changes in a protein expression from a gene comprising the target sequence.

[00431] In one aspect, the invention provides a method for developing a biologically active agent that modulates a cell signaling event associated with a disease gene. In some embodiments, a disease gene is any gene associated an increase in the risk of having or developing a disease. In some embodiments, the method comprises (a) contacting a test compound with a model cell of any one of the described embodiments; and (b) detecting a change in a readout that is indicative of a reduction or an augmentation of a cell signaling event associated with said mutation in said disease gene, thereby developing said biologically active agent that modulates said cell signaling event associated with said disease gene, [00432] In one aspect, the invention provides a recombinant polynucleotide comprising a guide sequence downstream of a direct repeat sequence, wherein the guide sequence when expressed directs sequence-specific binding of a Cpfl CRISPR-Cas complex to a corresponding target sequence present in a eukaryotic cell. In some embodiments, the target sequence is a viral sequence present in a eukaryotic cell. In some embodiments, the target sequence is a protooncogene or an oncogene.

[00433] In one aspect the invention provides for a method of selecting one or more cell(s) by introducing one or more mutations in a gene in the one or more cell (s), the method comprising: introducing one or more vectors into the cell (s), wherein the one or more vectors drive

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PCT/US2016/038181 expression of one or more of: Cpfl, a guide sequence linked to a direct repeat sequence, and an editing template; wherein the editing template comprises the one or more mutations that abolish Cpfl cleavage; allowing homologous recombination of the editing template with the target polynucleotide in the cell(s) to be selected; allowing a Cpfl CRISPR-Cas complex to bind to a target polynucleotide to effect cleavage of the target polynucleotide within said gene, wherein the Cpfl CRISPR-Cas complex comprises the Cpfl complexed with (1) the guide sequence that is hybridized to the target sequence within the target polynucleotide, and (2) the direct repeat sequence, wherein binding of the Cpfl CRISPR-Cas complex to the target polynucleotide induces cell death, thereby allowing one or more cell(s) in which one or more mutations have been introduced to be selected; this includes the present split Cpfl. In another preferred embodiment of the invention the cell to be selected may be a eukaryotic cell. Aspects of the invention allow for selection of specific cells without requiring a selection marker or a two-step process that may include a counter-selection system.

[00434] Herein there is the phrase “this includes the present split Cpfl” or similar text; and, this is to indicate that Cpfl in embodiments herein can be a split Cpfl as herein discussed.

[00435] In an aspect the invention involves a non-naturally occurring or engineered inducible Cpfl CRISPR-Cas system, comprising a first Cpfl fusion construct attached to a first half of an inducible heterodimer and a second Cpfl fusion construct attached to a second half of the inducible heterodimer, wherein the first CPfl fusion construct is operably linked to one or more nuclear localization signals, wherein the second CPfl fusion construct is operably linked to a nuclear export signal, wherein contact with an inducer energy source brings the first and second halves of the inducible heterodimer together, wherein bringing the first and second halves of the inducible heterodimer together allows the first and second Cpfl fusion constructs to constitute a functional Cpfl CRISPR-Cas system, wherein the Cpfl CRISPR-Cas system comprises a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell, and wherein the functional Cpfl CRISPR-Cas system edits the genomic locus to alter gene expression. In an embodiment of the invention the first half of the inducible heterodimer is FKBP12 and the second half of the inducible heterodimer is FRB. In another embodiment of the invention the inducer energy source is rapamycin.

[00436] An inducer energy source may be considered to be simply an inducer or a dimerizing agent. The term ‘inducer energy source’ is used herein throughout for consistency. The inducer

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PCT/US2016/038181 energy source (or inducer) acts to reconstitute the Cpfl. In some embodiments, the inducer energy source brings the two parts of the Cpfl together through the action of the two halves of the inducible dimer. The two halves of the inducible dimer therefore are brought tougher in the presence of the inducer energy source. The two halves of the dimer will not form into the dimer (dimerize) without the inducer energy source.

[00437] Thus, the two halves of the inducible dimer cooperate with the inducer energy source to dimerize the dimer. This in turn reconstitutes the Cpfl by bringing the first and second parts of the Cpfl together.

[00438] The CRISPR enzyme fusion constructs each comprise one part of the split Cpfl. These are fused, preferably via a linker such as a GlySer linker described herein, to one of the two halves of the dimer. The two halves of the dimer may be substantially the same two monomers that together that form the homodimer, or they may be different monomers that together form the heterodimer. As such, the two monomers can be thought of as one half of the full dimer.

[00439] The Cpfl is split in the sense that the two parts of the Cpfl enzyme substantially comprise a functioning Cpfl. That Cpfl may function as a genome editing enzyme (when forming a complex with the target DNA and the guide), such as a nickase or a nuclease (cleaving both strands of the DNA), or it may be a dead-Cpfl winch is essentially a DNA-binding protein with very' little or no catalytic activity, due to typically mutation(s) in its catalytic domains. [00440] The two parts of the split Cpfl can be thought of as the N’ terminal part and the C’ terminal part of the split Cpfl. The fusion is typically at the split point of the Cpfl. In other words, the C’ terminal of the N’ terminal part of the split Cpfl is fused to one of the dimer halves, whilst the N’ terminal of the C’ terminal part is fused to the other dimer half.

[00441] The Cpfl does not have to be split in the sense that the break is newly created. The split point is typically designed in silico and cloned into the constructs. Together, the two parts of the split Cpfl, the Ν’ terminal and C’ terminal parts, form a full Cpfl, comprising preferably at least 70% or more of the wildtype amino acids (or nucleotides encoding them), preferably at least 80% or more, preferably at least 90% or more, preferably at least 95% or more, and most preferably at least 99% or more of the wildtype amino acids (or nucleotides encoding them). Some trimming may be possible, and mutants are envisaged. Non-functional domains may be

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PCT/US2016/038181 removed entirely. What is important is that the two parts may be brought together and that the desired Cpfl function is restored or reconstituted.

[00442] The dimer may be a homodimer or a heterodimer.

[00443] One or more, preferably two, NLSs may be used in operable linkage to the first Cpfl construct. One or more, preferably two, NESs may be used in operable linkage to the first Cpfl construct. The NLSs and/or the NESs preferably flank the split Cpfl-dimer (i.e., half dimer) fusion, i.e., one NLS may be positioned at the Ν’ terminal of the first Cpfl construct and one NLS may be at the C’ terminal of the first Cpfl construct. Similarly, one NES may be positioned at the N’ terminal of the second Cpfl construct and one NES may be at the C’ terminal of the second Cpfl construct. Where reference is made to N’ or C’ terminals, it will be appreciated that these correspond to 5’ ad 3’ ends in the corresponding nucleotide sequence, [00444] A preferred arrangement is that the first Cpfl construct is arranged 5’-NLS-(N’ terminal Cpfl part)-linker-(first half of the dimer)-NLS-3’. A preferred arrangement is that the second Cpfl construct is arranged 5’-NES—(second half of the dimer)-linker-(C’ terminal Cpfl part)-NES-3’. A suitable promoter is preferably upstream of each of these constructs. The two constructs may be delivered separately or together.

[00445] In some embodiments, one or ail of the NES(s) in operable linkage to the second CPfl construct may be swapped out for an NLS. However, this may be typically not preferred and, in other embodiments, the localization signal in operable linkage to the second Cpfl construct is one or more NES(s).

[00446] It will also be appreciated that the NES may be operably linked to the N’ terminal fragment of the split Cpfl and that the NLS may be operably linked to the C’ terminal fragment of the split Cpfl. However, the arrangement where the NLS is operably linked to the N’ terminal fragment of the split Cpfl and that the NES is operably linked to the C’ terminal fragment of the split Cpfl may be preferred.

[00447] The NES functions to localize the second Cpfl fusion construct outside of the nucleus, at least until the inducer energy source is provided (e.g., at least until an energy source is provided to the inducer to perform its function). The presence of the inducer stimulates dimerization of the two Cpfl fusions within the cytoplasm and makes it thermodynamically worthwhile for the dimerized, first and second, Cpfl fusions to localize to the nucleus. Without being bound by theory, Applicants believe that the NES sequesters the second Cpfl fusion to the

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PCT/US2016/038181 cytoplasm (i.e., outside of the nucleus). The NLS on the first Cpfl fusion localizes it to the nucleus. In both cases, Applicants use the NES or NLS to shift an equilibrium (the equilibrium of nuclear transport) to a desired direction. The dimerization typically occurs outside of the nucleus (a very small fraction might happen in the nucleus) and the NLSs on the dimerized complex shift the equilibrium of nuclear transport to nuclear localization, so the dimerized and hence reconstituted Cpfl enters the nucleus, [00448] Beneficially, Applicants are able to reconstitute function in the split Cpfl. Transient transfection is used to prove the concept and dimerization occurs in the background in the presence of the inducer energy source. No activity is seen with separate fragments of the Cpfl. Stable expression through lentiviral delivery is then used to develop this and show that a split Cpfl approach can be used, [00449] This present split Cpfl approach is beneficial as it allows the Cpfl activity to be inducible, thus allowing for temporal control. Furthermore, different localization sequences may be used (i.e., the NES and NLS as preferred) to reduce background activity from auto-assembled complexes. Tissue specific promoters, for example one for each of the first and second Cpfl fusion constructs, may also be used for tissue-specific targeting, thus providing spatial control. Two different tissue specific promoters may be used to exert a finer degree of control if required. The same approach may be used in respect of stage-specific promoters or there may a mixture of stage and tissue specific promoters, where one of the first and second Cpfl fusion constructs is under the control of (i.e. operably linked to or comprises) a tissue-specific promoter, whilst the other of the first and second Cpf l fusion constructs is under the control of (i.e. operably linked to or comprises) a stage-specific promoter.

[00450] The inducible Cpfl CRISPR-Cas system comprises one or more nuclear localization sequences (NLSs), as described herein, for example as operably linked to the first Cpfl fusion construct. These nuclear localization sequences are ideally of sufficient strength to drive accumulation of said first Cpfl fusion construct in a detectable amount in the nucleus of a eukaryotic cell. Without wishing to be bound by theory, it is believed that a nuclear localization sequence is not necessary for Cpfl CRISPR-Cas complex activity in eukaryotes, but that including such sequences enhances activity of the system, especially as to targeting nucleic acid molecules in the nucleus, and assists with the operation of the present 2-part system.

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PCT/US2016/038181 [00451] Equally, the second Cpfl fusion construct is operably linked to a nuclear export sequence (NES). Indeed, it may be linked to one or more nuclear export sequences. In other words, the number of export sequences used with the second Cpfl fusion construct is preferably 1 or 2 or 3. Typically 2 Is preferred, but 1 is enough and so is preferred in some embodiments. Suitable examples of NL S and NES are known in the art. For example, a preferred nuclear export signal (NES) is human protein tyrosin kinase 2. Preferred signals will be species specific.

[00452] Where the FRB and FKBP system are used, the FKBP is preferably flanked by nuclear localization sequences (NLSs). Where the FRB and FKBP system are used, the preferred arrangement is Ν’ terminal Cpfl - FRB - NES : C’ terminal Cpfl-FKBP-NLS. Thus, the first Cpfl fusion construct would comprise the C’ terminal Cpfl part and the second Cpfl fusion construct would comprise the N’ terminal Cpfl part.

[00453] Another beneficial aspect to the present invention is that it may be turned on quickly, i.e, that is has a rapid response. It is believed, without being bound by theory, that Cpfl activity can be induced through dimerization of existing (already present) fusion constructs (through contact with the inducer energy source) more rapidly than through the expression (especially translation) of new fusion constructs. As such, the first and second Cpfl fusion constructs may be expressed in the target cell ahead of time, i.e. before Cpfl activity is required. Cpfl activity can then be temporally controlled and then quickly constituted through addition of the inducer energy source, which ideally acts more quickly (to dimerize the heterodimer and thereby provide Cpfl activity) than through expression (including induction of transcription) of Cpfl delivered by a vector, for example.

[00454] The terms Cpfl or Cpfl enzyme and CRISPR enzyme are used interchangeably herein unless otherwise apparent.

[00455] Applicants demonstrate that CPfl can be split into two components, which reconstitute a functional nuclease when brought back together. Employing rapamycin sensitive dimerization domains, Applicants generate a chemically inducible Cpfl for temporal control of Cpfl-mediated genome editing and transcription modulation. Put another way, Applicants demonstrate that Cpfl can be rendered chemically inducible by being split into two fragments and that rapamycin-sensitive dimerization domains may be used for controlled reassembly of the Cpfl. Applicants show that the re-assembled Cpfl may be used to mediate genome editing

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PCT/US2016/038181 (through nuclease/nickase activity) as well as transcription modulation (as a DNA-binding domain, the so-called “dead Cpfl”).

[00456] As such, the use of rapamycin-sensitive dimerization domains is preferred. Reassembly of the Cpfl is preferred. Reassembly can be determined by restoration of binding activity. Where the Cpfl is a nickase or induces a double-strand break, suitable comparison percentages compared to a wildtype are described herein, [00457] Rapamycin treatments can last 12 days. The dose can be 200nM. This temporal and/or molar dosage is an example of an appropriate dose for Human embryonic kidney 293FT (HEK293FT) cell lines and this may also be used in other cell lines. This figure can be extrapolated out for therapeutic use in vivo into, for example, mg/kg. However, it is also envisaged that the standard dosage for administering rapamycin to a subject is used here as well. By the “standard dosage”, it is meant the dosage under rapamycin’s normal therapeutic use or primary' indication (i.e. the dose used when rapamycin is administered for use to prevent organ rejection).

[00458] It is noteworthy that the preferred arrangement of Cpf 1 -FRB/FKBP pieces are separate and inactive until rapamycin-induced dimerization of FRB and FKBP results in reassembly of a functional full-length Cpfl nuclease. Thus, it is preferred that first Cpfl fusion construct attached to a first half of an inducible heterodimer is delivered separately and/or is localized separately from the second Cpfl fusion construct attached to a first half of an inducible heterodimer.

[00459] To sequester the Cpfl(N)-FRB fragment in the cytoplasm, where it is less likely to dimerize with the nuclear-localized Cpfl(C)-FKBP fragment, it is preferable to use on Cpfl(N)FRB a single nuclear export sequence (NFS) from the human protein tyrosin kinase 2 (Cpfl(N)FRB-NES). In the presence of rapamycin, Cpfl(N)-FRB-NES dimerizes with Cpfl(C)-FKBP2xNLS to reconstitute a complete Cpfl protein, which shifts the balance of nuclear trafficking toward nuclear import and allows DNA targeting.

[00460] High dosage of Cpfl can exacerbate indel frequencies at off-target (OT) sequences which exhibit few mismatches to the guide strand. Such sequences are especially susceptible, if mismatches are non-consecutive and/or outside of the seed region of the guide. Accordingly, temporal control of Cpfl activity could be used to reduce dosage in long-term expression

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PCT/US2016/038181 experiments and therefore result in reduced off-target indels compared to constitutively active Cpfl.

[00461] Viral delivery is preferred. In particular, a lentiviral or AAV delivery vector is envisaged. Applicants generate a split-Cpfl lentivirus construct, similar to the lentiCRISPR plasmid. The split pieces should be small enough to fit the ~4.7kb size limitation of AAV. [00462] Applicants demonstrate that stable, low copy expression of split Cpfl can be used to induce substantial indels at a targeted locus without significant mutation at off-target sites. Applicants clone Cpfl fragments (2 parts based on split 5, described herein).

[00463] A dead Cpfl may also be used, comprising a VP64 transactivation domain, for example added to Cpfl (C)-FKBP-2xNLS (dead-Cpfl(C)-FKBP~2xNL,S-VP64). These fragments reconstitute a catalytically inactive Cpfl-VP64 fusion (dead-Cpfl-VP64). Transcriptional activation is induced by VP64 in the presence of rapamycin to induce the dimerization of the Cpfl(C)-FKBP fusion and the Cpfl(N)-FRB fusion. In other words. Applicants test the inducibility of split dead-Cpfl-VP64 and show⁷ that transcriptional activation is induced by split dead-Cpfl-VP64 in the presence of rapamycin. As such, the present inducible Cpfl may be associated with one or more functional domain, such as a transcriptional activator or repressor or a nuclease (such as Fokl). A functional domain may be bound to or fused with one part of the split Cpfl.

[00464] A preferred arrangement is that the first Cpfl construct is arranged 5’-First Localization Signal-(N’ terminal CPfl part)-linker-(first half of the dimer)-First Localization Signal-3’ and the second Cpfl construct is arranged 5’- Second Localization Signal—(second half of the dimer)-linker-(C’ terminal Cpfl part)-Second Localization Signal-Functional Domain-3’, Here, a functional domain is placed at the 3’ end of the second Cpfl construct. Alternatively, a functional domain may be placed at the 5’ end of the first Cpfl construct. One or more functional domains may be used at the 3’ end or the 5’ end or at both ends. A suitable promoter is preferably upstream of each of these constructs. The two constructs may be delivered separately or together. The Localization Signals may be an NFS or an NFS, so long as they are not inter-mixed on each construct.

[00465] In an aspect the invention provides an inducible Cpfl CRISPR-Cas system wherein the Cpfl has a diminished nuclease activity of at least 97%, or 100% as compared with the Cpfl enzyme not having the at least one mutation.

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PCT/US2016/038181 [00466] Accordingly, it is also preferred that the Cpfl is a dead-Cpfl. Ideally, the split should always be so that the catalytic domain(s) are unaffected. For the dead-Cpfl the intention is that DNA binding occurs, but not cleavage or nickase activity is shown.

[00467] In an aspect the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein one or more functional domains is associated with the Cpfl. This functional domain may be associated with (i.e, bound to or fused with) one part of the split Cpfl or both. There may be one associated with each of the two parts of the split Cpfl. These may therefore be typically provided as part of the first and/or second Cpfl fusion constructs, as fusions within that construct. The functional domains are typically fused via a linker, such as GlySer linker, as discussed herein. The one or more functional domains may be transcriptional activation domain or a repressor domain. Although they may he different domains it is preferred that all the functional domains are either activator or repressor and that a mixture of the two is not used. [00468] The transcriptional activation domain may comprise VP64, p65, MyoDl, HSF1, RTA or SET7/9.

[00469] In an aspect, the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein the one or more functional domains associated with the Cpfl is a transcriptional repressor domain.

[00470] In an aspect, the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein the transcriptional repressor domain is a KRAB domain.

[00471] In an aspect, the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein the transcriptional repressor domain is a NuE domain, NcoR domain, SID domain or a SID4X domain.

[00472] In an aspect the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein the one or more functional domains associated with the adaptor protein have one or more activities comprising methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, RNA cleavage activity, DNA cleavage activity, DNA integration activity or nucleic acid binding activity.

[00473] Histone modifying domains are also preferred in some embodiments. Exemplary histone modifying domains are discussed below. Transposase domains, HR (Homologous Recombination) machinery domains, recombinase domains, and/or integrase domains are also

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PCT/US2016/038181 preferred as the present functional domains. In some embodiments, DNA integration activity includes HR machinery domains, integrase domains, recombinase domains and/or transposase domains.

[00474] In an aspect the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein the DNA cleavage activity is due to a nuclease.

[00475] In an aspect the invention provides an inducible Cpfl CRISPR-Cas system as herein discussed wherein the nuclease comprises a Fokl nuclease.

[00476] The use of such functional domains, which are preferred with the present split Cpfl system, is also discussed in detail in Konermann et al. (“Genome-scale transcriptional activation with an engineered CRISPR-Cas9 complex” Nature published 11 Dec 2014).

[00477] The present system may be used with any guide.

[00478] Modified guides may be used in certain embodiments. Particularly preferred are guides embodying the teachings of Konermann Nature 11 Dec 2014 paper mentioned above. These guides are modified so that protein-binding RNA portions (such as aptamers) are added. Such portion(s) may replace a portion of the guide. Corresponding RNA-binding protein domains can be used to then recognise the RNA and recruit functional domains, such as those described herein, to the guide. This is primarily for use with dead-Cpfl leading to transcriptional activation or repression or DNA cleavage through nucleases such as Fokl. The use of such guides in combination with dead-Cpfl is powerful, and it is especially powerful if the Cpfl itself is also associated with its own functional domain, as discussed herein. When a dead-Cpfl (with or without its own associated functional domain) is induced to reconstitute in accordance with the present invention, i.e. is a split Cpfl, then the tool is especially useful, [00479] A guide RNA (gRNA), also preferred for use in the present invention, can comprise a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell, wherein the gRNA is modified by the insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins, and wherein the adaptor protein is associated with one or more functional domains. The Cpfl may comprise at least one mutation, such that the Cpfl enzyme has no more than 5% of the nuclease activity of the Cpfl enzyme not having the at least one mutation; and/or at least one or more nuclear localization sequences. Also provided is a nonnaturally occurring or engineered composition comprising: one or more guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of

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PCT/US2016/038181 interest in a cell, a Cpfl enzyme comprising at least one or more nuclear localization sequences, wherein the CPfl enzyme comprises at least one mutation, such that the Cpfl enzyme has no more than 5% of the nuclease activity of the Cpfl enzyme not having the at least one mutation, wherein the at least one gRNA is modified by the insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins, and wherein the adaptor protein is associated with one or more functional domains.

[00480] The gRNA that is preferably modified by the insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins. The insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins is preferably an aptamer sequence or two or more aptamer sequences specific to the same or different adaptor protein(s). The adaptor protein preferably comprises MS2, PP7, ί()β, F2, GA, fr, JP501, Ml2, R17, BZ13, JP34, JP500, KUI, Ml 1, MX1, TW18, VK, SP, FI, ID2, NL95, TWI9, AP205, <]>Cb5, <j)Cb8r, <|>Cbl2r₃ cbCb23r, 7s, PRR1. Cell lines stably expressing inter alia split dead-Cpfl can be useful.

[00481] Applicants demonstrate that Cpfl can be split into two distinct fragments, which reconstitute a functional full-length Cpfl nuclease when brought back together using chemical induction. The split Cpfl architecture wall be useful for a variety of applications. For example, split CPfl may enable genetic strategies for restricting Cpfl activity to intersectsonal cell populations by putting each fragment under a different tissue specific promoter. Additionally, different chemically inducible dimerization domains such as APA and gibberellin may also be employed, [00482] The inducer energy source is preferably chemical induction.

[00483] The split position or location is the point at which the first part of the Cpfl enzyme is separated from the second part. In some embodiments, the first part will comprise or encode amino acids 1 to X, whilst the second pari will comprise or encode amino acids X+l to the end. In this example, the numbering is contiguous, but this may not always he necessary as amino acids (or the nucleotides encoding them) could be trimmed from the end of either of the split ends, provided that sufficient DNA binding activity and, if required, DNA nickase or cleavage activity is retained, for example at least 40%, 50%, 60%, 70%, 80%, 90% or 95% activity compared to wildtype Cpfl, [00484] The exemplary numbering provided herein may be in reference to the wildtype protein, preferably the wildtype FnCpfl. However, it is envisaged that mutants of the wildtype

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Cpfl such as of FnCpfl protein can be used. The numbering may also not follow exactly the FnCpfl numbering as, for instance, some Ν’ or C’ terminal truncations or deletions may be used, but this can be addressed using standard sequence alignment tools. Orthologs are also preferred as a sequence alignment tool.

[00485] Thus, the split position may be selected using ordinary skill in the art, for instance based on crystal data and/or computational structure predictions, [00486] For example, computational analysis of the primary structure of Cpfl nucleases reveals three distinct regions (Fig. 1). First a C-terminal RuvC like domain, which is the only functional characterized domain. Second a N-terminal alpha-helical region and thirst a mixed alpha and beta region, located between the RuvC like domain and the alpha-helical region. Several small stretches of unstructured regions are predicted within the Cpfl primary structure. Unstructured regions, which are exposed to the solvent and not conserved within different Cpfl orthologs, may represent preferred sides for splits (Fig. 2 and Fig. 3).

[00487] The following table presents non-limiting potential split regions within As and LbCpfl. A split site within such a region may be opportune.

Split region	AsCpfl	LbCpfl
1	575-588	566-571
2	631-645	754-757
3	653-664	-
4	818-844	-

[00488] For Fn, As and Lb Cpfl mutants, it should be readily apparent what the corresponding position for a potential split site is, for example, based on a sequence alignment. For non-Fn, As and Lb enzymes one can use the crystal structure of an ortholog if a relatively high degree of homology exists between the ortholog and the intended Cpfl, or one can use computational prediction.

[00489] Ideally, the split position should be located within a region or loop. Preferably, the split position occurs where an interruption of the amino acid sequence does not result in the partial or full destruction of a structural feature (e.g. alpha-helixes or beta-sheets). Unstructured regions (regions that do not show up in the crystal structure because these regions are not structured enough to he “frozen” in a crystal) are often preferred options. Applicants can for example make splits in unstructured regions that are exposed on the surface of Cpfl.

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PCT/US2016/038181 [00490] Applicants can follow the following procedure which is provided as a preferred example and as guidance. Since unstructured regions don’t show up in the crystal structure, Applicants cross-reference the surrounding amino acid sequence of the crystal with the primary amino acid sequence of the Cpfl. Each unstructured region can be made of for example about 3 to 10 amino acids, which does not show up in the crystal. Applicants therefore make the split in between these amino acids. To include more potential split sides Applicants include splits located in loops at the outside of Cpfl using the same criteria as with unstructured regions. [00491] In some embodiments, the split positon is in an outside loop of the Cpfl. In other preferred embodiments, the split position is in an unstructured region of the Cpfl. An unstructured region is typically a highly flexible outside loop whose structure cannot be readily determined from a crystal pattern.

[00492] Once the split position has been identified, suitable constructs can be designed. [00493] Typically, an NES is positioned at the N’ terminal end of the first part of the split amino acid (or the 5’ end of nucleotide encoding it). In that case, an NLS is positioned at the C’ terminal end of the second pari of the split amino acid (or the 3’ end of the nucleotide encoding it). In this way, the first Cpfl fusion construct may be operably linked to one or more nuclear export signals and the second Cpfl fusion construct may be operably linked to a nuclear localization signal.

[00494] Of course, the reverse arrangement may be provided, where an NLS is positioned at the N’ terminal end of the first part of the split amino acid (or the 5’ end of nucleotide encoding it). In that case, an NES is positioned at the C’ terminal end of the second part of the split amino acid (or the 3’ end of the nucleotide encoding it). Thus, the first Cpfl fusion construct may be operably linked to one or more nuclear localization signals and the second Cpfl fusion construct may be operably linked to a nuclear export signal.

[00495] Splits which keep the two parts (either side of the split) roughly the same length may be advantageous for packing purposes. For example, it is thought to be easier to maintain stoichiometry between both pieces when the transcripts are about the same size, [00496] In certain examples, the N- and C-term pieces of human codon-optimized Cpfl such as FnCpfl are fused to FRB and FKBP dimerization domains, respectively. This arrangement may be preferred. They may be switched over (i.e. N’ term to FKBP and C’ term to FRB).

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PCT/US2016/038181 [00497] Linkers such as 1GGGGSL are preferably used herein to separate the Cpfl fragment from the dimerization domain. (GGGGSfy is preferable because it is a relatively long linker (15 amino acids). The glycine residues are the most flexible and the serine residues enhance the chance that the linker is on the outside of the protein. (GGGGS)e (GGGGSjq or (GGGGS)i2 may preferably be used as alternatives. Other preferred alternatives are (GGGGS)i, (GGGGST. (GGGGS),, (GGGGS)₅, (GGGGS)₇, (GGGGS)₈, (GGGGS)_i0, or (GGGGS)n.

[00498] For example, (GGGGSfi may be included between the N’ term Cpfl fragment and FRB. For example, (GGGGSjs may be included between FKB and the C’ term Cpfl fragment. [00499] Alternative linkers are available, but highly flexible linkers are thought to work best to allow for maximum opportunity for the 2 parts of the Cpfl to come together and thus reconstitute Cpfl activity. One alternative is that the NLS of nucleoplasmin can be used as a linker.

[00500] A linker can also be used between the Cpfl and any functional domain. Again, a (GGGGSfy linker may be used here (or the 6, 9, or 12 repeat versions therefore) or the NLS of nucleoplasmin can be used as a linker between CPfl and the functional domain.

[00501] Alternatives to the FRB/FKBP system are envisaged. For example the ABA and gibberellin system.

[00502] Accordingly, preferred examples of the FKBP family are any one of the following inducible systems. FKBP which dimerizes with CalcineurinA (CNA), in the presence of FK506; FKBP which dimerizes with CyP-Fas, in the presence of FKCsA; FKBP which dimerizes with FRB, in the presence of Rapamycin; GyrB which dimerizes with GryB, in the presence of Coumermycin; GA1 which dimerizes with GID1, in the presence of Gibberellin; or Snap-tag which dimerizes with HaloTag, in the presence of HaXS.

[00503] Alternatives within the FKBP family itself are also preferred. For example, FKBP, which homo-dimerizes (i.e. one FKBP dimerizes with another FKBP) in the presence of FK1012. Thus, also provided is a non-naturally occurring or engineered inducible Cpfl CRISPR-Cas system, comprising;

a first Cpfl fusion construct attached to a first half of an inducible homoodimer and a second Cpfl fusion construct attached to a second half of the inducible homoodimer, wherein the first Cpfl fusion construct is operably linked to one or more nuclear localization signals,

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PCT/US2016/038181 wherein the second Cpfl fusion construct is operably linked to a (optionally one or more) nuclear export signal(s), wherein contact with an inducer energy source brings the first and second halves of the inducible homoodimer together, wherein bringing the first and second halves of the inducible homoodimer together allows the first and second CPfl fusion constructs to constitute a functional Cpfl CRISPR-Cas system, wherein the Cpfl CRISPR-Cas system comprises a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a ceil, and wherein the functional Cpfl CRISPR-Cas system binds to the target sequence and, optionally, edits the genomic locus to alter gene expression.

[00504] In one embodiment, the homodimer is preferably FKBP and the inducer energy source is preferably FK1012. In another embodiment, the homodimer is preferably GryB and the inducer energy source is preferably Coumermycin. In another embodiment, the homodimer is preferably ABA and the inducer energy source is preferably Gibberellin.

[00505] In other embodiments, the dimer is a heterodimer. Preferred examples of heterodimers are any one of the following inducible systems: FKBP which dimerizes with CalcineurinA (CNA), in the presence of FK506; FKBP which dimerizes with CyP-Fas, in the presence of FKCsA; FKBP which dimerizes with FRB, in the presence of Rapamycin, in the presence of Coumermycin; GAI which dimerizes with GID1, in the presence of Gibberellin; or Snap-tag which dimerizes with HaloTag, in the presence of HaXS.

[00506] Applicants used FKBP/FRB because it is well characterized and both domains are sufficiently small (<100 amino acids) to assist with packaging. Furthermore, rapamycin has been used for a long time and side effects are well understood. Large dimerization domains (>300 aa) should work too but may require longer linkers to make enable Cpfl reconstitution. [00507] Paulmurugan and Gambhir (Cancer Res, August 15, 2005 65, 7413) discusses the background to the FRB/FKBP/Rapamycin system. Another useful paper is the article by Crabtree et al. (Chemistry & Biology 13, 99-107, Jan 2006).

[00508] In an example, a single vector, an expression cassette (plasmid) is constructed. gRNA is under the control of a U6 promoter. Two different Cpfl splits are used. The split Cpfl construct is based on a first Cpfl fusion construct, flanked by NLSs, with FKBP fused to C

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PCT/US2016/038181 terminal part of the split CPfI via a GlySer linker; and a second CPf 1 fusion construct, flanked by NESs, with FRB fused with the N terminal part of the split CPfl via a GlySer linker. To separate the first and second Cpfl fusion constructs, P2A is used splitting on transcription. The Split Cpfl shows indel formation similar to wildtype in the presence of rapamycin, but markedly lower indel formation than the wildtype in the absence of rapamycin.

[00509] Accordingly, a single vector is provided. The vector comprises:

a first Cpfl fusion construct attached to a first half of an inducible dimer and a second Cpfl fusion construct attached to a second half of the inducible dimer, wherein the first Cpfl fusion construct is operably linked to one or more nuclear localization signals, wherein the second CPfl fusion construct is operably linked to one or more nuclear export signals, wherein contact with an inducer energy source brings the first and second halves of the inducible heterodimer together, wherein bringing the first and second halves of the inducible heterodimer together allows the first and second CPfl fusion constructs to constitute a functional Cpfl CRISPR-Cas system, wherein the Cpfl CRISPR-Cas system comprises a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell, and wherein the functional Cpfl CRISPR-Cas system hinds to the target sequence and, optionally, edits the genomic locus to alter gene expression. These elements are preferably provided on a single construct, for example an expression cassette, [00510] The first Cpfl fusion construct is preferably flanked by at least one nuclear localization signal at each end. The second CPfl fusion construct is preferably flanked by at least one nuclear export signal at each end.

[00511] Also provided is a method of treating a subject in need thereof, comprising inducing gene editing by transforming the subject with the polynucleotide encoding the system or any of the present vectors and administering an inducer energy source to the subject. A suitable repair template may also be provided, for example delivered by a vector comprising said repair template.

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PCT/US2016/038181 [00512] Also provided is a method of treating a subject in need thereof, comprising inducing transcriptional activation or repression by transforming the subject with the polynucleotide encoding the present system or any of the present vectors, wherein said polynucleotide or vector encodes or comprises the catalytically inactive Cpfl and one or more associated functional domains; the method further comprising administering an inducer energy source to the subject. [00513] Compositions comprising the present system for use in said method of treatment are also provided. Use of the present system in the manufacture of a medicament for such methods of treatment are also provided.

[00514] Examples of conditions treatable by the present system are described herein or in documents cited herein.

[00515] The single vector can comprise a transcript-splitting agent, for example P2A. P2.A splits the transcript in two, to separate the first and second CPfl fusion constructs. The splitting is due to “ribosomal skipping “. In essence, the ribosome skips an amino acid during translation, which breaks the protein chain and results in two separate polypeptides/proteins. The single vector is also useful for applications where low background activity is not of concern but a high inducible activity is desired.

[00516] One example would be the generation of clonal embryonic stem cell lines. The normal procedure is transient transfection with plasmids encoding wt CPfl or Cpfl nickases. These plasmids produce Cpfl molecules, which stay active for several days and have a higher chance of off target activity. Using the single expression vector for split Cpfl allows restricting “high” Cpfl activity to a shorter time window (e.g. one dose of an inducer, such as rapamycin). Without continual (daily) inducer (e.g. rapamycin) treatments the activity of single expression split Cpfl vectors is low⁷ and presents a reduced chance of causing unwanted off target effects. [00517] A peak of induced Cpfl activity is beneficial in some embodiments and may most easily be brought about using a single delivery vector, but it is also possible through a dual vector system (each vector delivering one half of the split CPfl). The peak, may be high activity and for a short timescale, typically the lifetime of the inducer.

[00518] Accordingly, provided is a method for generation of clonal embryonic stem cell lines, comprising transfecting one or more embryonic stem cells w⁷ith a polynucleotide encoding the present system or one of the present vectors to express the present split Cpfl and administering

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PCT/US2016/038181 or contacting the one or more stem cells with the present inducer energy source to induce reconstitution of the Cpfl. A repair template may be provided.

[00519] As with all methods described herein, it will be appreciated that suitable gRNA or guides will be required.

[00520] Where functional domains and the like are “associated” with one or other part of the enzyme, these are typically fusions. The term “associated with” is used here in respect of how one molecule ‘associates’ with respect to another, for example between parts of the Cpfl and a functional domain. In the case of such protein-protein interactions, this association may be viewed in terms of recognition in the way an antibody recognises an epitope. Alternatively, one protein may be associated with another protein via a fusion of the two, for instance one subunit being fused to another subunit. Fusion typically occurs by addition of the amino acid sequence of one to that of the other, for instance via splicing together of the nucleotide sequences that encode each protein or subunit. Alternatively, this may essentially be dewed as binding between two molecules or direct linkage, such as a fusion protein. In any event, the fusion protein may include a linker between the two subunits of interest (i.e. between the enzyme and the functional domain or between the adaptor protein and the functional domain). Thus, in some embodiments, the part of the CPfl is associated with a functional domain by binding thereto. In other embodiments, the CPfl is associated with a functional domain because the two are fused together, optionally via an intermediate linker. Examples of linkers include the GlySer linkers discussed herein.

[00521] Other examples of inducers include light and hormones. For light, the inducible dimers may be heterodimers and include first light-inducible half of a dimer and a second (and complimentary) light-inducible half of a dimer. A preferred example of first and second lightinducible dimer halves is the CIB1 and CRY2 system. The CIB1 domain is a heterodimeric binding partner of the light-sensitive Cryptochrome 2 (CRY2).

[00522] In another example, the blue light-responsive Magnet dimerization system (pMag and nMfrg) may be fused to the two parts of a split Cpfl protein. In response to light stimulation, pMag and nMag dimerize and Cpfl reassembles. For example, such system is described in connection with Cas9 in Nihongaki et al, (Nat. Biotechnol. 33, 755-790, 2015).

[00523] The invention comprehends that the inducer energy source may be heat, ultrasound, electromagnetic energy or chemical. In a preferred embodiment of the invention, the inducer

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PCT/US2016/038181 energy source may be an antibiotic, a small molecule, a hormone, a hormone derivative, a steroid or a steroid derivative. In a more preferred embodiment, the inducer energy source maybe abscisic acid (ABA), doxycycline (DOX), cumate, rapamycin, 4-hydroxytamoxifen (4OHT), estrogen or ecdysone. The invention provides that the at least one switch may be selected from the group consisting of antibiotic based inducible systems, electromagnetic energy based inducible systems, small molecule based Inducible systems, nuclear receptor based inducible systems and hormone based inducible systems. In a more preferred embodiment the at least one switch may be selected from the group consisting of tetracycline (Tet)/DOX inducible systems, light inducible systems, ABA inducible systems, cumate repressor/operator systems, 4OHT/estrogen inducible systems, ecdysone-based inducible systems and FKBP12/FRAP (FKBP12-rapamycin complex) inducible systems. Such inducers are also discussed herein and in PCT/US2013/051418, incorporated herein by reference.

[00524] In general, any use that can be made of a Cpfl, whether wt, nickase or a dead-Cpfl (with or without associated functional domains) can be pursued using the present split Cpfl approach. The benefit remains the inducible nature of the Cpfl activity.

[00525] As a further example, split CPfl fusions with fluorescent proteins like GFP can be made. This would allow imaging of genomic loci (see Dynamic Imaging of Genomic Loci in Living Human Cells by an Optimized CRISPR/Cas System Chen B et al. Cell 2013), but in an inducible manner. As such, in some embodiments, one or more of the Cpfl parts may be associated (and in particular fused with) a fluorescent protein, for example GFP.

[00526] Further experiments address whether there is a difference in off-target cutting, between wild type (wt) and split Cpfl, when on-target cutting is at the same level. To do this. Applicants use transient transfection of wt and split Cpfl plasmids and harvest at different time points. Applicants look for off-target activatation after finding a set of samples where on-target cutting is within +/- 5%. Applicants make cell lines with stable expression of wt or split Cpfl without guides (using lentiviius). After antibiotic selection, guides are delivered with a separate lent!virus and there is harvest at different time points to measure on-/off-target cutting, [00527] Applicants introduce a destabilizing sequence (PEST, see “Use of mRNA- and protein-destabilizing elements to develop a highly responsive reporter system” Voon DC et al. Nucleic Acids Research 2005) into the FRB(N)Cpfl-NES fragment to facilitate faster degradation and therefore reduced stability of the split dead-Cpfl-VP64 complex.

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PCT/US2016/038181 [00528] Such destabilizing sequences as described elsewhere in this specification (including PEST) can be advantageous for use with split Cpfl systems.

[00529] Cell lines stably expressing split dead-Cpfl-VP64 and MS2-p65-HSFl + guide are generated, A PLX resistance screen can demonstrate that a non-reversible, timed transcriptional activation can be useful in drug screens. This approach is may be advantageous when a split dead-Cpfl-VP64 is not reversible.

[00530] In one aspect the invention provides a non-naturally occurring or engineered Cpfl CRISPR-Cas system which may comprise at least one switch wherein the activity of said Cpfl CRISPR-Cas system is controlled by contact with at least one inducer energy source as to the switch. In an embodiment of the invention the control as to the at least one switch or the activity of said Cpfl CRISPR-Cas system may be activated, enhanced, terminated or repressed. The contact with the at least one inducer energy source may result in a first effect and a second effect. The first effect may be one or more of nuclear import, nuclear export, recruitment of a secondary component (such as an effector molecule), conformational change (of protein, DNA or RNA), cleavage, release of cargo (such as a caged molecule or a co-factor), association or dissociation. The second effect may be one or more of activation, enhancement, termination or repression of the control as to the at least one switch or the activity of said Cpfl CRISPR-Cas system. In one embodiment the first effect and the second effect may occur in a cascade.

[00531] In another aspect of the invention the Cpfl CRISPR-Cas system may further comprise at least one or more nuclear localization signal (NLS), nuclear export signal (NES), functional domain, flexible linker, mutation, deletion, alteration or truncation. The one or more of the NLS, the NES or the functional domain may be conditionally activated or inactivated. In another embodiment, the mutation may be one or more of a mutation in a transcription factor homology region, a mutation in a DNA binding domain (such as mutating basic residues of a basic helix loop helix), a mutation in an endogenous NLS or a mutation in an endogenous NES. The invention comprehends that the inducer energy source may be heat, ultrasound, electromagnetic energy or chemical. In a preferred embodiment of the invention, the inducer energy source may be an antibiotic, a small molecule, a hormone, a hormone derivative, a steroid or a steroid derivative. In a more preferred embodiment, the inducer energy source maybe abscisic acid GABA), doxycycline (DOX), cumate, rapamycin, 4-hydroxytamoxifen (4OHT), estrogen or ecdysone. The invention provides that the at least one switch may be selected from

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PCT/US2016/038181 the group consisting of antibiotic based inducible systems, electromagnetic energy based inducible systems, small molecule based inducible systems, nuclear receptor based inducible systems and hormone based inducible systems. In a more preferred embodiment the at least one switch may be selected from the group consisting of tetracycline (Tet)/DOX inducible systems, light inducible systems, ABA inducible systems, cumate repressor/operator systems, 4OHT/estrogen inducible systems, ecdysone-based inducible systems and FKBP12/FRAP (FKBP12-rapamycin complex) inducible systems.

[00532] Aspects of control as detailed in this application relate to at least one or more switch(es). The term “switch” as used herein refers to a system or a set of components that act in a coordinated manner to affect a change, encompassing all aspects of biological function such as activation, repression, enhancement or termination of that function. In one aspect the term switch encompasses genetic switches which comprise the basic components of gene regulatory proteins and the specific DNA sequences that these proteins recognize. In one aspect, switches relate to inducible and repressible systems used in gene regulation. In general, an inducible system may be off unless there is the presence of some molecule (called an inducer) that allows for gene expression. The molecule is said to “induce expression”. The manner by which this happens is dependent on the control mechanisms as well as differences in cell type. A repressible system is on except in the presence of some molecule (called a corepressor) that suppresses gene expression. The molecule is said to “repress expression”. The manner by which this happens is dependent on the control mechanisms as well as differences in cell type. The term “inducible” as used herein may encompass all aspects of a switch irrespective of the molecular mechanism involved. Accordingly a switch as comprehended by the invention may include but is not limited to antibiotic based inducible systems, electromagnetic energy based inducible systems, small molecule based inducible systems, nuclear receptor based inducible systems and hormone based inducible systems. In preferred embodiments the switch may be a tetracycline (Tet)/DOX inducible system, a light inducible systems, a Abscisic acid (ABA) inducible system, a cumate repressor/operator system, a 4OHT/estrogen inducible system, an ecdysone-based inducible systems or a FKBP12/FRAP (FKBP12-rapamycin complex) inducible system.

[00533] The present Cpfl CRISPR-Cas system may be designed to modulate or alter expression of individual endogenous genes in a temporally and spatially precise manner. The Cpfl CRISPR-Cas system may be designed to bind to the promoter sequence of the gene of

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PCT/US2016/038181 interest to change gene expression. The Cpfl may be spilt into two where one half is fused to one half of the cryptochrome heterodimer (cryptochrome-2 or CIBT), while the remaining cryptochrome partner is fused to the other half of the Cpfl. In some aspects, a transcriptional effector domain may also be included in the Cpfl CRISPR-Cas system. Effector domains may be either activators, such as VP 16, VP64, or p65, or repressors, such as KRAB, EnR, or SID. In unstimulated state, the one half Cpfl-cryptochrome2 protein localizes to the promoter of the gene of interest, but is not bound to the CIB1-effector protein. Upon stimulation with blue spectrum light, cryptochrome-2 becomes activated, undergoes a conformational change, and reveals its binding domain. CIB1, in turn, binds to cryptochrome-2 resulting in localization of the second half of the Cpfl to the promoter region of the gene of interest and initiating genome editing which may result in gene overexpression or silencing. Aspects of LITEs are further described in Liu, H et al. , Science. 2008 and Kennedy M et al.. Nature Methods 2010, the contents of which are herein incorporated by reference in their entirety.

[00534] Activator and repressor domains which may further modulate function may be selected on the basis of species, strength, mechanism, duration, size, or any number of other parameters. Preferred effector domains include, but are not limited to, a transposase domain, integrase domain, recombinase domain, resol vase domain, invertase domain, protease domain, DNA methyltransferase domain, DNA demethylase domain, histone acetylase domain, histone deacetylases domain, nuclease domain, repressor domain, activator domain, nuclear-localization signal domains, transcription-protein recruiting domain, cellular uptake activity associated domain, nucleic acid binding domain or antibody presentation domain.

[00535] There are several different ways to generate chemical inducible systems as well: 1. ABI-PYL based system inducible by Abscisic Acid (ABA) (see, e.g., website at stke.sciencemag.org/cgi/content/abstract/sigtrans;4/164/rs2), 2. FKBP-FRB based system inducible by rapamycin (or related chemicals based on rapamycin) (see, e.g., website at nature.com/nmeth/joumal/v2/n6/full/nmeth763.html), 3. GIDl-GAI based system inducible by Gibberellin (GA) (see, e.g., website at nature. com/nchembio/journal/v8/n5/full/nchembio.922.html).

[00536] Another system contemplated by the present invention is a chemical inducible system based on change in sub-cellular localization. Applicants also comprehend an inducible Cpfl CRISPR-Cas system engineered to target a genomic locus of interest wherein the Cpfl enzyme is

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PCT/US2016/038181 split into two fusion constructs that are further linked to different parts of a chemical or energy sensitive protein. This chemical or energy sensitive protein wall lead to a change in the subcellular localization of either half of the CPfl enzyme (i.e. transportation of either half of the Cpfl enzyme from cytoplasm into the nucleus of the cells) upon the binding of a chemical or energy transfer to the chemical or energy sensitive protein. This transportation of fusion constructs from one sub-cellular compartments or organelles, in which its activity is sequestered due to lack of substrate for the reconstituted Cpfl CRISPR-Cas system, into another one in which the substrate is present would allow the components to come together and reconstitute functional activity and to then come in contact with its desired substrate (i.e. genomic DNA in the mammalian nucleus) and result in activation or repression of target gene expression.

[00537] Other inducible systems are contemplated such as, but not limited to, regulation by heavy-metals [Mayo KE et al., Cell 1982, 29:99-108; Searle PF et al., Mol Cell Biol 1985, 5:1480-1489 and Brinster RL et al., Nature (London) 1982, 296:39-42], steroid hormones [Hynes NE et al., Proc Natl Acad Sci LISA 1981, 78:2038-2042; Klock G et al., Nature (London) 1987, 329:734-736 and Lee F et al., Nature (London) 1981, 294:228-232.], heat shock [Nouer L: Heat Shock Response. Boca Raton, FL: CRC; 1991] and other reagents have been developed [Mullick A, Massie B: Transcription, translation and the control of gene expression. In Encyclopedia of Cell Technology Edited by: Speir RE. Wiley; 2000:1140-1164 and Fussenegger M, . Biotechnol Prog 2001, 17:1-51], However, there are limitations with these inducible mammalian promoters such as leakiness of the off state and pleiotropic effects of inducers (heat shock, heavy metals, glucocorticoids etc.). The use of insect hormones (ecdysone) has been proposed in an attempt to reduce the interference with cellular processes in mammalian cells [No D et al,, Proc Natl Acad Sci EISA 1996, 93:3346-3351], Another elegant system uses rapamycin as the inducer [Rivera VM et al., Nat Med 1996, 2:1028-1032] but the role of rapamycin as an immunosuppressant was a major limitation to its use in vivo and therefore it was necessary⁷ to find a biologically inert compound [Saez E et al., Proc Natl Acad Sci USA 2000, 97:1451214517] for the control of gene expression.

[00538] In particular embodiments, the gene editing systems described herein are placed under the control of a passcode kill switch, which is a mechanisms which efficiently kills the host cell when the conditions of the cell are altered. This is ensured by introducing hybrid LaclGalR family transcription factors, which require the presence of IPTG to be switched on (Chan et

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PCT/US2016/038181 al. 2015 Nature Nature Chemical Biology doi:10.1038/nchembio.l979 which can be used to drive a gene encoding an enzyme critical for cell-survival. By combining different transcription factors sensitive to different chemicals, a “code” can be generated, This system can be used to spatially and temporally control the extent of CRISPR-induced genetic modifications, which can be of interest in different fields including therapeutic applications and may also be of interest to avoid the “escape” of GMOs from their intended environment.

Seif-inactivating systems [00539] Once all copies of a gene in the genome of a cell have been edited, continued CRISRP/Cpfl expression in that cell is no longer necessary. Indeed, sustained expression would be undesirable in case of off-target effects at unintended genomic sites, etc. Thus time-limited expression would be useful. Inducible expression offers one approach, but in addition Applicants envisage a SelfInactivating CRISPR-Cpfl system that relies on the use of a non-coding guide target sequence within the CRISPR vector itself. Thus, after expression begins, the CRISPR system will lead to its own destruction, but before destruction is complete it will have time to edit the genomic copies of the target gene (which, with a normal point mutation in a diploid cell, requires at most two edits). Simply, the self inactivating CRISPR-Cas system includes additional RNA (i.e., guide RNA) that targets the coding sequence for the CRISPR enzyme itself or that targets one or more non-coding guide target sequences complementary to unique sequences present in one or more of the following:

[00540] (a) within the promoter driving expression of the non-coding RNA elements, [00541] (b) within the promoter driving expression of the Cpfl gene, [00542] (c) within lOObp of the ATG translational start codon in the Cpfl coding sequence, [00543] (d) within the inverted terminal repeat (iTR) of a viral delivery vector, e.g., in the

AAV genome.

[00544] Furthermore, that RNA can be delivered via a vector, e.g,, a separate vector or the same vector that is encoding the CRISPR complex. When provided by a separate vector, the CRISPR RNA that targets Cpfl expression can be administered sequentially or simultaneously. When administered sequentially, the CRISPR RNA that targets Cpfl expression is to be delivered after the CRISPR RNA that is intended for e.g. gene editing or gene engineering. This period may be a period of minutes (e.g. 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes). This period may be a period of hours (e.g. 2 hours, 4 hours, 6 hours, 8

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PCT/US2016/038181 hours, 12 hours, 24 hours). This period may be a period of days (e.g. 2 days, 3 days, 4 days, 7 days). This period may be a period of weeks (e.g. 2 weeks, 3 weeks, 4 weeks). This period may be a period of months (e.g. 2 months, 4 months, 8 months, 12 months). This period may be a period of years (2 years, 3 years, 4 years). In this fashion, the Cas enzyme associates with a first gRNA capable of hybridizing to a first target, such as a genomic locus or loci of interest and undertakes the function(s) desired of the CRISPR-Cas system (e.g., gene engineering), and subsequently the Cpfl enzyme may then associate with the second gRNA capable of hybridizing to the sequence comprising at least part of the Cpfl or CRISPR cassette. Where the gRNA targets the sequences encoding expression of the Cpfl protein, the enzyme becomes impeded and the system becomes self inactivating. In the same manner, CRISPR RNA that targets Cpfl expression applied via, for example liposome, lipofection, nanoparticles, microvesicles as explained herein, may be administered sequentially or simultaneously. Similarly, selfinactivation may be used for inactivation of one or more guide RNA used to target one or more targets.

[00545] In some aspects, a single gRNA is provided that is capable of hybridization to a sequence downstream of a CRISPR enzyme start codon, whereby after a period of time there is a loss of the CRISPR. enzyme expression. In some aspects, one or more gRNA(s) are provided that are capable of hybridization to one or more coding or non-coding regions of the polynucleotide encoding the CRISPR-Cas system, whereby after a period of time there is a inactivation of one or more, or in some cases all, of the CRISPR-Cas systems. In some aspects of the system, and not to be limited by theory, the cell may comprise a plurality of CRISPR-Cas complexes, wherein a first subset of CRISPR complexes comprise a first gRNA capable of targeting a genomic locus or loci to be edited, and a second subset of CRISPR complexes comprise at least one second gRNA capable of targeting the polynucleotide encoding the CRISPR-Cas system, wherein the first subset of CRISPR-Cas complexes mediate editing of the targeted genomic locus or loci and the second subset of CRISPR complexes eventually inactivate the CRISPR-Cas system, thereby inactivating further CRISPR-Cas expression in the cell.

[00546] Thus the invention provides a CRISPR-Cas system comprising one or more vectors for delivery to a eukaryotic cell, wherein the vector(s) encode(s): (i) a CRISPR enzyme, more particularly Cpfl; (ii) a first guide RNA capable of hybridizing to a target sequence in the cell; and (iii) a second guide RNA capable of hybridizing to one or more target sequence(s) in the

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PCT/US2016/038181 vector which encodes the CRISPR enzyme, When expressed within the cell, the first guide RNA directs sequence-specific binding of a first CRISPR complex to the target sequence in the cell; the second guide RNA directs sequence-specific binding of a second CRISPR complex to the target sequence in the vector which encodes the CRISPR enzyme; the CRISPR complexes comprise a CRISPR enzyme bound to a guide RNA, whereby a guide RNA can hybridize to its target sequence; and the second CRISPR complex inactivates the CRISPR-Cas system to prevent continued expression of the CRISPR enzyme by the cell.

[00547] Further characteristics of the vector(s), the encoded enzyme, the guide sequences, etc. are disclosed elsewhere herein. The system can encode (i) a CRISPR enzyme, more particularly Cpfl; (ii) a first gRNA comprising a sequence capable of hybridizing to a first target sequence in the cell, (iii) a second guide RNA capable of hybridizing to the vector which encodes the CRISPR enzvme. Similarly, the enzvme can include one or more NLS, etc.

[00548] The various coding sequences (CRISPR enzyme, guide RNAs) can be included on a single vector or on multiple vectors. For instance, it is possible to encode the enzyme on one vector and the various RNA sequences on another vector, or to encode the enzyme and one gRNA on one vector, and the remaining gRNA on another vector, or any other permutation. In general, a system using a total of one or two different vectors is preferred.

[00549] Where multiple vectors are used, it is possible to deliver them in unequal numbers, and ideally with an excess of a vector which encodes the first guide RNA relative to the second guide RNA, thereby assisting in delaying final inactivation of the CRISPR system until genome editing has had a chance to occur.

[00550] The first guide RNA can target any target sequence of interest within a genome, as described elsewhere herein. The second guide RNA targets a sequence within the vector which encodes the CRISPR Cas9 enzyme, and thereby inactivates the enzyme’s expression from that vector. Thus the target sequence in the vector must be capable of inactivating expression. Suitable target sequences can be, for instance, near to or within the translational start codon for the Cpfl coding sequence, in a non-coding sequence in the promoter driving expression of the non-coding RNA elements, within the promoter driving expression of the Cpfl gene, within lOObp of the ATG translational start codon in the Cpfl coding sequence, and/or within the inverted terminal repeat (iTR) of a viral deliver)' vector, e.g., in the AAV genome. A double stranded break near this region can induce a frame shift in the Cpfl coding sequence, causing a

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PCT/US2016/038181 loss of protein expression. An alternative target sequence for the “self-inactivating” guide RNA would aim to edit/inactivate regulatory⁷ regions/sequences needed for the expression of the CRISPR-Cpfi system or for the stability of the vector. For instance, if the promoter for the Cpfl coding sequence is disrupted then transcription can be inhibited or prevented. Similarly, if a vector includes sequences for replication, maintenance or stability then it is possible to target these. For instance, in a AAV vector a useful target sequence is within the iTR. Other useful sequences to target can be promoter sequences, polyadenlyation sites, etc.

[00551] Furthermore, if the guide RNAs are expressed in array format, the “self-inactivating” guide RNAs that target both promoters simultaneously will result in the excision of the intervening nucleotides from within the CRISPR-Cas expression construct, effectively leading to its complete inactivation. Similarly, excision of the intervening nucleotides will result where the guide RNAs target both ITRs, or targets two or more other CRISPR-Cas components simultaneously. Self-inactivation as explained herein is applicable, in general, with CRISPRCpfl systems in order to provide regulation of the CRISPR-Cpfi. For example, self-inactivation as explained herein may be applied to the CRISPR repair of mutations, for example expansion disorders, as explained herein. As a result of this self-inactivation, CRISPR repair is only transiently active.

[00552] Addition of non-targeting nucleotides to the 5’ end (e.g. 1 - 10 nucleotides, preferably 1-5 nucleotides) of the “self-inactivating” guide RNA can be used to delay its processing and/or modify its efficiency as a means of ensuring editing at the targeted genomic locus prior to CRISPR-Cpfi shutdown.

[00553] In one aspect of the self-inactivating AAV-CRISPR-Cpfl system, plasmids that coexpress one or more gRNA targeting genomic sequences of interest (e.g. 1-2, 1-5, 1-10, 1 -15, 120, 1-30) may be established with “self-inactivating” gRNAs that target an LbCpfl sequence at or near the engineered ATG start site (e.g. within 5 nucleotides, within 15 nucleotides, within 30 nucleotides, within 50 nucleotides, within 100 nucleotides). A regulatory sequence in the U6 promoter region can also be targeted with an gRNA. The U6-driven gRNAs may be designed in an array format such that multiple gRNA sequences can be simultaneously released. When first delivered into target tissue/cells (left cell) gRNAs begin to accumulate while Cpfl levels rise in the nucleus. Cpfl complexes with all of the gRNAs to mediate genome editing and selfinactivation of the CRISPR-Cpfi plasmi ds.

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PCT/US2016/038181 [00554] One aspect of a self-inactivating CRISPR-Cpfl system is expression of singly or in tandam array format from 1 up to 4 or more different guide sequences; e.g. up to about 20 or about 30 guides sequences. Each individual self inactivating guide sequence may target a different target. Such may be processed from, e.g, one chimeric po!3 transcript. Pol3 promoters such as U6 or Hl promoters may be used. Pol2 promoters such as those mentioned throughout herein. Inverted terminal repeat (iTR) sequences may flank the Pol3 promoter - gRNA(s)-Poi2 promoter- Cpfl.

[00555] One aspect of a chimeric, tandem array transcript is that one or more guide(s) edit the one or more target(s) while one or more self inactivating guides inactivate the CRISPR/Cpfl system. Thus, for example, the described CRISPR-Cpfl system for repairing expansion disorders may be directly combined with the self-inactivating CRISPR-Cpfl system described herein. Such a system may, for example, have two guides directed to the target region for repair as well as at least a third guide directed to self-inactivation of the CRISPR-Cpfl. Reference is made to Application Ser. No. PCT/US2014/069897, entitled “Compositions And Methods Of Use Of Crispr-Cas Systems In Nucleotide Repeat Disorders,” published Dec. 12, 2014 as W 0/2015/089351.

Gene Editing or Altering a Target Lori with Cpfl [00556] The double strand break or single strand break in one of the strands advantageously should be sufficiently close to target position such that correction occurs. In an embodiment, the distance is not more than 50, 100, 200, 300, 350 or 400 nucleotides. While not wishing to be bound by theory', it is believed that the break should be sufficiently close to target position such that the break is within the region that is subject to exonuclease-mediated removal during end resection. If the distance between the target position and a break is too great, the mutation may not be included in the end resection and, therefore, may not be corrected, as the template nucleic acid sequence may only be used to correct sequence within the end resection region.

[00557] In an embodiment, in which a guide RNA and a Type V/Type VI molecule, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, preferably a Cpfl nuclease induce a double strand break for the purpose of inducing HDR-mediated correction, the cleavage site is between 0-200 bp (e.g., 0 to 175, 0 to 150, 0 to 125, 0 to 100, 0 to 75, 0 to 50, 0 to 25, 25 to 200, 25 to 175, 25 to 150, 25 to 125, 25 to 100, 25 to 75, 25 to 50, 50 to 200, 50 to 175, 50 to 150, 50 to 125, 50 to 100, 50 to 75, 75 to 200, 75 to 175, 75 to 150, 75 to 1 25, 75 to 100 bp) away from

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PCT/US2016/038181 the target position. In an embodiment, the cleavage site is between 0- 100 bp (e.g., 0 to 75, 0 to 50, 0 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, 50 to 75 or 75 to 100 bp) away from the target position. In a further embodiment, two or more guide RNAs complexing with Cpfl or an ortholog or homolog thereof, may be used to induce multiplexed breaks for purpose of inducing HDR-mediated correction.

[00558] The homology arm should extend at least as far as the region in which end resection may occur, e.g., in order to allow the resected single stranded overhang to find a complementary region within the donor template. The overall length could be limited by parameters such as plasmid size or viral packaging limits. In an embodiment, a homology arm may not extend into repeated elements. Exemplary homology arm lengths include a least 50, 100, 250, 500, 750 or 1000 nucleotides.

[00559] Target position, as used herein, refers to a site on a target nucleic acid or target gene (e.g., the chromosome) that is modified by a Type V/Type VI, in particular Cpf1/C2c1/C2c2 or an ortholog or homolog thereof, preferably Cpfl molecule-dependent process. For example, the target position can be a modified Cpfl molecule cleavage of the target nucleic acid and template nucleic acid directed modification, e.g., correction, of the target position. In an embodiment, a target position can be a site between two nucleotides, e.g., adjacent nucleotides, on the target nucleic acid into which one or more nucleotides is added. The target position may comprise one or more nucleotides that are altered, e.g., corrected, by a template nucleic acid. In an embodiment, the target position is within a target sequence (e.g,, the sequence to which the guide RNA binds). In an embodiment, a target position is upstream or downstream of a target sequence (e.g., the sequence to which the guide RNA binds), [00560] A template nucleic acid, as that term is used herein, refers to a nucleic acid sequence which can be used in conjunction with a Type V/Type VI molecule, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, preferably a Cpfl molecule and a guide RNA molecule to alter the structure of a target position. In an embodiment, the target nucleic acid is modified to have some or all of the sequence of the template nucleic acid, typically at or near cleavage site(s). In an embodiment, the template nucleic acid is single stranded. In an alternate embodiment, the template nuceic acid is double stranded. In an embodiment, the template nucleic acid is DNA, e.g., double stranded DNA. In an alternate embodiment, the template nucleic acid is single stranded DNA.

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PCT/US2016/038181 [00561] In an embodiment, the template nucleic acid alters the structure of the target position by participating in homologous recombination. In an embodiment, the template nucleic acid alters the sequence of the target position. In an embodiment, the template nucleic acid results in the incorporation of a modified, or non-naturally occurring base into the target nucleic acid. [00562] The template sequence may undergo a breakage mediated or catalyzed recombination with the target sequence. In an embodiment, the template nucleic acid may include sequence that corresponds to a site on the target sequence that is cleaved by an Cpfl mediated cleavage event. In an embodiment, the template nucleic acid may include sequence that corresponds to both, a first site on the target sequence that is cleaved in a first Cpfl mediated event, and a second site on the target sequence that is cleaved in a second Cpfl mediated event.

[00563] In certain embodiments, the template nucleic acid can include sequence which results in an alteration in the coding sequence of a translated sequence, e.g., one which results in the substitution of one antino acid for another in a protein product, e.g., transforming a mutant allele into a wild type allele, transforming a wild type allele into a mutant allele, and/or introducing a stop codon, insertion of an amino acid residue, deletion of an amino acid residue, or a nonsense mutation. In certain embodiments, the template nucleic acid can include sequence which results in an alteration in a non-coding sequence, e.g., an alteration in an exon or in a 5' or 3' nontranslated or non-transcribed region. Such alterations include an alteration in a control element, e.g., a promoter, enhancer, and an alteration in a cis-acting or trans-acting control element. [00564] A template nucleic acid having homology with a target position in a target gene may be used to alter the structure of a target sequence. The template sequence may be used to alter an unwanted structure, e.g., an unwanted or mutant nucleotide. The template nucleic acid may include sequence which, when integrated, results in: decreasing the activity of a positive control element; increasing the activity of a positive control element; decreasing the activity of a negative control element; increasing the activity of a negative control element; decreasing the expression of a gene, increasing the expression of a gene; increasing resistance to a disorder or disease; increasing resistance to viral entry; correcting a mutation or altering an unwanted amino acid residue conferring, increasing, abolishing or decreasing a biological property of a gene product, e.g., increasing the enzymatic activity of an enzyme, or increasing the ability of a gene product to interact with another molecule.

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PCT/US2016/038181 [00565] The template nucleic acid may include sequence which results in: a change in sequence of 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12 or more nucleotides of the target sequence. In an embodiment, the template nucleic acid may be 20+/- 10, 30+/- 10, 40+/- 10, 50+/- 10, 60+/- 10, 70+/- 10, 80+/- 10, 90+/- 10, 10()+/- 10, 1 1()+/- 10, 120+-/- 10, 130+/- 10, 140+/- 10, 150+/- 10, 160+/- 10, 170+/- 10, 1 80+/- 10, 190+/- 10, 200+/- 10, 210+/-10, of 220+/- 10 nucleotides in length. In an embodiment, the template nucleic acid may be 30+/-20, 40+/-20, 50+/-20, 60+/-20, 70+/- 20, 80+/-20, 90+/-20, 100+/-20, 1 10+/-20, 120+/-20, 130+/-20, 140+/-20, I 50+/-20, 160+/-20, 170+/-20, 180+/-20, 190+/-20, 200+/-20, 210+/-20, of 220+/-20 nucleotides in length. In an embodiment, the template nucleic acid is 10 to 1 ,000, 20 to 900, 30 to 800, 40 to 700, 50 to 600, 50 to 500, 50 to 400, 50 to300, 50 to 200, or 50 to 100 nucleotides in length.

[00566] A template nucleic acid comprises the following components: [5' homology arm][replacement sequence]-[3' homology arm]. The homology arms provide for recombination into the chromosome, thus replacing the undesired element, e.g., a mutation or signature, with the replacement sequence. In an embodiment, the homology arms flank the most distal cleavage sites. In an embodiment, the 3' end of the 5' homology arm is the position next to the 5' end of the replacement sequence. In an embodiment, the 5' homology arm can extend at least 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 nucleotides 5' from the 5' end of the replacement sequence. In an embodiment, the 5' end of the 3' homology arm is the position next to the 3' end of the replacement sequence. In an embodiment, the 3' homology arm can extend at least 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 nucleotides 3' from the 3' end of the replacement sequence.

[00567] In certain embodiments, one or both homology arms may be shortened to avoid including certain sequence repeat elements. For example, a 5’ homology arm may he shortened to avoid a sequence repeat element. In other embodiments, a 3' homology arm may be shortened to avoid a sequence repeat element. In some embodiments, both the 5' and the 3' homology arms may be shortened to avoid including certain sequence repeat elements.

[00568] In certain embodiments, a template nucleic acids for correcting a mutation may designed for use as a single-stranded oligonucleotide. When using a single-stranded oligonucleotide, 5’ and 3’ homology arms may range up to about 200 base pairs (bp) in length, e.g., at least 25, 50, 75, 100, 125, 150, 175, or 200 bp in length.

Cpfl Effector Protein Complex System Promoted Non-Homoiogous End-Joining

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PCT/US2016/038181 [00569] In certain embodiments, nuclease-induced non-homologous end-joining (NHEJ) can be used to target gene-specific knockouts. Nuclease-induced NHEJ can also be used to remove (e.g., delete) sequence in a gene of interest. Generally, NHEJ repairs a double-strand break in the DNA by joining together the two ends; however, generally, the original sequence is restored only if two compatible ends, exactly as they were formed by the double-strand break, are perfectly ligated. The DNA ends of the double-strand break are frequently the subject of enzymatic processing, resulting in the addition or removal of nucleotides, at one or both strands, prior to rejoining of the ends. This results in the presence of insertion and/or deletion (indel) mutations in the DNA sequence at the site of the NHEJ repair. Two-thirds of these mutations typically alter the reading frame and, therefore, produce a non-functional protein. Additionally, mutations that maintain the reading frame, but which insert or delete a significant amount of sequence, can destroy functionality of the protein. This is locus dependent as mutations in critical functional domains are likely less tolerable than mutations in non-critical regions of the protein. The indel mutations generated by NHEJ are unpredictable in nature; however, at a given break site certain indel sequences are favored and are over represented in the population, likely due to small regions of microhomology. The lengths of deletions can vary widely; most commonly in the 150 bp range, but they can easily be greater than 50 bp, e.g., they can easily reach greater than about 100-200 bp. Insertions tend to be shorter and often include short duplications of the sequence immediately surrounding the break site. However, it is possible to obtain large insertions, and in these cases, the inserted sequence has often been traced to other regions of the genome or to plasmid DNA present in the cells.

[00570] Because NHEJ is a mutagenic process, it may also be used to delete small sequence motifs as long as the generation of a specific final sequence is not required. If a double-strand break is targeted near to a short target sequence, the deletion mutations caused by the NHEJ repair often span, and therefore remove, the unwanted nucleotides. For the deletion of larger DNA segments, introducing two double-strand breaks, one on each side of the sequence, can result in NHEJ between the ends with removal of the entire intervening sequence. Both of these approaches can be used to delete specific DNA sequences; however, the error-prone nature of NHEJ may still produce indel mutations at the site of repair.

[00571] Both double strand cleaving Type V/Type VI molecule, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, preferably Cpfl molecules and single strand, or nickase, Type

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V/Type VI molecule, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, preferably Cpfl molecules can be used in the methods and compositions described herein to generate NHEJ- mediated indels. NHEJ-mediated indels targeted to the gene, e.g., a coding region, e.g., an early coding region of a gene of interest can be used to knockout (i.e., eliminate expression of) a gene of interest. For example, early coding region of a gene of interest includes sequence immediately following a transcription start site, within a first exon of the coding sequence, or within 500 bp of the transcription start site (e.g., less than 500, 450, 400, 350, 300, 250, 200, 150, 100 or 50 bp).

[00572] In an embodiment, in which a guide RN A and Type V/Type VI molecule, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof preferably Cpfl nuclease generate a double strand break for the purpose of inducing NHEJ-mediated indels, a guide RNA may be configured to position one double-strand break in close proximity to a nucleotide of the target position. In an embodiment, the cleavage site may be between 0-500 bp away from the target position (e.g., less than 500, 400, 300, 200, 100, 50, 40, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 bp from the target position).

[00573] In an embodiment, in which two guide RNAs complexing with Type V/Type VI molecules, in particular Cpfl/C2cl/C2c2 or an ortholog or homolog thereof, preferably Cpfl nickases induce two single strand breaks for the purpose of inducing NHEJ-mediated indels, two guide RNAs may be configured to position two single-strand breaks to provide for NHEJ repair a nucleotide of the target position.

[00574] Unlike CRISPR-Cas-mediated gene knockout, which permanently eliminates expression by mutating the gene at the DNA level, CRISPR-Cas knockdown allows for temporary reduction of gene expression through the use of artificial transcription factors. Mutating key residues in both DNA cleavage domains of the Cpfl protein, such as FnCpfl protein (e.g. the D917A and H1006A mutations of the FnCpfl protein or D908A, E993A, D1263A according to AsCpfl protein or D832A, E925A, D947A or D1180A according to LbCpf 1 protein) results in the generation of a catalytically inactive Cpfl. A catalytically inactive Cpfl complexes with a guide RNA and localizes to the DNA sequence specified by that guide RNA's targeting domain, however, it does not cleave the target DNA. Fusion of the inactive Cpfl protein, such as FnCpfl protein (e.g. the D917A and H1006A mutations) to an effector

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PCT/US2016/038181 domain, e.g., a transcription repression domain, enables recruitment of the effector to any DNA site specified by the guide RNA. In certain embodiments, Cpfl may be fused to a transcriptional repression domain and recruited to the promoter region of a gene. Especially for gene repression, it is contemplated herein that blocking the binding site of an endogenous transcription factor would aid in downregulating gene expression. In another embodiment, an inactive Cpfl can be fused to a chromatin modifying protein. Altering chromatin status can result in decreased expression of the target gene.

[00575] In an embodiment, a guide RNA molecule can be targeted to a known transcription response elements (e.g., promoters, enhancers, etc.), a known upstream activating sequences, and/or sequences of unknown or known function that are suspected of being able to control expression of the target DN A. [00576] In some methods, a target polynucleotide can be inactivated to effect the modification of the expression in a cell. For example, upon the binding of a CRISPR complex to a target sequence in a cell, the target polynucleotide is inactivated such that the sequence is not transcribed, the coded protein is not produced, or the sequence does not function as the wild-type sequence does. For example, a protein or microRNA coding sequence may be inactivated such that the protein is not produced.

[00577] In certain embodiments, the CRISPR. enzyme comprises one or more mutations selected from the group consisting of D917A, E1006A and D1225A and/or the one or more mutations is in a RuvC domain of the CRISPR enzyme or is a mutation as otherwise as discussed herein. In some embodiments, the CRISPR enzyme has one or more mutations in a catalytic domain, wherein when transcribed, the direct repeat sequence forms a single stem loop and the guide sequence directs sequence-specific binding of a CRISPR complex to the target sequence, and wherein the enzyme further comprises a functional domain. In some embodiments, the functional domain is a transcriptional activation domain, preferably VP64. In some embodiments, the functional domain is a transcription repression domain, preferably KRAB. In some embodiments, the transcription repression domain is SID, or concatemers of SID (eg SID4X). In some embodiments, the functional domain is an epigenetic modifying domain, such that an epigenetic modifying enzyme is provided. In some embodiments, the functional domain is an activation domain, which may be the P65 activation domain.

Delivery of the Cpfl Effector Protein Complex or Components Thereof

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PCT/US2016/038181 [00578] Through this disclosure and the knowledge in the art, CRISPR-Cas system, specifically the novel CRISPR systems described herein, or components thereof or nucleic acid molecules thereof (including, for instance HDR template) or nucleic acid molecules encoding or providing components thereof may be delivered by a delivery system herein described both generally and in detail.

[00579] Vector delivery/, e.g,, plasmid, viral delivery: The CRISPR enzyme, for instance a Cpfl, and/or any of the present RNAs, for instance a guide RNA, can be delivered using any suitable vector, e.g,, plasmid or viral vectors, such as adeno associated virus (AAV), lentivirus, adenovirus or other viral vector types, or combinations thereof. Cpfl and one or more guide RNAs can be packaged into one or more vectors, e.g., plasmid or viral vectors. In some embodiments, the vector, e.g,, plasmid or viral vector is delivered to the tissue of interest by, for example, an intramuscular injection, while other times the delivery is via intravenous, transdermal, intranasal, oral, mucosal, or other delivery methods. Such delivery may be either via a single dose, or multiple doses. One skilled in the art understands that the actual dosage to be delivered herein may vary greatly depending upon a variety of factors, such as the vector choice, the target ceil, organism, or tissue, the general condition of the subject to be treated, the degree of transformation/modification sought, the administration route, the administration mode, the type of transformation/modification sought, etc.

[00580] Such a dosage may further contain, for example, a carrier (water, saline, ethanol, glycerol, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil, etc.), a diluent, a pharmaceutically-acceptable carrier (e.g., phosphate-buffered saline), a pharmaceutically-acceptable excipient, and/or other compounds known in the art. The dosage may further contain one or more pharmaceutically acceptable salts such as, for example, a mineral acid salt such as a hydrochloride, a hydrobromide, a phosphate, a sulfate, etc.; and the salts of organic acids such as acetates, propionates, malonates, benzoates, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, gels or gelling materials, flavorings, colorants, microspheres, polymers, suspension agents, etc. may also be present herein. In addition, one or more other conventional pharmaceutical ingredients, such as preservatives, humectants, suspending agents, surfactants, antioxidants, anticaking agents, fillers, chelating agents, coating agents, chemical stabilizers, etc. may also be present, especially if the dosage form is a reconstitutable form. Suitable exemplary ingredients include

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PCT/US2016/038181 microcrystalline cellulose, carboxymethylcellulose sodium, polysorbate 80, phenylethyl alcohol, chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, parachlorophenol, gelatin, albumin and a combination thereof. A thorough discussion of pharmaceutically acceptable excipients is available in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. 1991) which is incorporated by reference herein.

[00581] In an embodiment herein the delivery is via an adenovirus, which may be at a single booster dose containing at least 1 x 10⁵ particles (also referred to as particle units, pu) of adenoviral vector. In an embodiment herein, the dose preferably is at least about 1 x 10⁶ particles (for example, about 1 x 10⁶-1 x 10¹² particles), more preferably at least about 1 x 10 particles, more preferably at least about 1 x 10⁸ particles (e.g., about 1 x 1()⁸-I x 10¹¹ particles or about 1 x 10⁸-l x I0^l2 particles), and most preferably at least about 1 x 10° particles (e.g., about 1 x 10⁹-l x 1()¹⁰ particles or about 1 x 10⁹-l x 1()¹² particles), or even at least about 1 x IO¹⁰ particles (e.g., about 1 x 10^1,J-l x 10^u particles) of the adenoviral vector. Alternatively, the dose comprises no more than about 1 x 10¹⁴ particles, preferably no more than about 1 x 10¹³ particles, even more preferably no more than about 1 x IO⁴² particles, even more preferably no more than about 1 x 10¹¹ particles, and most preferably no more than about I x 10¹° particles (e.g., no more than about 1 x 10⁹ articles). Thus, the dose may contain a single dose of adenoviral vector with, for example, about 1x10° particle units (pu), about 2 x 10⁶ pu, about 4 x 10⁶ pu, about 1x10' pu, about 2x10' pu, about 4 x 10' pu, about 1 x 1()⁸ pu, about 2 x 10⁸ pu, about 4 x IO⁸ pu, about 1 x 10⁹ pu, about 2 x 10⁹ pu, about 4 x I0^y pu, about I x 10ⁱ⁰ pu, about 2 X 1()¹⁰ pu, about 4 x 10¹⁴' pu, about 1 x 10ⁿ pu, about 2 x 10¹¹ pu, about 4 x 10¹¹ pu, about 1 x 10'² pu, about 2 x 10¹² pu, or about 4 x IO⁴² pu of adenoviral vector. See, for example, the adenoviral vectors in U.S. Patent No. 8,454,972 B2 to Nabel, et. al., granted on June 4, 2013, incorporated by reference herein, and the dosages at col 29, lines 36-58 thereof. In an embodiment herein, the adenovirus is delivered via multiple doses.

[00582] In an embodiment herein, the delivery⁷ is via an AAV. A therapeutically effective dosage for in vivo delivery' of the AAV to a human is believed to be in the range of from about 20 to about 50 ml of saline solution containing from about 1 x IO¹⁰ to about I x IO¹⁰ functional AAV/ml solution. The dosage may be adjusted to balance the therapeutic benefit against any side effects. In an embodiment herein, the AAV dose is generally in the range of concentrations of

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50 8 ~Ό from about 1 x 10' to 1 x 10' genomes AAV, from about 1 x 10 to 1 x 10² genomes AAV, from about 1 x 10^!0 to about 1 x 10'⁶ genomes, or about 1 x 10¹¹ to about 1 x 10¹⁶ genomes AAV. A human dosage may be about I x 10^ij genomes AAV. Such concentrations may be delivered in from about 0.001 ml to about 100 ml, about 0.05 to about 50 ml, or about 10 to about 25 ml of a carrier solution. Other effective dosages can be readily established by one of ordinary skill in the art through routine trials establishing dose response curves. See, for example, U.S. Patent No. 8,404,658 B2 to Hajjar, et al., granted on March 26, 2013, at col. 27, lines 45-60.

[00583] In an embodiment herein the delivery is via a plasmid. In such plasmid compositions, the dosage should be a sufficient amount of plasmid to elicit a response. For instance, suitable quantities of plasmid DNA in plasmid compositions can be from about 0.1 to about 2 mg, or from about 1 pg to about 10 pg per 70 kg individual. Plasmids of the invention will generally comprise (i) a promoter, (ii) a sequence encoding a CRISPR. enzyme, operably linked to said promoter; (iii) a selectable marker; (iv) an origin of replication; and (v) a transcription terminator downstream of and operably linked to (ii). The plasmid can also encode the RNA components of a CRISPR complex, but one or more of these may instead be encoded on a different vector. [00584] The doses herein are based on an average 70 kg individual. The frequency of administration is within the ambit of the medical or veterinary practitioner (e.g., physician, veterinarian), or scientist skilled in the art. It is also noted that mice used in experiments are typically about 20g and from mice experiments one can scale up to a 70 kg individual.

[00585] The dosage used for the compositions provided herein include dosages for repeated administration or repeat dosing. In particular embodiments, the administration is repeated within a period of several weeks, months, or years. Suitable assays can be performed to obtain an optimal dosage regime. Repeated administration can allow the use of lower dosage, which can positively affect off-target modifications.

[00586] In some embodiments the RNA molecules of the invention are delivered in liposome or lipofectin formulations and the like and can be prepared by methods well known to those skilled in the art. Such methods are described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and 5,580,859, which are herein incorporated by reference. Delivery systems aimed specifically at the enhanced and improved delivery of siRNA into mammalian cells have been developed, (see, for example, Shen et al FEBS Let. 2003, 539:111-114; Xia et al., Nat. Biotech.

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2002, 20:1006-1010; Reich et al., Mol. Vision. 2003, 9: 210-216; Sorensen et al., J. Mol. Biol.

2003, 327: 761-766; Lewis et al., Nat. Gen. 2002, 32: 107-108 and Simeoni et al., NAR 2003, 31, 11: 2717-2724) and may be applied to the present invention. siRNA has recently been successfully used for inhibition of gene expression in primates (see for example. Tolentino et al., Retina 24(4):660 which may also be applied to the present invention.

[00587] Indeed, RNA delivery is a useful method of in vivo delivery. It is possible to deliver Cpfl and gRNA (and, for instance, HR repair template) into cells using liposomes or nanoparticles. Thus delivery of the CRISPR enzyme, such as a Cpfl and/or delivery of the RNAs of the invention may be in RNA form and via microvesicles, liposomes or particle or particles. For example, Cpfl mRNA and gRNA can be packaged into liposomal particles for delivery in vivo. Liposomal transfection reagents such as lipofectamine from Life Technologies and other reagents on the market can effectively deliver RNA molecules into the liver.

[00588] Means of delivery' of RNA also preferred include delivery of RNA via particles (Cho, S., Goldberg, M., Son, S., Xu, Q., Yang, F., Mei, Y., Bogatyrev, S., Langer, R. and Anderson, D., Lipid-like nanoparticles for small interfering RNA delivery' to endothelial cells, Advanced Functional Materials, 19: 3112-3118, 2010) or exosomes (Schroeder, A., Levins, C., Cortez, C., Langer, R., and Anderson, D., Lipid-based nanotherapeutics for siRNA delivery', Journal of Internal Medicine, 267: 9-21, 2010, PMID: 20059641). Indeed, exosomes have been shown to be particularly useful in delivery siRNA, a system with some parallels to the CRISPR system. For instance, El-Andaloussi S, et al. (“Exosome-mediated delivery of siRNA in vitro and in vivo.” NatProtoc. 2012 Dec;7(12):2112-26. doi: 10.1038/nprot.2012.131. Epub 2012 Nov 15.) describe how exosomes are promising tools for drug delivery across different biological barriers and can be harnessed for delivery of siRNA in vitro and in vivo. Their approach is to generate targeted exosomes through transfection of an expression vector, comprising an exosomal protein fused with a peptide ligand. The exosomes are then purify and characterized from transfected cell supernatant, then RNA is loaded into the exosomes. Delivery' or administration according to the invention can be performed with exosomes, in particular but not limited to the brain. Vitamin E (α-tocopherol) may be conjugated with CRISPR Cas and delivered to the brain along with high density lipoprotein (HDL), for example In a similar manner as was done by Uno et al, (HUMAN GENE THERAPY 22:711—719 (June 2011)) for delivering short-interfering RNA (siRNA) to the brain. Mice were infused via Osmotic minipumps (model 1007D; Alzet, Cupertino, CA) filled

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PCT/US2016/038181 with phosphate-buffered saline (PBS) or free TocsiBACE or Toe-siBACE/HDL and connected with Brain Infusion Kit 3 (Alzet). A brain-infusion cannula was placed about 0.5mm posterior to the bregma at midline for infusion into the dorsal third ventricle. Uno et al. found that as little as 3 nmol of Toc-siRNA with HDL could induce a target reduction in comparable degree by the same ICV infusion method. A similar dosage of CRISPR Cas conjugated to α-toeopherol and coadministered with HDL targeted to the brain may be contemplated for humans in the present invention, for example, about 3 nmol to about 3 μηιοί of CRISPR Cas targeted to the brain may be contemplated. Zou et al. ((HUMAN GENE THERAPY 22:465-475 (April 2011)) describes a method of lentiviral-mediated delivery of short-hairpin RNAs targeting PKCy for in vivo gene silencing in the spinal cord of rats. Zou et al. administered about 10 μΐ of a recombinant lentivirus having a. titer of 1 x 1()⁹ transducing units (TU)/ml by an intrathecal catheter. A similar dosage of CRISPR Cas expressed in a lentiviral vector targeted to the brain may be contemplated for humans in the present invention, for example, about 10-50 ml of CRISPR Cas targeted to the brain in a lentivirus having a titer of I χ 10⁹ transducing units (TU)/ml may be contemplated. [00589] Preassembled recombinant CRISPR-Cpfl complexes comprising Cpfl and crRNA may be transfected, for example by electroporation, resulting in high mutation rates and absence of detectable off-target mutations. Hur, J.K. et al, Targeted mutagenesis in mice by electroporation of Cpfl ribonucleoproteins, Nat Biotechnol. 2016 Jun 6. doi: 10.1038/nbt.3596. [Epub ahead of print] [00590] In terms of local delivery to the brain, this can be achieved in various ways. For instance, material can be delivered intrastriatally e.g. by injection. Injection can be performed stereotactically via a craniotomy, [00591] Enhancing NHEJ or HR efficiency is also helpful for deliver}'. It is preferred that NHEJ efficiency is enhanced by co-expressing end-processing enzymes such as Trex2 (Dumitrache et al. Genetics. 2011 August; 188(4): 787-797). It is preferred that HR efficiency is increased by transiently inhibiting NHEJ machineries such as Ku70 and Ku86. HR efficiency can also be increased by co-expressing prokaryotic or eukaryotic homologous recombination enzymes such as RecBCD, RecA.

[00592] Ways to package inventive Cpfl coding nucleic acid molecules, e.g., DNA, into vectors, e.g., viral vectors, to mediate genome modification in vivo include:

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PCT/US2016/038181 • To achieve NHEJ-mediated gene knockout:

® Single virus vector:

® Vector containing two or more expression cassettes:

® Promoter-Cpfl coding nucleic acid molecule -terminator ® Promoter-gRNAl -terminator ® Promoter-gRNA2-terminator ® Promoter-gRNA(N)-terminator (up to size limit of vector) ® Double virus vector:

® Vector 1 containing one expression cassette for driving the expression of Cpfl ® Promoter-Cpfl coding nucleic acid molecule-terminator ® Vector 2 containing one more expression cassettes for driving the expression of one or more guideRNAs ® Promoter-gRNA 1 -terminator ® Promoter-gRNA(N)-terminator (up to size limit of vector) ® To mediate homology-directed repair.

® In addition to the single and double virus vector approaches described above, an additional vector can be used to deliver a homology-direct repair template.

[00593] The promoter used to drive Cpfl coding nucleic acid molecule expression can include:

— AAV ITR can serve as a promoter: this is advantageous for eliminating the need for an additional promoter element (which can take up space in the vector). The additional space freed up can be used to drive the expression of additional elements (gRNA, etc.). Also, ITR activity is relatively weaker, so can be used to reduce potential toxicity due to over expression of Cpfl.

— For ubiquitous expression, promoters that can be used include: CMV, CAG, CBh, PGK, SV40, Ferritin heavy or light chains, etc.

[00594] For brain or other CNS expression, can use promoters: SynapsinI for all neurons, CaMKIIalpha for excitatory neurons, GAD67 or GAD65 or VGAT for GABAergic neurons, etc. [00595] For liver expression, can use Albumin promoter.

[00596] For lung expression, can use use SP-B.

[00597] For endothelial cells, can use ICAM.

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PCT/US2016/038181 [00598] For hematopoietic cells can use EFNbeta or CD45.

[00599] For Osteoblasts can one can use the OG-2.

[00600] The promoter used to drive guide RNA can include:

— Pol III promoters such as U6 or Hl — Use of Pol II promoter and intronic cassettes to express gRNA

Adeno associated virus (AAV) [00601] Cpfl and one or more guide RNA can he delivered using adeno associated virus (AAV), lentivirus, adenovirus or other plasmid or viral vector types, in particular, using formulations and doses from, for example, US Patents Nos, 8,454,972 (formulations, doses for adenovirus), 8,404,658 (formulations, doses for AAV) and 5,846,946 (formulations, doses for DNA plasmids) and from clinical trials and publications regarding the clinical trials involving lentivirus, AAV and adenovirus. For examples, for AAV, the route of administration, formulation and dose can be as in US Patent No. 8,454,972 and as in clinical trials involving AAV. For Adenovirus, the route of administration, formulation and dose can be as in US Patent No. 8,404,658 and as in clinical trials involving adenovirus. For plasmid delivery, the route of administration, formulation and dose can be as in US Patent No 5,846,946 and as in clinical studies involving plasmids. Doses may be based on or extrapolated to an average 70 kg individual (e.g. a male adult human), and can be adjusted for patients, subjects, mammals of different weight and species. Frequency of administration is within the ambit of the medical or veterinary practitioner (e.g., physician, veterinarian), depending on usual factors including the age, sex, general health, other conditions of the patient or subject and the particular condition or symptoms being addressed. The viral vectors can be injected into the tissue of interest. For celltype specific genome modification, the expression of Cpfl can be driven by a cell-type specific promoter. For example, liver-specific expression might use the Albumin promoter and neuronspecific expression (e.g. for targeting CNS disorders) might use the Synapsin I promoter.

[00602] In terms of in vivo delivery, AAV is advantageous over other viral vectors for a couple of reasons:

Low toxicity (this may be due to the purification method not requiring ultra centrifugation of cell particles that can activate the immune response) and

Low probability of causing insertional mutagenesis because it doesn’t integrate into the host genome.

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PCT/US2016/038181 [00603] AAV has a packaging limit of 4.5 or 4.75 Kb. This means that Cpfl as well as a promoter and transcription terminator have to be all fit into the same viral vector. Constructs larger than 4.5 or 4.75 Kb will lead to significantly reduced virus production. SpCas9 is quite large, the gene itself is over 4,1 Kb, which makes it difficult for packing into AAV. Therefore embodiments of the invention include utilizing homologs of Cpfl that are shorter.

[00604] As to AAV, the AAV can be AAV1, AAV2, AAV5 or any combination thereof. One can select the AAV of the AAV with regard to the cells to be targeted; e.g., one can select AAV serotypes 1, 2, 5 or a hybrid capsid ΑΑΛ/Ί, AAV2, AAV5 or any combination thereof for targeting brain or neuronal cells; and one can select AAV4 for targeting cardiac tissue. AAV8 is useful for delivery to the liver. The herein promoters and vectors are preferred individually. A tabulation of certain AAV serotypes as to these cells (see Grimm, D. et al, J. Virol. 82: 58875911 (2008)) is as follows:

Cell Line AAV-1 AAV-2 AAV-3 AAV-4 AAV-5 AAV-6 AAV-8 AAV-9

Huh-7	13	100	2.5	0.0	0.1	10	0.7	0.0
HEK293	25	100	2.5	0.1	0.1	5	0.7	0.1
HeLa	3	100	2.0	0.1	6.7	I	0.2	0.1
HepG2	3	100	16.7	0.3	1.7	5	0.3	ND
HeplA	20	100	0.2	1.0	0.1	1	0.2	0.0
911	J 7	100	π	0.2	0.1	17	0.1	ND
CHO	100	100	14	1,4	333	50	10	1.0
COS	33	100	33	3.3	5.0	14	2.0	0.5
MeWo	10	100	20	0.3	6.7	10	1.0	0.2
NIH3T3	10	100	2.9	2.9	0.3	10	0.3	ND
A549	14	100	20	ND	0.5	10	0.5	0.1
HT1180	20	100	10	0,1	0.3	33	0.5	0.1
Monocytes	1111	100	ND	ND	125	1429	ND	ND
Immature DC	2500	100	ND	ND	299	2857	ND	ND
Mature DC	2222	100	ND	ND	333	3 j j .>	ND	ND

Lentivirus [00605] Lentiviruses are complex retroviruses that have the ability to infect and express their genes in both mitotic and post-mitotic cells. The most commonly known lentivirus is the human immunodeficiency virus (HIV), which uses the envelope glycoproteins of other viruses to target a broad range of cell types.

[00606] Lentiviruses may be prepared as follows. After cloning pCasESIO (which contains a lentiviral transfer plasmid backbone), HEK293FT at low passage ip 5} were seeded in a T-75

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PCT/US2016/038181 flask to 50% confluence the day before transfection in DMEM with 10% fetal bovine serum and without antibiotics. After 20 hours, media was changed to OptiMEM (serum-free) media and transfection was done 4 hours later. Cells were transfected with 10 pg of lentiviral transfer plasmid (pCasESlO) and the following packaging plasmids: 5 pg of pMD2.G (VSV-g pseudotype), and 7.5ug of psPAX2 (gag/pol/rev/tat). Transfection was done in 4mL OptiMEM with a cationic lipid delivery agent (50uL Lipofectamine 2000 and lOOul Plus reagent). After 6 hours, the media was changed to antibiotic-free DMEM with 10% fetal bovine serum. These methods use serum during cell culture, but serum-free methods are preferred.

[00607] Lentivirus may be purified as follows. Viral supernatants were harvested after 48 hours. Supernatants were first cleared of debris and filtered through a 0.45um low protein binding (PVDF) filter. They were then spun in a ultracentrifuge for 2 hours at 24,000 rpm. Viral pellets were resuspended in 50ul of DMEM overnight at 4C. They were then aliquotted and immediately frozen at -80°C.

[00608] In another embodiment, minimal non-primate lentiviral vectors based on the equine infectious anemia virus (EIAV) are also contemplated, especially for ocular gene therapy (see, e.g., Balagaan, J Gene Med 2006; 8: 275 - 285). In another embodiment, RetinoStat®, an equine infectious anemia virus-based lentiviral gene therapy vector that expresses angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the web form of age-related macular degeneration is also contemplated (see, e.g., Binley et al., HUMAN GENE THERAPY 23:980-991 (September 2012)) and this vector may he modified for the CRISPR-Cas system of the present invention.

[00609] In another embodiment, self-inactivating lentiviral vectors with an siRNA targeting a common exon shared by HIV tat/rev, a nucleolar-localizing TAR decoy, and an anti-CCR5specific hammerhead ribozyme (see, e.g., DiGiusto et al. (2010) Sci Transl Med 2:36ra43) may be used/and or adapted to the CRISPR-Cas system of the present invention. A minimum of 2.5 χ 106 CD34+ cells per kilogram patient weight may be collected and prestimulated for 16 to 20 hours in X-V1V0 15 medium (Lonza) containing 2 pmol/L-glutamine, stem cell factor (100 ng/ml), Flt-3 ligand (Flt-3L) (100 ng/ml), and thrombopoietin (10 ng/ml) (CellGenix) at a density of 2 χ 106 cells/ml. Prestimulated cells may be transduced with lentiviral at a multiplicity of infection of 5 for 16 to 24 hours in 75-cm2 tissue culture flasks coated with fibronectin (25 mg/cm2) (RetroNectin,Takara Bio Inc.).

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PCT/US2016/038181 [00610] Lentiviral vectors have been disclosed as in the treatment for Parkinson’s Disease, see, e.g., US Patent Publication No. 20120295960 and US Patent Nos. 7303910 and 7351585. Lentiviral vectors have also been disclosed for the treatment of ocular diseases, see e.g., LIS Patent Publication Nos. 20060281180, 20090007284, US20110117189; US20090017543; US20070054961, US20100317109. Lentiviral vectors have also been disclosed for delivery to the brain, see, e.g,, US Patent Publication Nos. US20110293571; US20110293571, US20040013648, US20070025970, US20090111106 and US Patent No. US7259015.

[00611] RNA delivery: The CRISPR enzyme, for instance a Cpfl, and/or any of the present RNAs, for instance a guide RNA, can also be delivered in the form of RNA. Cpfl mRNA can be generated using in vitro transcription. For example, Cpfl mRNA can be synthesized using a PCR cassette containing the following elements: T7_promoter-kozak sequence (GCCACC)-Cpfl-3’ UTR from beta globin-poly A tail (a string of 120 or more adenines). The cassette can be used for transcription by T7 polymerase. Guide RNAs can also be transcribed using in vitro transcription from a cassette containing T7 promoter-GG-guide RNA sequence.

[00612] To enhance expression and reduce possible toxicity, the CRISPR enzyme-coding sequence and/or the guide RNA can be modified to include one or more modified nucleoside e.g. using pseudo-U or 5-Methyl-C.

[00613] mRNA delivery methods are especially promising for liver delivery currently.

[00614] Much clinical work on RNA delivery has focused on RNAi or antisense, but these systems can be adapted for delivery of RNA for implementing the present invention. References below to RNAi etc. should be read accordingly.

Particle delivery systems and/or formulations:

[00615] Several types of particle delivery systems and/or formulations are known to be useful in a diverse spectrum of biomedical applications. In general, a particle is defined as a small object that behaves as a whole unit with respect to its transport and properties. Particles are further classified according to diameter Coarse particles cover a range between 2,500 and 10,000 nanometers. Fine particles are sized between 100 and 2,500 nanometers, Ultrafine particles, or nanoparticles, are generally between 1 and 100 nanometers in size. The basis of the

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100-nm limit is the fact that novel properties that differentiate particles from the bulk material typically develop at a critical length scale of under 100 nm.

[00616] As used herein, a particle delivery⁷ system/formulation is defined as any biological delivery system/formulation which includes a particle in accordance with the present invention. A particle in accordance with the present invention is any entity having a greatest dimension (e.g. diameter) of less than 100 microns (pm). In some embodiments, inventive particles have a greatest dimension of less than 10 μ m. In some embodiments, inventive particles have a greatest dimension of less than 2000 nanometers (nm). In some embodiments, inventive particles have a greatest dimension of less than 1000 nanometers (nm). In some embodiments, inventive particles have a greatest dimension of less than 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. Typically, inventive particles have a greatest dimension (e.g,, diameter) of 500 nm or less. In some embodiments, inventive particles have a greatest dimension (e.g., diameter) of 250 nm or less. In some embodiments, inventive particles have a greatest dimension (e.g., diameter) of 200 nm or less. In some embodiments, inventive particles have a greatest dimension (e.g., diameter) of 150 nm or less. In some embodiments, inventive particles have a greatest dimension (e.g., diameter) of 100 nm or less. Smaller particles, e.g., having a greatest dimension of 50 nm or less are used in some embodiments of the invention. In some embodiments, inventive particles have a greatest dimension ranging between 25 nm and 200 nm. [00617] Particle characterization (including e.g., characterizing morphology, dimension, etc.) is done using a variety of different techniques. Common techniques are electron microscopy (TEM, SEM), atomic force microscopy (AFM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF), ultraviolet-visible spectroscopy, dual polarisation interferometry and nuclear magnetic resonance (NMR). Characterization (dimension measurements) may be made as to native particles (i.e., preloading) or after loading of the cargo (herein cargo refers to e.g., one or more components of CRISPR-Cas system e.g., CRISPR enzyme or mRNA or guide RNA, or any combination thereof, and may include additional carriers and/or excipients) to provide particles of an optimal size for delivery for any in vitro, ex vivo and/or in vivo application of the present invention. In certain preferred embodiments, particle dimension (e.g., diameter) characterization is based on measurements using dynamic laser scattering (DLS).

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Mention is made of US Patent No. 8,709,843; US Patent No. 6,007,845; US Patent No. 5,855,913; US Patent No. 5,985,309; US. Patent No. 5,543,158; and the publication by James E. Dahlman and Carmen Barnes et al. Nature Nanotechnology (2014) published online 11 May 2014, doi:10.1038/nnano.2014,84, concerning particles, methods of making and using them and measurements thereof.

[00618] Particles delivery systems within the scope of the present invention may be provided in any form, including but not limited to solid, semi-solid, emulsion, or colloidal particles. As such any of the delivery systems described herein, including but not limited to, e.g., lipid-based systems, liposomes, micelles, microvesicles, exosomes, or gene gun may be provided as particle delivery systems within the scope of the present invention.

Particles [00619] It will be appreciated that refernec made herein to particles or nanoparticles can be interchangeable, where approapriate. CRISPR enzyme mRNA and guide RNA may be delivered simultaneously using particles or lipid envelopes; for instance, CRISPR enzyme and RNA of the invention, e.g., as a complex, can be delivered via a particle as in Dahlman et al., WO2015089419 A2 and documents cited therein, such as 7C1 (see, e.g., James E. Dahlman and Carmen Bames et al. Nature Nanotechnology (2014) published online 11 May 2014, doi: 10.1038/nnano.2014.84), e.g., delivery particle comprising lipid or lipidoid and hydrophilic polymer, e.g., cationic lipid and hydrophilic polymer, for instance wherein the the cationic lipid comprises l,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or l,2,-ditetradecanoyl~5«~ glycero-3-phosphocholine (DMPC) and/or wherein the hydrophilic polymer comprises ethylene glycol or polyethylene glycol (PEG); and/or wherein the particle further comprises cholesterol (e.g., particle from formulation 1 == DOTAP 100, DMPC 0, PEG 0, Cholesterol 0; formulation number 2 = DOTAP 90, DMPC 0, PEG 10, Cholesterol 0; formulation number 3 = DOTAP 90, DMPC 0, PEG 5, Cholesterol 5), wherein particles are formed using an efficient, multistep process wherein first, effector protein and RNA are mixed together, e.g., at a 1:1 molar ratio, e.g., at room temperature, e.g., for 30 minutes, e.g., in sterile, nuclease free IX PBS; and separately, DOTAP, DMPC, PEG, and cholesterol as applicable for the formulation are dissolved in alcohol, e.g., 100% ethanol; and, the two solutions are mixed together to form particles containing the complexes).

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PCT/US2016/038181 [00620] Nucleic acid-targeting effector proteins (such as a Type V protein such Cpfl) mRNA and guide RNA may be delivered simultaneously using particles or lipid envelopes. Examples of suitable particles include but are not limited to those described in US 9,301,923.

[00621] For example, Su X, Fricke J, Kavanagh DG, Irvine DJ (“In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles” Mol Pharm. 2011 Jun 6,8(3):774-87, doi: 10.1021/mp100390w, Epub 2011 Apr I) describes biodegradable core-shell structured nanoparticles with a poly(P-amino ester) (PBAE) core enveloped by a phospholipid bilayer shell. These were developed for in vivo mRNA delivery'. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Such are, therefore, preferred for delivering RNA of the present invention.

[00622] In one embodiment, particles/nanoparticles based on self assembling bioadhesive polymers are contemplated, which may be applied to oral delivery of peptides, intravenous delivery of peptides and nasal delivery of peptides, all to the brain. Other embodiments, such as oral absorption and ocular delivery of hydrophobic drugs are also contemplated. The molecular envelope technology involves an engineered polymer envelope which is protected and delivered to the site of the disease (see, e.g., Mazza, M. et al. ACSNano, 2013. 7(2): 1016-1026; Slew, A., et al. Mol Pharm, 2012. 9(1):14-28: Lalatsa, A., et al. J Contr Rel, 2012. 161(2):523-36; Lalatsa, A., et al., Mol Pharm, 2012. 9(6): 1665-80; Lalatsa, A., et al. Mol Pharm, 2012. 9(6): 1764-74; Garrett, N.L., et al, J Biophotonics, 2012. 5(5-6):458-68; Garrett, N.L., et al. J Raman Spect, 2012. 43(5):681-688; Ahmad, S., et al. J Royal Soc Interface 2010. 7:8423-33; Uchegbu, I.F. Expert Opin Drug Deliv, 2006. 3(5):629-40, Qu, X,,et al. Biomacromolecules, 2006. 7(12):34529 and Uchegbu, kF., et al. Int J Pharm, 2001. 224:185-199). Doses of about 5 mg/kg are contemplated, with single or multiple doses, depending on the target tissue.

[00623] In one embodiment, particles/nanoparticles that can deliver RNA to a cancer cell to stop tumor growth developed by Dan Anderson’s lab at MIT may be used/and or adapted to the CRISPR Cas system of the present invention. In particular, the Anderson lab developed fully automated, combinatorial systems for the synthesis, purification, characterization, and formulation of new biomaterials and nanoformulations. See, e.g., Alabi et al,, Proc Natl Acad Sci U S A. 2013 Aug 6;110(32): 12881-6; Zhang et al., Adv Mater. 2013 Sep 6;25(33):4641 -5; Jiang et al., Nano Lett. 2013 Mar 13; 13(3): 1059-64; Karagiannis et al., ACS Nano. 2012 Oct

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23;6(10):8484-7; Whitehead et al., ACS Nano. 2012 Aug 28;6(8):6922-9 and Lee et al., Nat Nanotechnol. 2012 Jun 3;7(6):389-93.

[00624] US patent application 20110293703 relates to lipidoid compounds are also particularly useful in the administration of polynucleotides, which may be applied to deliver the CRISPR Cas system of the present invention. In one aspect, the aminoalcohol lipidoid compounds are combined with an agent to be delivered to a cell or a subject to form microparticles, nanoparticles, liposomes, or micelles. The agent to be delivered by the particles, liposomes, or micelles may be in the form of a gas, liquid, or solid, and the agent may be a polynucleotide, protein, peptide, or small molecule. The minoalcohol lipidoid compounds may be combined with other aminoalcohol lipidoid compounds, polymers (synthetic or natural), surfactants, cholesterol, carbohydrates, proteins, lipids, etc, to form the particles. These particles may then optionally be combined with a pharmaceutical excipient to form a pharmaceutical composition.

[00625] US Patent Publication No. 20110293703 also provides methods of preparing the aminoalcohol lipidoid compounds. One or more equivalents of an amine are allowed to react with one or more equivalents of an epoxide-terminated compound under suitable conditions to form an aminoalcohol lipidoid compound of the present invention. In certain embodiments, all the amino groups of the amine are fully reacted with the epoxide-terminated compound to form tertian,'· amines. In other embodiments, all the amino groups of the amine are not fully reacted with the epoxide-terminated compound to form tertiary amines thereby resulting in primary or secondary amines in the aminoalcohol lipidoid compound. These primary or secondary amines are left as is or may be reacted with another electrophile such as a different epoxide-terminated compound. As will be appreciated by one skilled in the art, reacting an amine with less than excess of epoxide-terminated compound will result in a plurality of different aminoalcohol lipidoid compounds with various numbers of tails. Certain amines may he fully functionalized with two epoxide-derived compound tails while other molecules will not be completely functionalized with epoxide-derived compound tails. For example, a diamine or polyamine may include one, two, three, or four epoxide-derived compound tails off the various amino moieties of the molecule resulting in primary, secondary, and tertiary amines. In certain embodiments, all the amino groups are not fully functionalized. In certain embodiments, two of the same types of epoxide-terminated compounds are used. In other embodiments, two or more different epoxide172

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PCT/US2016/038181 terminated compounds are used. The synthesis of the aminoalcohol lipidoid compounds is performed with or without solvent, and the synthesis may be performed at higher temperatures ranging from 30-100 °C., preferably at approximately 50-90 °C. The prepared aminoalcohol lipidoid compounds may be optionally purified. For example, the mixture of aminoalcohol lipidoid compounds may be purified to yield an aminoalcohol lipidoid compound with a particular number of epoxide-derived compound tails. Or the mixture may be purified to yield a particular stereo- or regioisomer. The aminoalcohol lipidoid compounds may also be alkylated using an alkyl halide (e.g., methyl iodide) or other alkylating agent, and/or they may be acylated. [00626] US Patent Publication No. 20110293703 also provides libraries of aminoalcohol lipidoid compounds prepared by the inventive methods. These aminoalcohol lipidoid compounds may be prepared and/or screened using high-throughput techniques involving liquid handlers, robots, microtiter plates, computers, etc. In certain embodiments, the aminoalcohol lipidoid compounds are screened for their ability to transfect polynucleotides or other agents (e.g., proteins, peptides, small molecules) into the cell.

[00627] US Patent Publication No. 20130302401 relates to a class of poly(beta-amino alcohols) (PBAAs) has been prepared using combinatorial polymerization. The inventive PBAAs may be used in biotechnology and biomedical applications as coatings (such as coatings of films or multilayer films for medical devices or implants), additives, materials, excipients, nonbiofouling agents, micropatteming agents, and cellular encapsulation agents. When used as surface coatings, these PBAAs elicited different levels of inflammation, both in vitro and in vivo, depending on their chemical structures. The large chemical diversity of this class of materials allowed us to identify polymer coatings that inhibit macrophage activation in vitro. Furthermore, these coatings reduce the recruitment of inflammatory cells, and reduce fibrosis, following the subcutaneous implantation of carboxylated polystyrene microparticles. These polymers may be used to form polyelectrolyte complex capsules for cell encapsulation. The invention may also have many other biological applications such as antimicrobial coatings, DNA or siRNA delivery, and stem cell tissue engineering. The teachings of US Patent Publication No, 20130302401 maybe applied to the CRISPR Cas system of the present invention. In some embodiments, sugarbased particles may be used, for example GalNAc, as described herein and with reference to WO2014118272 (incorporated herein by reference) and Nair, JK et al., 2014, Journal of the

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American Chemical Society 136 (49), 16958-16961) and the teaching herein, especially in respect of delivery applies to all particles unless otherwise apparent.

[00628] In another embodiment, lipid nanoparticles (LNPs) are contemplated. An anti transthyretin small interfering RNA has been encapsulated in lipid nanoparticles and delivered to humans (see, e.g., Coelho et al., N Engl J Med 2013;369:819-29), and such a system may be adapted and applied to the CRISPR Cas system of the present invention. Doses of about 0.01 to about 1 mg per kg of body weight administered intravenously are contemplated. Medications to reduce the risk of infusion-related reactions are contemplated, such as dexamethasone, acetampinophen, diphenhydramine or cetirizine, and ranitidine are contemplated. Multiple doses of about 0.3 mg per kilogram every 4 weeks for five doses are also contemplated, [00629] LNPs have been shown to be highly effective in delivering siRNAs to the liver (see, e.g., Tabemero et al,, Cancer Discovery, April 2013, Vol, 3, No. 4, pages 363-470) and are therefore contemplated for delivering RNA encoding CRISPR Cas to the liver. A dosage of about four doses of 6 mg/kg of the LNP every two weeks may be contemplated. Tabemero et al. demonstrated that tumor regression was observed after the first 2 cycles of LNPs dosed at 0.7 mg/kg, and by the end of 6 cycles the patient had achieved a partial response with complete regression of the lymph node metastasis and substantial shrinkage of the liver tumors. A complete response was obtained after 40 doses in this patient, who has remained in remission and completed treatment after receiving doses over 26 months. Two patients with RCC and extrahepatic sites of disease including kidney, lung, and lymph nodes that were progressing following prior therapy with VEGF pathway inhibitors had stable disease at all sites for approximately 8 to 12 months, and a patient with PNET and liver metastases continued on the extension study for 18 months (36 doses) with stable disease.

[00630] However, the charge of the LNP must be taken into consideration. As cationic lipids combined with negatively charged lipids to induce nonbilayer structures that facilitate intracellular delivery. Because charged LNPs are rapidly cleared from circulation following intravenous injection, ionizable cationic lipids with pKa values below' 7 were developed (see, e.g., Rosin et al, Molecular Therapy, vol. 19, no. 12, pages 1286-2200, Dec. 2011), Negatively charged polymers such as RNA may be loaded into LNPs at low' pH values (e.g., pH 4) where the ionizable lipids display a positive charge. However, at physiological pH values, the LNPs

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PCT/US2016/038181 exhibit a low surface charge compatible with longer circulation times. Four species of ionizable cationic lipids have been focused upon, namely l,2-dilineoyl-3-dimethylammonium-propane (DLinDAP), 1,2-dilinoleyloxy-3 -Ν,Ν-dimethylaminopropane (DLinDMA), 1,2-dilinoleyloxyketo-N,N-dimethyl-3-aminopropane (DLinKDMA), and 1,2-dilinoleyl-4-(2dimethylaminoethyl)-[I,3]-dioxolane (DLinKC2-DMA). It has been shown that LNP siRNA systems containing these lipids exhibit remarkably different gene silencing properties in hepatocytes in vivo, with potencies varying according to the series DLinKC2DMA>DLinKDMA>DLinDMA»DLinDAP employing a Factor VII gene silencing model (see, e.g., Rosin et al, Molecular Therapy, vol. 19, no. 12, pages 1286-2200, Dec. 2011). A dosage of 1 pg/ml of LNP or CRISPR-Cas RNA in or associated with the LNP may be contemplated, especially for a formulation containing DLinKC2-DMA.

[00631] Preparation of LNPs and CRISPR Cas encapsulation may be used/and or adapted from Rosin et al, Molecular Therapy, vol. 19, no. 12, pages 1286-2200, Dec. 2011). The cationic lipids l,2-dilineoyl-3-dimethylammonium-propane (DLinDAP), I,2-dilinoleyloxy-3-N,Ndimethylaminopropane (DLinDMA), l,2-dilinoleyloxyketo-N,N-dimethyl-3-aminopropane (DLinK-DMA), l,2-dilinoleyl-4-(2-dimethylaminoethyl)-[l,3]-dioxolane (DLinKC2-DMA), (3o-[2-(methoxypolyethyleneglycol 2000) succinoyl]-1,2-dimyristoyl-sn-glycol (PEG-S-DMG), and R-3-[(<o-methoxy-poly(ethylene glycol)2000) carbamoyl]-l,2-dimyristyloxlpropyl-3-amine (PEG-C-DOMG) may be provided by Tekmira Pharmaceuticals (Vancouver, Canada) or synthesized. Cholesterol may be purchased from Sigma (St Louis, MO), The specific CRISPR Cas RNA may be encapsulated in LNPs containing DLinDAP, DLinDMA, DLinK-DMA, and DLinKC2-DMA (cationic lipid:DSPC:CHOL: PEGS-DMG or PEG-C-DOMG at 40:10:40:10 molar ratios). When required, 0.2% SP-DiOC18 (Invitrogen, Burlington, Canada) may be incorporated to assess cellular uptake, intracellular delivery, and biodistribution. Encapsulation may be performed by dissolving lipid mixtures comprised of cationic lipid:DSPC:cholesterol:PEG-c-DOMG (40:10:40:10 molar ratio) in ethanol to a final lipid concentration of 10 mmol/1. This ethanol solution of lipid may be added drop-wise to 50 mmol/1 citrate, pH 4.0 to form multilamellar vesicles to produce a final concentration of 30% ethanol vol/voi. Large unilamellar vesicles may be formed following extrusion of multilamellar vesicles through two stacked 80 nm Nuclepore polycarbonate filters using the Extruder (Northern Lipids, Vancouver, Canada). Encapsulation may be achieved by adding RNA dissolved at 2 mg/ml in 50

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PCT/US2016/038181 mmol/1 citrate, pH 4.0 containing 30% ethanol vol/vol drop-wise to extruded preformed large unilamellar vesicles and incubation at 31 °C for 30 minutes with constant mixing to a final RNA/lipid weight ratio of 0.06/1 wt/wt. Removal of ethanol and neutralization of formulation buffer were performed by dialysis against phosphate-buffered saline (PBS), pH 7.4 for 16 hours using Spectra/Por 2 regenerated cellulose dialysis membranes. Nanoparticle size distribution may be determined by dynamic light scattering using a NICOMP 370 particle sizer, the vesicle/intensity modes, and Gaussian fitting (Nicomp Particle Sizing, Santa Barbara, CA). The particle size for all three LNP systems may be -70 nm in diameter. RNA encapsulation efficiency may be determined by removal of free RNA using VivaPureD MiniH columns (Sartorius Stedim Biotech) from samples collected before and after dialysis. The encapsulated RNA may be extracted from the eluted nanoparticles and quantified at 260 nm, RNA to lipid ratio was determined by measurement of cholesterol content in vesicles using the Cholesterol E enzymatic assay from Wako Chemicals USA (Richmond, VA). In conjunction with the herein discussion of LNPs and PEG lipids, PEGylated liposomes or LNPs are likewise suitable for delivery of a CRISPR-Cas system or components thereof.

[00632] Preparation of large LNPs may be used/and or adapted from Rosin et al, Molecular Therapy, vol. 19, no. 12, pages 1286-2200, Dec. 2011. A lipid premix solution (20.4 mg/ml total lipid concentration) may be prepared in ethanol containing DLinKC2-DMA, DSPC, and cholesterol at 50; 10:38.5 molar ratios. Sodium acetate may be added to the lipid premix at a molar ratio of 0.75:1 (sodium acetate:DLinKC2-DMA). The lipids may be subsequently hydrated by combining the mixture with 1.85 volumes of citrate buffer (10 mmol/1, pH 3.0) with vigorous stirring, resulting in spontaneous liposome formation in aqueous buffer containing 35% ethanol. The liposome solution may be incubated at 37 °C to allow⁷ for time-dependent increase in particle size. Aliquots may be removed at various times during incubation to investigate changes in liposome size by dynamic light scattering (Zetasizer Nano ZS, Malvern Instruments, Worcestershire, UK). Once the desired particle size is achieved, an aqueous PEG lipid solution (stock =^;: 10 mg/ml PEG-DMG in 35% (vol/vol) ethanol) may be added to the liposome mixture to yield a final PEG molar concentration of 3.5% of total lipid. Upon addition of PEG-lipids, the liposomes should their size, effectively quenching further growth. RNA may then be added to the empty liposomes at an RNA to total lipid ratio of approximately 1:10 (wt:wt), followed by

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PCT/US2016/038181 incubation for 30 minutes at 37 °C to form loaded LNPs. The mixture may be subsequently dialyzed overnight in PBS and filtered with a 0.45-μηι syringe filter.

[00633] Spherical Nucleic Acid (SNA™) constructs and other nanoparticles (particularly gold nanoparticles) are also contemplated as a means to delivery/ CRISPR-Cas system to intended targets. Significant data show that AuraSense Therapeutics' Spherical Nucleic Acid (SNA™) constructs, based upon nucleic acid-functionalized gold nanoparticles, are useful.

[00634] Literature that may be employed in conjunction with herein teachings include: Cutler et al., J. Am. ('hem. Soc. 2011 133:9254-9257, Hao et al., Small. 2011 7:3158-3162, Zhang et al., ACS Nano. 2011 5:6962-6970, Cutler et al., J. Am. Chem. Soc. 2012 134:1376-1391, Young et al., Nano Lett. 2012 12:3867-71, Zheng et al., Proc. Natl. Acad. Sci. LISA. 2012 109:1197580, Mirkin, Nanomedicine 2012 7:635-638 Zhang et al., J. Am. Chem. Soc. 2012 134:164881691, Weintraub, Nature 2013 495:S14-S16, Choi et al., Proc. Natl. Acad. Sci. USA. 2013 110(19):7625-7630, Jensen et al., Sci. Transl. Med. 5, 209ral52 (2013) and Mirkin, et al.. Small, 10:186-192.

[00635] Self-assembling nanoparticles with RNA may be constructed with polyethyleneimine (PEI) that is PEGylated with an Arg-Gly-Asp (RGD) peptide ligand attached at the distal end of the polyethylene glycol (PEG). This system has been used, for example, as a means to target tumor neovasculature expressing integrins and deliver siRNA inhibiting vascular endothelial growth factor receptor-2 (VEGF R2) expression and thereby achieve tumor angiogenesis (see, e.g., Schiffelers et al,, Nucleic Acids Research, 2004, Vol. 32, No. 19). Nanoplexes may be prepared by mixing equal volumes of aqueous solutions of cationic polymer and nucleic acid to give a net molar excess of ionizable nitrogen (polymer) to phosphate (nucleic acid) over the range of 2 to 6. The electrostatic interactions between cationic polymers and nucleic acid resulted in the formation of polyplexes with average particle size distribution of about 100 nm, hence referred to here as nanoplexes. A dosage of about 100 to 200 mg of CRISPR Cas is envisioned for delivery in the self-assembling nanoparticles of Schiffelers et al.

[00636] The nanoplexes of Bartlett et al. (PNAS, September 25, 2007,vol. 104, no. 39) may also be applied to the present invention. The nanoplexes of Bartlett et al. are prepared by mixing equal volumes of aqueous solutions of cationic polymer and nucleic acid to give a net molar excess of ionizable nitrogen (polymer) to phosphate (nucleic acid) over the range of 2 to 6. The electrostatic interactions between cationic polymers and nucleic acid resulted in the formation of

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PCT/US2016/038181 polyplexes with average particle size distribution of about 100 nm, hence referred to here as nanoplexes. The DOTA-siRNA of Bartlett et al. was synthesized as follows: 1,4,7,10tetraazacyclododecane-l,4,7,10-tetraacetic acid mono(N-hydroxysuccinimide ester) (DOTANHSester) was ordered from Macrocyclics (Dallas, TX). The amine modified RNA sense strand with a 100-fold molar excess of DOTA-NHS-ester in carbonate buffer (pH 9) was added to a microcentrifuge tube. The contents were reacted by stirring for 4 h at room temperature. The DOTA-RNAsense conjugate was ethanol-precipitated, resuspended in water, and annealed to the unmodified antisense strand to yield DOTA-siRNA. All liquids were pretreated with Chelex-100 (Bio-Rad, Hercules, CA) to remove trace metal contaminants. Tf-targeted and nontargeted siRNA nanoparticles may be formed by using cyclodextrin-containing polycations. Typically, nanoparticles were formed in water at a charge ratio of 3 (+/-) and an siRNA concentration of 0.5 g/liter. One percent of the adamantane-PEG molecules on the surface of the targeted nanoparticles were modified with Tf (adamantane-PEG-Tf). The nanoparticles were suspended in a 5% (wt/vol) glucose carrier solution for injection.

[00637] Davis et al. (Nature, Vol 464, 15 April 2010) conducts a RNA clinical trial that uses a targeted nanoparticle-delivery system (clinical trial registration number NCT00689065). Patients with solid cancers refractory to standard-of-care therapies are administered doses of targeted nanoparticles on days 1, 3, 8 and 10 of a 21-day cycle by a 30-min intravenous infusion. The nanoparticles consist of a synthetic delivery system containing: (1) a linear, cyclodextrin-based polymer (CDP), (2) a human transferrin protein (TF) targeting ligand displayed on the exterior of the nanoparticle to engage TF receptors (TFR) on the surface of the cancer cells, (3) a hydrophilic polymer (polyethylene glycol (PEG) used to promote nanoparticle stability in biological fluids), and (4) siRNA designed to reduce the expression of the RRM2 (sequence used in the clinic was previously denoted siR2B+5). The TFR has long been known to be upregulated in malignant cells, and RRM2 is an established anti-cancer target. These nanoparticles (clinical version denoted as CALAA-01) have been shown to be well tolerated in multi-dosing studies in non-human primates. Although a single patient with chronic myeloid leukaemia has been administered siRNAby liposomal delivery, Davis et al.’s clinical trial is the initial human trial to systemically deliver siRNA with a targeted delivery system and to treat patients with solid cancer. To ascertain whether the targeted delivery' system can provide effective delivery of functional siRNA to human tumours, Davis et al. investigated biopsies from three patients from

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PCT/US2016/038181 three different dosing cohorts; patients A, B and C, all of whom had metastatic melanoma and received CALAA-Q1 doses of 18, 24 and 30 mg m'² siRNA, respectively. Similar doses may also be contemplated for the CRISPR Cas system of the present invention. The delivery of the invention may be achieved with nanoparticles containing a linear, cyclodextrin-based polymer (CDP), a human transferrin protein (TF) targeting ligand displayed on the exterior of the nanoparticle to engage TF receptors (TFR) on the surface of the cancer cells and/or a hydrophilic polymer (for example, polyethylene glycol (PEG) used to promote nanoparticle stability in biological fluids).

[00638] In terms of this invention, it is preferred to have one or more components of CRISPR complex, e.g., CRISPR enzyme or mRNA or guide RNA delivered using nanoparticles or lipid envelopes. Other delivery systems or vectors are may be used in conjunction with the nanoparticle aspects of the invention.

[00639] In general, a nanoparticle” refers to any particle having a diameter of less than 1000 nm. In certain preferred embodiments, nanoparticles of the invention have a greatest dimension (e.g., diameter) of 500 nm or less. In other preferred embodiments, nanoparticles of the invention have a greatest dimension ranging between 25 nm and 200 nm. In other preferred embodiments, nanoparticles of the invention have a greatest dimension of 100 nm or less. In other preferred embodiments, nanoparticles of the invention have a greatest dimension ranging between 35 nm and 60 nm.

[00640] Nanoarticles encompassed in the present invention may be provided in different forms, e.g., as solid nanoparticles (e.g., metal such as silver, gold, iron, titanium), non-metal, lipid-based solids, polymers), suspensions of nanoparticles, or combinations thereof. Metal, dielectric, and semiconductor nanoparticles may be prepared, as well as hybrid structures (e.g., core-shell nanoparticles). Nanoparticles made of semiconducting material may also be labeled quantum dots if they are small enough (typically sub 10 nm) that quantization of electronic energy levels occurs. Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents and may be adapted for similar purposes in the present invention. [00641] Semi-solid and soft nanoparticles have been manufactured, and are within the scope of the present invention. A prototype nanoparticle of semi-solid nature is the liposome. Various types of liposome nanoparticles are currently used clinically as deliver)' systems for anticancer drugs and vaccines. Nanoparticles with one half hydrophilic and the other half hydrophobic are

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PCT/US2016/038181 termed Janus particles and are particularly effective for stabilizing emulsions. They can selfassemble at water/oil interfaces and act as solid surfactants.

[00642] US Patent No. 8,709,843, incorporated herein by reference, provides a drug delivery system for targeted delivery of therapeutic agent-containing particles to tissues, cells, and intracellular compartments. The invention provides targeted particles comprising comprising polymer conjugated to a surfactant, hydrophilic polymer or lipid.

[00643] US Patent No. 6,007,845, incorporated herein by reference, provides particles which have a core of a multiblock copolymer formed by covalently linking a multifunctional compound with one or more hydrophobic polymers and one or more hydrophilic polymers, and conatin a biologically active material.

[00644] US Patent No. 5,855,913, incorporated herein by reference, provides a particulate composition having aerodynamically light particles having a tap density of less than 0.4 g/cm3 with a mean diameter of between 5 pm and 30 μ m, incorporating a surfactant on the surface thereof for drug delivery to the pulmonary system.

[00645] US Patent No. 5,985,309, incorporated herein by reference, provides particles incorporating a surfactant and/or a hydrophilic or hydrophobic complex of a positively or negatively charged therapeutic or diagnostic agent and a charged molecule of opposite charge for delivery to the pulmonary system.

[00646] US. Patent No. 5,543,158, incorporated herein by reference, provides biodegradable injectable particles having a biodegradable solid core containing a biologically active material and poly(alkylene glycol) moieties on the surface.

[00647] WO2012135025 (also published as US20120251560), incorporated herein by reference, describes conjugated polyethyleneimine (PEI) polymers and conjugated azamacrocycles (collectively referred to as “conjugated lipomer” or “lipomers”). In certain embodiments, it can envisioned that such conjugated lipomers can be used in the context of the CRISPR-Cas system to achieve in vitro, ex vivo and in vivo genomic perturbations to modify gene expression, including modulation of protein expression, [00648] In one embodiment, the nanoparticle may be epoxide-modified lipid-polymer, advantageously 7C1 (see, e.g., James E. Dahlman and Carmen Barnes et al. Nature Nanotechnology (2014) published online 11 May 2014, doi:I0.1038/nnano.20I4.84). C71 was synthesized by reacting C15 epoxide-terminated lipids with PEI600 at a 14:1 molar ratio, and

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PCT/US2016/038181 was formulated with C14PEG2000 to produce nanoparticles (diameter between 35 and 60 nm) that were stable in PBS solution for at least 40 days.

[00649] An epoxide-modified lipid-polymer may be utilized to deliver the CRISPR-Cas system of the present invention to pulmonary, cardiovascular or renal cells, however, one of skill in the art may adapt the system to deliver to other target organs. Dosage ranging from about 0.05 to about 0.6 mg/kg are envisioned. Dosages over several days or weeks are also envisioned, with a total dosage of about 2 mg/kg.

Exosomes [00650] Exosomes are endogenous nano-vesicles that transport RNAs and proteins, and which can deliver RNA to the brain and other target organs. To reduce immunogenicity, Alvarez-Erviti et al. (2011, Nat Biotechnol 29: 341) used self-derived dendritic cells for exosome production. Targeting to the brain was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous RNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA deliver}⁷ was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease.

[00651] To obtain a pool of immunologically inert exosomes, Alvarez-Erviti et al. harvested bone marrow from inbred C57BL/6 mice with a homogenous major histocompatibility complex (MHC) haplotype. As immature dendritic cells produce large quantities of exosomes devoid of T-cell activators such as MHC-Π and CD86, Alvarez-Erviti et al, selected for dendritic cells with granulocyte/macrophage-colony stimulating factor (GM-CSF) for 7 d. Exosomes were purified from the culture supernatant the following day using well-established ultracentrifugation protocols. The exosomes produced were physically homogenous, with a size distribution peaking at 80 nm in diameter as determined by nanoparticle tracking analysis (NTA) and electron microscopy. Alvarez-Erviti et al. obtained 6-12 pg of exosomes (measured based on protein concentration) per IO⁶ cells.

[00652] Next Alvarez-Erviti et al. investigated the possibility of loading modified exosomes with exogenous cargoes using electroporation protocols adapted for nanoscale applications. As

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PCT/US2016/038181 electroporation for membrane particles at the nanometer scale is not well-characterized, nonspecific Cy5-labeled RNA was used for the empirical optimization of the electroporation protocol. The amount of encapsulated RNA was assayed after ultracentrifugation and lysis of exosomes. Electroporation at 400 V and 125 μΕ resulted in the greatest retention of RNA and was used for all subsequent experiments.

[00653] Alvarez-Erviti et al, administered 150 gg of each BACE1 siRNA encapsulated in 150 pg of RVG exosomes to normal C57BL/6 mice and compared the knockdown efficiency to four controls: untreated mice, mice injected with RVG exosomes only, mice injected with BACE1 siRNA complexed to an in vivo cationic liposome reagent and mice injected with BACE1 siRNA complexed to RVG-9R, the RVG peptide conjugated to 9 D-arginines that electrostatically binds to the siRNA. Cortical tissue samples were analyzed 3 d after administration and a significant protein knockdown (45%, P < 0.05, versus 62%, P < 0.01) in both siRNA-RVG-9R-treated and siRNARVG exosome-treated mice was observed, resulting from a significant decrease in BACE1 mRNA levels (66% [+ or -] 15%, P < 0.001 and 61% [+ or -] 13% respectively, P < 0.01). Moreover, Applicants demonstrated a significant decrease (55%, P < 0.05) in the total [beta]-amyloid 1-42 levels, a main component of the amyloid plaques in Alzheimer’s pathology, in the RVG-exosome-treated animals. The decrease observed was greater than the β-amyloid 140 decrease demonstrated in normal mice after intraventricular injection of BACE1 inhibitors. Alvarez-Erviti et al. carried out 5'-rapid amplification of cDNA ends (RACE) on BACE1 cleavage product, which provided evidence of RNAi-mediated knockdown by the siRNA.

[00654] Finally, Alvarez-Erviti et al. investigated whether KNA-RVG exosomes induced immune responses in vivo by assessing IL-6, IP-10, TNFa and IFN-α serum concentrations. Following exosome treatment, nonsignificant changes in all cytokines were registered similar to siRNA-transfection reagent treatment in contrast to siRNA-RVG-9R, which potently stimulated IL-6 secretion, confirming the immunologically inert profile of the exosome treatment. Given that exosomes encapsulate only 20% of siRNA, delivery with RVG-exosome appears to be more efficient than RVG-9R deliver)/ as comparable mRNA knockdown and greater protein knockdown was achieved with fivefold less siRNA without the corresponding level of immune stimulation. This experiment demonstrated the therapeutic potential of RVG-exosome technology, which is potentially suited for long-term silencing of genes related to neurodegenerative diseases. The exosome delivery system of Alvarez-Erviti et al. may be applied

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PCT/US2016/038181 to deliver the CRISPR-Cas system of the present invention to therapeutic targets, especially neurodegenerative diseases. A dosage of about 100 to 1000 mg of CRISPR Cas encapsulated in about 100 to 1000 mg of RVG exosomes may be contemplated for the present invention.

[00655] Εί-Andaloussi et al, (Nature Protocols 7,2112-2126(2012)) discloses how exosomes derived from cultured cells can be harnessed for delivery' of RNA in vitro and in vivo. This protocol first describes the generation of targeted exosomes through transfection of an expression vector, comprising an exosomal protein fused with a peptide ligand. Next, El-Andaloussi et al. explain how to purify and characterize exosomes from transfected cell supernatant. Next, ElAndaloussi et al. detail crucial steps for loading RNA into exosomes. Finally, El-Andaloussi et al. outline how to use exosomes to efficiently deliver RNA in vitro and in vivo in mouse brain. Examples of anticipated results in which exosome-mediated RNA delivery is evaluated by functional assays and imaging are also provided. The entire protocol takes ~3 weeks. Delivery or administration according to the invention may be performed using exosomes produced from selfderived dendritic cells. From the herein teachings, this can be employed in the practice of the invention.

[00656] In another embodiment, the plasma exosomes of Wahlgren et al. (Nucleic Acids Research, 2012, Vol. 40, No. 17 el30) are contemplated. Exosomes are nano-sized vesicles (3090nm in size) produced by many cell types, including dendritic cells (DC), B cells, T cells, mast cells, epithelial cells and tumor cells. These vesicles are formed by inward budding of late endosomes and are then released to the extracellular environment upon fusion with the plasma membrane. Because exosomes naturally carry RNA between cells, this property may be useful in gene therapy, and from this disclosure can be employed in the practice of the instant invention. [00657] Exosomes from plasma can be prepared by centrifugation of buffy coat at 900g for 20 min to isolate the plasma followed by harvesting cell supernatants, centrifuging at 300g for 10 min to eliminate cells and at 16 500g for 30 min followed by filtration through a 0.22 mm filter. Exosomes are pelleted by ultracentrifugation at 120 OOOg for70 min. Chemical transfection of siRNA into exosomes is carried out according to the manufacturer’s instructions in RNAi Human/Mouse Starter Kit (Quiagen, Hilden, Germany). siRNA is added to 100 ml PBS at a final concentration of 2 mmol/ml. After adding HiPerFect transfection reagent, the mixture is incubated for 10 min at RT. In order to remove the excess of micelles, the exosomes are reisolated using aldehyde/sulfate latex beads. The chemical transfection of CRISPR Cas into

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PCT/US2016/038181 exosomes may be conducted similarly to siRNA. The exosomes may be co-cultured with monocytes and lymphocytes isolated from the peripheral blood of healthy donors. Therefore, it may be contemplated that exosomes containing CRISPR Cas may be introduced to monocytes and lymphocytes of and autologously reintroduced into a human. Accordingly, delivery or administration according to the invention may be performed using plasma exosomes.

[00658] Delivery or administration according to the invention can be performed with liposomes. Liposomes are spherical vesicle structures composed of a uni- or multilamellar lipid bilayer surrounding internal aqueous compartments and a relatively impermeable outer lipophilic phospholipid bilayer. Liposomes have gained considerable attention as drug delivery carriers because they are biocompatible, nontoxic, can deliver both hydrophilic and lipophilic drug molecules, protect their cargo from degradation by plasma enzymes, and transport their load across biological membranes and the blood brain barrier (BBB) (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi: 10.1155/2011/469679 for review).

[00659] Liposomes can be made from several different types of lipids; however, phospholipids are most commonly used to generate liposomes as drug carriers. Although liposome formation is spontaneous when a lipid film is mixed with an aqueous solution, it can also he expedited by applying force in the form of shaking by using a homogenizes sonicator, or an extrusion apparatus (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi: 10.1155/2011/469679 for review).

[00660] Several other additives may be added to liposomes in order to modify their structure and properties. For instance, either cholesterol or sphingomyelin may be added to the liposomal mixture in order to help stabilize the liposomal structure and to prevent the leakage of the liposomal inner cargo. Further, liposomes are prepared from hydrogenated egg phosphatidylcholine or egg phosphatidylcholine, cholesterol, and dicetyl phosphate, and their mean vesicle sizes were adjusted to about 50 and 100 nm. (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi: 10.1155/2011/469679 for review).

[00661 ] A liposome formulation may he mainly comprised of natural phospholipids and lipids such as l,2-distearoryl-sn-glycero-3-phosphatidyl choline (DSPC), sphingomyelin, egg

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PCT/US2016/038181 phosphatidylcholines and monosialoganglioside. Since this formulation is made up of phospholipids only, liposomal formulations have encountered many challenges, one of the ones being the instability in plasma. Several attempts to overcome these challenges have been made, specifically in the manipulation of the lipid membrane. One of these attempts focused on the manipulation of cholesterol. Addition of cholesterol to conventional formulations reduces rapid release of the encapsulated bioactive compound into the plasma or 1,2-dioleoyl-sn-glycero-3phosphoethanolamine (DOPE) increases the stability (see, e.g., Spuch and Navarro, Journal of Drug Deliver)', vol. 2011, Article ID 469679, 12 pages, 2011. doi: 10.1155/2011/469679 tor review).

[00662] In a particularly advantageous embodiment, Trojan Horse liposomes (also known as Molecular Trojan Horses) are desirable and protocols may be found at http://cshprotocols.cshlp.Org/content/2010/4/pdb.prot5407.long. These particles allow delivery of a transgene to the entire brain after an intravascular injection. Without being bound by limitation, it is believed that neutral lipid particles with specific antibodies conjugated to surface allow crossing of the blood brain barrier via endocytosis. Applicant postulates utilizing Trojan Horse Liposomes to deliver the CRISPR family of nucleases to the brain via an intravascular injection, which would allow whole brain transgenic animals without the need for embryonic manipulation. About 1-5 g of DNA or RNA may be contemplated for in vivo administration in liposomes.

[00663] In another embodiment, the CRISPR Cas system or components thereof may be administered in liposomes, such as a stable nucleic-acid-lipid particle (SNALP) (see, e.g., Morrissey et al,, Nature Biotechnology, Vol, 23, No, 8, August 2005), Daily intravenous injections of about 1, 3 or 5 mg/kg/day of a specific CRISPR Cas targeted in a SNALP are contemplated. The daily treatment may be over about three days and then weekly for about five weeks. In another embodiment, a specific CRISPR Cas encapsulated SNALP) administered by intravenous injection to at doses of about 1 or 2.5 mg/kg are also contemplated (see, e.g., Zimmerman et al., Nature Letters, Vol. 441, 4 May 2006). The SNALP formulation may contain the lipids 3-N-[(wmethoxypoly(ethylene glycol) 2000) carbamoyl] -1,2-dimyristyloxypropylamine (PEG-C-DM A), 1,2-dilinoleyioxy-N,N-dimethyl-3-aminopropane (DLinDMA), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, in a 2:40:10:48 molar per cent ratio (see, e.g., Zimmerman et al., Nature Letters, Vol. 441, 4 May 2006).

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PCT/US2016/038181 [00664] In another embodiment, stable nucleic-acid-lipid particles (SNALPs) have proven to be effective delivery molecules to highly vascularized HepG2-derived liver tumors but not in poorly vascularized HCT-116 derived liver tumors (see, e.g., Li, Gene Therapy (2012) 19, 775780). The SNALP liposomes may be prepared by formulating D-Lin-DMA and PEG-C-DMA with distearoylphosphatidyl choline (DSPC), Cholesterol and siRNA using a 25:1 lipid/siRNA ratio and a 48/40/10/2 molar ratio of Cholesterol/D-Lin-DMA/DSPC/PEG-C-DMA. The resulted SNALP liposomes are about 80-100 nm in size.

[00665] In yet another embodiment, a SNALP may comprise synthetic cholesterol (SigmaAldrich, St Louis, MO, USA), dipalmitoylphosphatidylcholine (Avanti Polar Lipids, Alabaster, AL, USA), 3 -N-[(w-m ethoxy polyethylene glycol )2000)carbamoyl]-1,2dimyrestyloxypropylamine, and cationic l,2-dilinoleyloxy-3-N,Ndimethylaminopropane (see, e.g., Geisbert et al., Lancet 2010; 375: 1896-905). A dosage of about 2 mg/kg total CRISPR Cas per dose administered as, for example, a bolus intravenous infusion may be contemplated.

[00666] In yet another embodiment, a SNALP may comprise synthetic cholesterol (SigmaAldrich), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; Avanti Polar Lipids Inc.), PEGcDMA, and l,2-dilinoleyloxy-3-(N;N-dimethyl)aminopropane (DLinDMA) (see, e.g., Judge, J. Clin. Invest. 119:661-673 (2009)). Formulations used for in vivo studies may comprise a final lipid/RNA mass ratio of about 9:1.

[00667] The safety profile of RNAi nanomedicines has been reviewed by Barros and Gollob of Alnylam Pharmaceuticals (see, e.g.. Advanced Drug Delivery Reviews 64 (2012) 1730-1737). The stable nucleic acid lipid particle (SNALP) is comprised of four different lipids — an ionizable lipid (DLinDMA) that is cationic at low pH, a neutral helper lipid, cholesterol, and a diffusible polyethylene glycol (PEG)-lipid. The particle is approximately 80 nm in diameter and is charge-neutral at physiologic pH. During formulation, the ionizable lipid serves to condense lipid with the anionic RNA during particle formation. When positively charged under increasingly acidic endosomal conditions, the ionizable lipid also mediates the fusion of SNALP with the endosomal membrane enabling release of RNA into the cytoplasm. The PEG-lipid stabilizes the particle and reduces aggregation during formulation, and subsequently provides a neutral hydrophilic exterior that improves pharmacokinetic properties.

[00668] To date, two clinical programs have been initiated using SNALP formulations with RNA. Tekmira Pharmaceuticals recently completed a phase I single-dose study of SNALP-ApoB

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PCT/US2016/038181 in adult volunteers with elevated LDL cholesterol. ApoB is predominantly expressed in the liver and jejunum and is essential for the assembly and secretion of VLDL and LDL. Seventeen subjects received a single dose of SNALP-ApoB (dose escalation across 7 dose levels). There was no evidence of liver toxicity (anticipated as the potential dose-limiting toxicity based on preclinical studies). One (of two) subjects at the highest dose experienced flu-like symptoms consistent with immune system stimulation, and the decision was made to conclude the trial, [00669] Alnylam Pharmaceuticals has similarly advanced ALN-TTR01, which employs the SNALP technology described above and targets hepatocyte production of both mutant and wildtype TTR to treat TTR amyloidosis (ATTR). Three ATTR syndromes have been described: familial amyloidotic polyneuropathy (TAP) and familial amyloidotic cardiomyopathy (FAC) — both caused by autosomal dominant mutations in TTR; and senile systemic amyloidosis (SSA) cause by wildtype TTR. A placebo-controlled, single dose-escalation phase I trial of ALNTTR01 was recently completed in patients with ATTR, ALN-TTR01 was administered as a 15minute IV infusion to 31 patients (23 with study drug and 8 with placebo) within a dose range of 0.01 to 1.0 mg/kg (based on siRNA). Treatment was well tolerated with no significant increases in liver function tests. Infusion-related reactions were noted in 3 of 23 patients at>0.4 mg/kg; all responded to slowing of the infusion rate and all continued on study. Minimal and transient elevations of serum cytokines IL-6, IP-10 and IL-Ira were noted in two patients at the highest dose of 1 mg/kg (as anticipated from preclinical and NHP studies). Lowering of serum TTR, the expected pharmacodynamics effect of ALN-TTR01, was observed at 1 mg/kg.

[00670] In yet another embodiment, a SNALP may be made by solubilizing a cationic lipid, DSPC, cholesterol and PEG-lipid e.g., in ethanol, e.g., at a molar ratio of 40:10:40:10, respectively (see, Semple et al., Nature Niotechnology, Volume 28 Number 2 February 2010, pp. 172-177). The lipid mixture was added to an aqueous buffer (50 mM citrate, pFl 4) with mixing to a final ethanol and lipid concentration of 30% (vol/vol) and 6.1 mg/ml, respectively, and allowed to equilibrate at 22 °C for 2 min before extrusion. The hydrated lipids were extruded through two stacked 80 nm pore-sized filters (Nuclepore) at 22 °C using a Lipex Extruder (Northern Lipids) until a vesicle diameter of 70-90 nm, as determined by dynamic light scattering analysis, was obtained. This generally required 1-3 passes. The siRNA (solubilized in a 50 mM citrate, pEl 4 aqueous solution containing 30% ethanol) was added to the preequilibrated (35 °C) vesicles at a rate of-5 ml/min with mixing. After a final target siRNA/lipid

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PCT/US2016/038181 ratio of 0.06 (wt/wt) was reached, the mixture was incubated for a further 30 min at 35 °C to allow vesicle reorganization and encapsulation of the siRNA. The ethanol was then removed and the external buffer replaced with PBS (155 mM NaCl, 3 mM NazHPCU, I mM KH2PO4, pH 7.5) by either dialysis or tangential flow⁷ diafiltration. siRNA were encapsulated in SNALP using a controlled step-wise dilution method process. The lipid constituents of KC2-SNALP were DLinKC2-DMA (cationic lipid), dipalmitoylphosphatidylcholine (DPPC; Avanti Polar Lipids), synthetic cholesterol (Sigma) and PEG-C-DMA used at a molar ratio of 57.1:7.1:34.3:1.4. Upon formation of the loaded particles, SNALP were dialyzed against PBS and filter sterilized through a 0.2 pm filter before use. Mean particle sizes were 75-85 nm and 90-95% of the siRNA was encapsulated within the lipid particles. The final siRNA/lipid ratio in formulations used for in vivo testing was —0.15 (wt/wt), LNP-siRNA systems containing Factor VII siRNA were diluted to the appropriate concentrations in sterile PBS immediately before use and the formulations were administered intravenously through the lateral tail vein in a total volume of 10 ml/kg, This method and these delivery systems may be extrapolated to the CRISPR Cas system of the present invention.

[00671] Other cationic lipids, such as amino lipid 2,2-dilinoleyl-4-dimethylaminoethyl-[l,3]dioxolane (DLin-KC2-DMA) may be utilized to encapsulate CRISPR. Cas or components thereof or nucleic acid molecule(s) coding therefor e.g., similar to SiRNA (see, e.g., Jayaraman, Angew. Chem. Int. Ed. 2012, 51, 8529 -8533), and hence may be employed in the practice of the invention. A preformed vesicle with the following lipid composition may be contemplated: amino lipid, distearoylphosphatidylcholine (DSPC), cholesterol and (R)-2,3-bis(octadecyloxy) propyl-1-(methoxy poly(ethylene glycol)2000)propylcarbamate (PEG-lipid) in the molar ratio 40/10/40/10, respectively, and a FVII siRNA/total lipid ratio of approximately 0.05 (w/w). To ensure a narrow⁷ particle size distribution in the range of 70-90 nm and a low⁷ polydispersity index of 0.11+0.04 (n=56), the particles may be extruded up to three times through 80 nm membranes prior to adding the guide RNA. Particles containing the highly potent amino lipid 16 may be used, in which the molar ratio of the four lipid components 16, DSPC, cholesterol and PEG-lipid (50/10/38.5/1.5) which may be further optimized to enhance in vivo activity.

[00672] Michael S D Kormann et al. (Expression of therapeutic proteins after delivery of chemically modified mRNA in mice: Nature Biotechnology, Volume:29, Pages: 154-157

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PCT/US2016/038181 (2011)) describes the use of lipid envelopes to deliver RNA. Use of lipid envelopes is also preferred in the present invention.

[00673] In another embodiment, lipids may be formulated with the CRISPR Cas system of the present invention or component(s) thereof or nucleic acid molecule(s) coding therefor to form lipid nanoparticles (LNPs). Lipids include, but are not limited to, DLin-KC2-DMA4, C12-200 and colipids disteroylphosphatidyl choline, cholesterol, and PEG-DMG may be formulated with CRISPR Cas instead of siRNA (see, e.g., Novobrantseva, Molecular Therapy-Nucleic Acids (2012) 1, e4; doi:10.1038/mtna.2011.3) using a spontaneous vesicle formation procedure. The component molar ratio may be about 50/10/38.5/1.5 (DLin-KC2-DMA or 02200/disteroylphosphatidyl choline/cholesterol/PEG-DMG). The final lipid:siRNA weight ratio may be —12:1 and 9:1 in the case of DLin-KC2-DMA and Cl2-200 lipid nanoparticles (LNPs), respectively. The formulations may have mean particle diameters of ~80 nm with >90% entrapment efficiency. A 3 mg/kg dose may be contemplated.

[00674] Tekmira has a portfolio of approximately 95 patent families, in the U.S. and abroad, that are directed to various aspects of LNPs and LNP formulations (see, e.g., U.S. Pat. Nos. 7,982,027; 7,799,565; 8,058,069; 8,283,333; 7,901,708; 7,745,651; 7,803,397; 8,101,741;

8,188,263; 7,915,399; 8,236,943 and 7,838,658 and European Pat. Nos 1766035; 1519714; 1781593 and 1664316), all of which may be used and/or adapted to the present invention.

[00675] The CRISPR Cas system or components thereof or nucleic acid molecule(s) coding therefor may be delivered encapsulated in PLGA Microspheres such as that further described in US published applications 20130252281 and 20130245107 and 20130244279 (assigned to Modema Therapeutics) which relate to aspects of formulation of compositions comprising modified nucleic acid molecules which may encode a protein, a protein precursor, or a partially or fully processed form of the protein or a protein precursor. The formulation may have a molar ratio 50:10:38.5:1.5-3.0 (cationic lipid:fusogenic lipid:cholesterol:PEG lipid). The PEG lipid may be selected from, but is not limited to PEG-c-DOMG, PEG-DMG. The fusogenic lipid may be DSPC. See also, Schrum et al.. Delivery and Formulation of Engineered Nucleic Acids, US published application 20120251618.

[00676] Nanomerics’ technology addresses bioavailability challenges for a broad range of therapeutics, including low' molecular weight hydrophobic drugs, peptides, and nucleic acid based therapeutics (plasmid, siRNA, miRNA). Specific administration routes for which the

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PCT/US2016/038181 technology has demonstrated clear advantages include the oral route, transport across the bloodbrain-barrier, deliver}' to solid tumours, as well as to the eye. See, e.g., Mazza et al., 2013, ACS Nano. 2013 Feb 26;7(2): 1016-26; Uchegbu and Slew, 2013, J Pharm Sci. 102(2):305-10 and Lalatsa et al·, 2012, J Control Release. 2012 Jui 20; 161(2):523-36.

[00677] US Patent Publication No. 20050019923 describes cationic dendrimers for delivering bioactive molecules, such as polynucleotide molecules, peptides and polypeptides and/or pharmaceutical agents, to a mammalian body. The dendrimers are suitable for targeting the delivery of the bioactive molecules to, for example, the liver, spleen, lung, kidney or heart (or even the brain). Dendrimers are synthetic 3-dimensional macromolecules that are prepared in a step-wise fashion from simple branched monomer units, the nature and functionality of which can be easily controlled and varied. Dendrimers are synthesised from the repeated addition of building blocks to a multifunctional core (divergent approach to synthesis), or towards a multifunctional core (convergent approach to synthesis) and each addition of a 3-dimensional shell of building blocks leads to the formation of a higher generation of the dendrimers. Polypropylenimine dendrimers start from a diaminobutane core to which is added twice the number of amino groups by a double Michael addition of acrylonitrile to the primary amines followed by the hydrogenation of the nitriles. This results in a doubling of the amino groups. Polypropyl enimine dendrimers contain 100% protonable nitrogens and up to 64 terminal amino groups (generation 5, DAB 64). Protonable groups are usually amine groups which are able to accept protons at neutral pH, The use of dendrimers as gene delivery agents has largely focused on the use of the polyamidoamine, and phosphorous containing compounds with a mixture of amine/amide or N—P(O₂)S as the conjugating units respectively with no work being reported on the use of the lower generation polypropyl enimine dendrimers for gene delivery'. Polypropyl enimine dendrimers have also been studied as pH sensitive controlled release systems for drug delivery and for their encapsulation of guest molecules when chemically modified by peripheral amino acid groups. The cytotoxicity and interaction of polypropylenimine dendrimers with DNA as well as the transfection efficacy of DAB 64 has also been studied.

[00678] LIS Patent Publication No. 20050019923 is based upon the observation that, contrary' to earlier reports, cationic dendrimers, such as polypropylenimine dendrimers, display suitable properties, such as specific targeting and low toxicity, for use in the targeted delivery' of bioactive molecules, such as genetic material. In addition, derivatives of the cationic dendrimer

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PCT/US2016/038181 also display suitable properties for the targeted delivery' of bioactive molecules. See also, Bioactive Polymers, US published application 20080267903, which discloses Various polymers, including cationic polyamine polymers and dendrimeric polymers, are shown to possess anti-proliferative activity, and may therefore be useful for treatment of disorders characterised by undesirable cellular proliferation such as neoplasms and tumours, inflammatory disorders (including autoimmune disorders), psoriasis and atherosclerosis. The polymers may be used alone as active agents, or as deliver)' vehicles for other therapeutic agents, such as drug molecules or nucleic acids for gene therapy. In such cases, the polymers' own intrinsic antitumour activity may complement the activity of the agent to be delivered. The disclosures of these patent publications may be employed in conjunction with herein teachings for deliver)' of CRISPR Cas system(s) or component(s) thereof or nucleic acid molecule(s) coding therefor. Supercharged proteins [00679] Supercharged proteins are a class of engineered or naturally occurring proteins with unusually high positive or negative net theoretical charge and may be employed in delivery of CRISPR Cas system(s) or component(s) thereof or nucleic acid molecule(s) coding therefor. Both supernegatively and superpositively charged proteins exhibit a remarkable ability to withstand thermally or chemically induced aggregation. Superpositively charged proteins are also able to penetrate mammalian cells. Associating cargo with these proteins, such as plasmid DNA, RNA, or other proteins, can enable the functional deliver)' of these macromolecules into mammalian cells both in vitro and in vivo. David Liu’s lab reported the creation and characterization of supercharged proteins in 2007 (Lawrence et al., 2007, Journal of the American Chemical Society 129, 10110-10112).

[00680] The nonviral deliver)/ of RNA and plasmid DNA into mammalian cells are valuable both for research and therapeutic applications (Akinc et al., 2010, Nat. Biotech. 26, 561-569). Purified +36 GFP protein (or other superpositively charged protein) is mixed with RNAs in the appropriate serum-free media and allowed to complex prior addition to cells. Inclusion of serum at this stage inhibits formation of the supercharged protein-RNA complexes and reduces the effectiveness of the treatment. The following protocol has been found to be effective for a variety of cell lines (McNaughton et al., 2009, Proc. Natl. Acad. Sci. USA 106, 6111-6116) (However, pilot experiments varying the dose of protein and RNA should be perfonned to optimize the procedure for specific cell lines):

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PCT/US2016/038181 [00681] (1) One day before treatment, plate i χ 10⁵ cells per well in a 48-well plate.

[00682] (2) On the day of treatment, dilute purified +36 GFP protein in serumfree media to a final concentration 200nM. Add RNA to a final concentration of 50nM, Vortex to mix and incubate at room temperature for lOmin.

[00683] (3) During incubation, aspirate media from cells and wash once with PBS. [00684] (4) Following incubation of +36 GFP and RNA, add the protein-RNA complexes to cells.

[00685] (5) Incubate cells with complexes at 37 °C for 4h.

[00686] (6) Following incubation, aspirate the media and wash three times with 20 U/mL heparin PBS. Incubate cells with serum-containsng media for a further 48h or longer depending upon the assay for activity.

[00687] (7) Analyze cells by immunoblot, qPCR, phenotypic assay, or other appropriate method.

[00688] David Liu’s lab has further found +36 GFP to be an effective plasmid delivery reagent in a range of cells. As plasmid DNA is a larger cargo than siRNA, proportionately more +36 GFP protein is required to effectively complex plasmids. For effective plasmid delivery Applicants have developed a variant of +36 GFP bearing a C-terminal HA2 peptide tag, a known endosome-disrupting peptide derived from the influenza virus hemagglutinin protein. The following protocol has been effective in a variety of cells, but as above it is advised that plasmid DNA and supercharged protein doses be optimized for specific cell lines and delivery applications:

[00689] (1) One day before treatment, plate 1 χ 10⁵ per well in a 48-well plate. (2)

On the d [00690] ay of treatment, dilute purified J?36 GFP protein in serumfree media to a final concentration 2 mM. Add Img of plasmid DNA. Vortex to mix and incubate at room temperature for lOmin.

[00691] (3) During incubation, aspirate media from cells and wash once with PBS.

[00692] (4) Following incubation of p36 GFP and plasmid DNA, gently add the protein-DNA complexes to cells.

[00693] (5) Incubate cells with complexes at 37 C for 4h.

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PCT/US2016/038181 [00694] (6) Following incubation, aspirate the media and wash with PBS. Incubate cells in serum-containing media and incubate for a further 24-48h.

[00695] (7) Analyze plasmid delivery (e.g., by plasmid-driven gene expression) as appropriate.

[00696] See also, e.g., McNaughton et al., Proc. Natl. Acad. Sci. USA 106, 6111-6116 (2009); Cronican et al,, ACS Chemical Biology 5, 747-752 (2010); Cronican et al.. Chemistry/ & Biology 18, 833-838 (2011); Thompson et al., Methods in Enzymology 503, 293-319 (2012); Thompson, D.B., et ah, Chemistry & Biology 19 (7), 831-843 (2012). The methods of the super charged proteins may he used and/or adapted for delivery of the CRISPR Cas system of the present invention. These systems of Dr. Lui and documents herein in conjunction with herein teaching can he employed in the delivery/ of CRISPR Cas system(s) or component(s) thereof or nucleic acid molecule(s) coding therefor.

Ceil Penetrating Peptides (CPPs) [00697] In yet another embodiment, cell penetrating peptides (CPPs) are contemplated for the delivery of the CRISPR Cas system. CPPs are short peptides that facilitate cellular uptake of various molecular cargo (from nanosize particles to small chemical molecules and large fragments of DNA). The term “cargo” as used herein includes but is not limited to the group consisting of therapeutic agents, diagnostic probes, peptides, nucleic acids, antisense oligonucleotides, plasmids, proteins, particles, including nanoparticles, liposomes, chromophores, small molecules and radioactive materials. In aspects of the invention, the cargo may also comprise any component of the CRISPR Cas system or the entire functional CRISPR Cas system. Aspects of the present invention further provide methods for delivering a desired cargo into a subject comprising: (a) preparing a complex comprising the cell penetrating peptide of the present invention and a desired cargo, and (b) orally, intraarticularly, intraperitoneally, intrathecally, intrarterially, intranasally, intraparenchymally, subcutaneously, intramuscularly, intravenously, dermally, intrarectally, or topically administering the complex to a subject. The cargo is associated with the peptides either through chemical linkage via covalent bonds or through non-covalent interactions.

[00698] The function of the CPPs are to deliver the cargo into cells, a process that commonly occurs through endocytosis with the cargo delivered to the endosomes of living mammalian cells. Cell-penetrating peptides are of different sizes, amino acid sequences, and charges but all

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CPPs have one distinct characteristic, which is the ability to translocate the plasma membrane and facilitate the delivery of various molecular cargoes to the cytoplasm or an organelle. CPP translocation may be classified into three main entry mechanisms: direct penetration in the membrane, endocytosis-mediated entry, and translocation through the formation of a transitory structure. CPPs have found numerous applications in medicine as drug deliver}⁷ agents in the treatment of different diseases including cancer and virus inhibitors, as well as contrast agents for cell labeling. Examples of the latter include acting as a carrier for GFP, MRI contrast agents, or quantum dots. CPPs hold great potential as in vitro and in vivo delivery vectors for use in research and medicine. CPPs typically have an amino acid composition that either contains a high relative abundance of positively charged amino acids such as lysine or arginine or has sequences that contain an alternating pattern of polar/charged amino acids and non-polar, hydrophobic amino acids. These two types of structures are referred to as polycationic or amphipathic, respectively. A third class of CPPs are the hydrophobic peptides, containing only apolar residues, with low net charge or have hydrophobic amino acid groups that are crucial for cellular uptake. One of the initial CPPs discovered was the trans-activating transcriptional activator (Tat) from Human Immunodeficiency Vims 1 (HIV-1) which was found to be efficiently taken up from the surrounding media by numerous cell types in culture. Since then, the number of known CPPs has expanded considerably and small molecule synthetic analogues with more effective protein transduction properties have been generated. CPPs include but are not limited to Penetratin, Tat (48-60), Transportan, and (R-AhX-R4) (Ahx=aminohexanoyl). [00699] US Patent 8,372,951, provides a CPP derived from eosinophil cationic protein (ECP) which exhibits highly cell-penetrating efficiency and low⁷ toxicity. Aspects of delivering the CPP with its cargo into a vertebrate subject are also provided. Further aspects of CPPs and their delivery are described in U. S. patents 8,575,305, 8;614,194 and 8,044,019. CPPs can be used to deliver the CRISPR-Cas system or components thereof. That CPPs can be employed to deliver the CRISPR-Cas system or components thereof is also provided in the manuscript “Gene disruption by cell-penetrating peptide-mediated deliver}/ of Cas9 protein and guide RNA”, by Suresh Ramakrishna, Abu-Bonsrah Kw⁷aku Dad, Jagadish Beloor, et al. Genome Res. 2014 Apr 2. [Epub ahead of print], incorporated by reference in its entirety, wherein it is demonstrated that treatment with CPP-conjugated recombinant Cas9 protein and CPP-complexed guide RNAs lead to endogenous gene disruptions in human cell lines. In the paper the Cas9 protein was conjugated

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PCT/US2016/038181 to CPP via a thioether bond, whereas the guide RNA was complexed with CPP, forming condensed, positively charged particles. It was shown that simultaneous and sequential treatment of human cells, including embryonic stem cells, dermal fibroblasts, HEK293T cells, HeLa cells, and embryonic carcinoma cells, with the modified Cas9 and guide RNA led to efficient gene disruptions with reduced off-target mutations relative to plasmid transfections.

Implantable devices [00700] In another embodiment, implantable devices are also contemplated for delivery of the CRISPR Cas system or component(s) thereof or nucleic acid molecule(s) coding therefor. For example, US Patent Publication 20110195123 discloses an implantable medical device which elutes a drug locally and in prolonged period is provided, including several types of such a device, the treatment modes of implementation and methods of implantation. The device comprising of polymeric substrate, such as a matrix for example, that is used as the device body, and drugs, and in some cases additional scaffolding materials, such as metals or additional polymers, and materials to enhance visibility and imaging. An implantable delivery device can be advantageous in providing release locally and over a prolonged period, where drug is released directly to the extracellular matrix (ECM) of the diseased area such as tumor, inflammation, degeneration or for symptomatic objectives, or to injured smooth muscle cells, or for prevention. One kind of drug is RNA, as disclosed above, and this system may be used/and or adapted to the CRISPR Cas system of the present invention. The modes of implantation in some embodiments are existing implantation procedures that are developed and used today for other treatments, including brachytherapy and needle biopsy. In such cases the dimensions of the new implant described in this invention are similar to the original implant. Typically a few devices are implanted during the same treatment procedure.

[00701] US Patent Publication 20110195123, provides a drug delivery implantable or insertable system, including systems applicable to a cavity such as the abdominal cavity and/or any other type of administration in which the drug delivery system is not anchored or attached, comprising a biostable and/or degradable and/or bioabsorbable polymeric substrate, which may for example optionally be a matrix. It should be noted that the term insertion also includes implantation. The drug delivery system is preferably implemented as a Loder as described in US Patent Publication 20110195123,

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PCT/US2016/038181 [00702] The polymer or plurality of polymers are biocompatible, incorporating an agent and/or plurality of agents, enabling the release of agent at a controlled rate, wherein the total volume of the polymeric substrate, such as a matrix for example, in some embodiments is optionally and preferably no greater than a maximum volume that permits a therapeutic level of the agent to be reached. As a non-limiting example, such a volume is preferably within the range of 0.1 nr’ to 1000 mm³, as required by the volume for the agent load. The Loder may optionally be larger, for example when incorporated with a device whose size is determined by functionality, for example and without limitation, a knee joint, an intra-uterine or cervical ring and the like.

[00703] The diug delivery' system (for delivering the composition) is designed in some embodiments to preferably employ degradable polymers, wherein the main release mechanism is bulk erosion; or in some embodiments, non degradable, or slowly degraded polymers are used, wherein the main release mechanism is diffusion rather than bulk erosion, so that the outer part functions as membrane, and its internal part functions as a drug reservoir, which practically is not affected by the surroundings for an extended period (for example from about a week to about a few months). Combinations of different polymers with different release mechanisms may also optionally be used. The concentration gradient at the surface is preferably maintained effectively constant during a significant period of the total drug releasing period, and therefore the diffusion rate is effectively constant (termed zero mode diffusion). By the term constant it is meant a diffusion rate that is preferably maintained above the lower threshold of therapeutic effectiveness, but which may still optionally feature an initial burst and/or may fluctuate, for example increasing and decreasing to a certain degree. The diffusion rate is preferably so maintained for a prolonged period, and it can be considered constant to a certain level to optimize the therapeutically effective period, for example the effective silencing period.

[00704] The drug delivery system optionally and preferably is designed to shield the nucleotide based therapeutic agent from degradation, whether chemical in nature or due to attack from enzymes and other factors in the body of the subject.

[00705] The drug delivery system of US Patent Publication 20110195123 is optionally associated with sensing and/or activation appliances that are operated at and/or after implantation of the device, by non and/or minimally invasive methods of activation and/or acceleration/deeeleration, for example optionally including but not limited to thermal heating and

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PCT/US2016/038181 cooling, laser beams, and ultrasonic, including focused ultrasound and/or RF (radiofrequency) methods or devices.

[00706] According to some embodiments of US Patent Publication 20110195123, the site for local delivery may optionally include target sites characterized by high abnormal proliferation of cells, and suppressed apoptosis, including tumors, active and or chronic inflammation and infection including autoimmune diseases states, degenerating tissue including muscle and nervous tissue, chronic pain, degenerative sites, and location of bone fractures and other wound locations for enhancement of regeneration of tissue, and injured cardiac, smooth and striated muscle.

[00707] The site for implantation of the composition, or target site, preferably features a radius, area and/or volume that is sufficiently small for targeted local delivery. For example, the target site optionally has a diameter in a range of from about 0.1 mm to about 5 cm.

[00708] The location of the target site is preferably selected for maximum therapeutic efficacy. For example, the composition of the drug delivery’ system (optionally with a device for implantation as described above) is optionally and preferably implanted within or in the proximity of a tumor environment, or the blood supply associated thereof.

[00709] For example the composition (optionally with the device) is optionally implanted within or in the proximity to pancreas, prostate, breast, liver, via the nipple, within the vascular system and so forth.

[00710] The target location is optionally selected from the group comprising, consisting essentially of, or consisting of (as non-limiting examples only, as optionally any site within the body may be suitable for implanting a Loder): 1. brain at degenerative sites like in Parkinson or Alzheimer disease at the basal ganglia, white and gray matter; 2. spine as in the case of amyotrophic lateral sclerosis (ALS); 3. uterine cervix to prevent HPV infection; 4. active and chronic inflammatory'joints; 5. dermis as in the case of psoriasis; 6. sympathetic and sensoric nervous sites for analgesic effect, 7. Intra osseous implantation; 8. acute and chronic infection sites; 9. Intra vaginal; 10. Inner ear—auditory system, labyrinth of the inner ear, vestibular system; 11. Intratracheal; 12. Intra-cardiac; coronary, epicardiac; 13. urinary' bladder; 14. biliary' system; 15. parenchymal tissue including and not limited to the kidney, liver, spleen; 16. lymph nodes; 17. salivary glands; 18. dental gums; 19. Intra-articular (into joints); 20. Intra-ocular; 21.

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Brain tissue; 22. Brain ventricles; 23. Cavities, including abdominal cavity (for example but without limitation, for ovary cancer); 24. Intra esophageal and 25. Intra rectal.

[00711] Optionally insertion of the system (for example a device containing the composition) is associated with injection of material to the ECM at the target site and the vicinity of that site to affect local pH and/or temperature and/or other biological factors affecting the diffusion of the drug and/or drug kinetics in the ECM, of the target site and the vicinity of such a site.

[00712] Optionally, according to some embodiments, the release of said agent could be associated with sensing and/or activation appliances that are operated prior and/or at and/or after insertion, by non and/or minimally invasive and/or else methods of activation and/or acceleration/deceleration, including laser beam, radiation, thermal heating and cooling, and ultrasonic, including focused ultrasound and/or RF (radiofrequency) methods or devices, and chemical activators.

[00713] According to other embodiments of US Patent Publication 20110195123, the drug preferably comprises a RNA, for example for localized cancer cases in breast, pancreas, brain, kidney, bladder, lung, and prostate as described below. Although exemplified with RNAi, many drugs are applicable to be encapsulated in Loder, and can be used in association with this invention, as long as such drugs can be encapsulated with the Loder substrate, such as a matrix for example, and this system may be used and/or adapted to deliver the CRISPR Cas system of the present invention.

[00714] As another example of a specific application, neuro and muscular degenerative diseases develop due to abnormal gene expression. Local delivery of RNAs may have therapeutic properties for interfering with such abnormal gene expression. Local delivery of anti apoptotic, anti inflammatory and anti degenerative drugs including small drugs and macromolecules may also optionally be therapeutic. In such cases the Loder is applied for prolonged release at constant rate and/or through a dedicated device that is implanted separately. All of this may be used and/or adapted to the CRISPR Cas system of the present invention. [00715] As yet another example of a specific application, psychiatric and cognitive disorders are treated with gene modifiers. Gene knockdown is a treatment option. Loders locally delivering agents to central nervous system sites are therapeutic options for psychiatric and cognitive disorders including but not limited to psychosis, bi-polar diseases, neurotic disorders and behavioral maladies. The Loders could also deliver locally drugs including small drugs and

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PCT/US2016/038181 macromolecules upon implantation at specific brain sites. All of this may be used and/or adapted to the CRISPR Cas system of the present invention.

[00716] As another example of a specific application, silencing of innate and/or adaptive immune mediators at local sites enables the prevention of organ transplant rejection. Local delivery of RNAs and immunomodulating reagents with the Coder implanted into the transplanted organ and/or the implanted site renders local immune suppression by repelling immune cells such as CDS activated against the transplanted organ. All of this may be used/and or adapted to the CRISPR Cas system of the present invention.

[00717] As another example of a specific application, vascular growth factors including VEGFs and angiogenin and others are essential for neovascularization. Local delivery of the factors, peptides, peptidomimetics, or suppressing their repressors is an important therapeutic modality; silencing the repressors and local delivery of the factors, peptides, macromolecules and small drugs stimulating angiogenesis with the Loder is therapeutic for peripheral, systemic and cardiac vascular disease.

[00718] The method of insertion, such as implantation, may optionally already be used for other types of tissue implantation and/or for insertions and/or for sampling tissues, optionally without modifications, or alternatively optionally only with non-major modifications in such methods. Such methods optionally include but are not limited to brachytherapy methods, biopsy, endoscopy with and/or without ultrasound, such as ERCP, stereotactic methods into the brain tissue, Laparoscopy, including implantation with a laparoscope into joints, abdominal organs, the bladder wall and body cavities.

[00719] Implantable device technology herein discussed can be employed with herein teachings and hence by this disclosure and the knowledge in the art, CRISPR-Cas system or components thereof or nucleic acid molecules thereof or encoding or providing components may be delivered via an implantable device.

Patient-specific screening methods [00720] A nucleic acid-targeting system that targets DNA, e.g., trinucleotide repeats can be used to screen patients or patent samples for the presence of such repeats. The repeats can be the target of the RNA of the nucleic acid-targeting system, and if there is binding thereto by the nucleic acid-targeting system, that binding can be detected, to thereby indicate that such a repeat is present. Thus, a nucleic acid-targeting system can be used to screen patients or patient samples for the presence of the repeat. The

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PCT/US2016/038181 patient can then be administered suitable compound(s) to address the condition; or, can be administered a nucleic acid-targeting system to bind to and cause insertion, deletion or mutation and alleviate the condition.

[00721 ] The invention uses nucleic acids to bind target DNA sequences.

CRISPR effector protein mRNA and guide RNA [00722] CRISPR enzyme mRNA and guide RNA might also be delivered separately. CRISPR enzyme mRNA can be delivered prior to the guide RNA to give time for CRISPR enzyme to be expressed. CRISPR enzyme mRNA might be administered 1-12 hours (preferably around 2-6 hours) prior to the administration of guide RNA .

[00723] Alternatively, CRISPR enzyme mRNA and guide RNA can be administered together. Advantageously, a second booster dose of guide RNA can be administered 1-12 hours (preferably around 2-6 hours) after the initial administration of CRISPR enzyme mRNA + guide RNA.

[00724] The CRISPR effector protein of the present invention, i.e. Cpfl effector protein is sometimes referred to herein as a CRISPR Enzyme. It will be appreciated that the effector protein is based on or derived from an enzyme, so the term, ‘effector protein’ certainly includes ‘enzyme’ in some embodiments. However, it will also be appreciated that the effector protein may, as required in some embodiments, have DNA or RNA binding, but not necessarily cutting or nicking, activity, including a dead-Cas effector protein function.

[00725] Additional administrations of CRISPR enzyme mRNA and/or guide RNA might be useful to achieve the most efficient levels of genome modification. In some embodiments, phenotypic alteration is preferably the result of genome modification when a genetic disease is targeted, especially in methods of therapy and preferably where a repair template is provided to correct or alter the phenotype.

[00726] In some embodiments diseases that may be targeted include those concerned with disease-causing splice defects.

[00727] In some embodiments, cellular targets include Hemopoietic Stem/Progenitor Cells (CD34+); Human T cells; and Eye (retinal cells) - for example photoreceptor precursor cells. [00728] In some embodiments Gene targets include: Human Beta Globin -- HBB (for treating Sickle Cell Anemia, including by stimulating gene-conversion (using closely related HBD gene as an endogenous template)); CD3 (T-Cells); and CEP920 - retina (eye).

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PCT/US2016/038181 [00729] In some embodiments disease targets also include: cancer, Sickle Cell Anemia (based on a point mutation); HIV; Beta-Thalassemia; and ophthalmic or ocular disease - for example Leber Congenital Amaurosis (LCA)-causing Splice Defect.

[00730] In some embodiments delivery methods include: Cationic Lipid Mediated “direct” delivery of Enzyme-Guide complex (RiboNucleoProtein) and electroporation of plasmid DNA. [00731] Inventive methods can further comprise delivery of templates, such as repair templates, which may be dsODN or ssODN, see below. Deliver}⁷ of templates may be via the cotemporaneous or separate from delivery of any or all the CRISPR enzyme or guide and via the same delivery mechanism or different. In some embodiments, it is preferred that the template is delivered together with the guide, and, preferably, also the CRISPR enzyme. An example may be an AAV vector, [00732] Inventive methods can further comprise: (a) delivering to the cell a double-stranded oligodeoxynucleotide (dsODN) comprising overhangs complimentary to the overhangs created by said double strand break, wherein said dsODN is integrated into the locus of interest; or -(b) delivering to the cell a single-stranded oligodeoxynucleotide (ssODN), wherein said ssODN acts as a template for homology directed repair of said double strand break. Inventive methods can he for the prevention or treatment of disease in an individual, optionally wherein said disease is caused by a defect in said locus of interest. Inventive methods can be conducted in vivo in the individual or ex vivo on a cell taken from the individual, optionally wherein said cell is returned to the individual.

[00733] For minimization of toxicity and off-target effect, it will be important to control the concentration of CRISPR enzyme mRNA and guide RNA delivered. Optimal concentrations of CRISPR enzyme mRNA and guide RNA can he determined by testing different concentrations in a cellular or animal model and using deep sequencing the analyze the extent of modification at potential off-target genomic loci. For example, for the guide sequence targeting 5’GAGTCCGAGCAGAAGAAGAA-3’ (SEQ ID NO: 23) in the EMX1 gene of the human genome, deep sequencing can be used to assess the level of modification at the following two off-target loci, 1: 5’-GAGTCCTAGCAGGAGAAGAA-3’ (SEQ ID NO: 24) and 2: 5’GAGTCTAAGCAGAAGAAGAA-3’ (SEQ ID NO: 25). The concentration that gives the highest level of on-target modification while minimizing the level of off-target modification should be chosen for in vivo deliver}⁷.

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Inducible Systems [00734] In some embodiments, a CRISPR enzyme may form a component of an inducible system. The inducible nature of the system would allow for spatiotemporal control of gene editing or gene expression using a form of energy. The form of energy may include hut is not limited to electromagnetic radiation, sound energy, chemical energy and thermal energy. Examples of inducible system include tetracycline inducible promoters (Tet-On or Tet-Off), small molecule two-hybrid transcription activations systems (FKBP, ABA, etc), or light inducible systems (Phytochrome, LOV domains, or cryptochrome). In one embodiment, the CRISPR enzyme may be a part of a Light Inducible Transcriptional Effector (LITE) to direct changes in transcriptional activity in a sequence-specific manner. The components of a light may include a CRISPR enzyme, a light-responsive cytochrome heterodimer (e.g. from Arabidopsis thaliana), and a transcriptional activation/repression domain. Further examples of inducible DNA binding proteins and methods for their use are provided in US 61/736,465 and US 61/721,283,and WO 2014/018423 A2 which is hereby incorporated by reference in its entirety. Self-Inactivating Systems [00735] Once all copies of a gene in the genome of a cell have been edited, continued CRISRP/Cpflp expression in that cell is no longer necessary. Indeed, sustained expression would be undesirable in case of off-target effects at unintended genomic sites, etc. Thus timelimited expression would be useful. Inducible expression offers one approach, but in addition Applicants have engineered a Self-Inactivating CRISPR system that relies on the use of a noncoding guide target sequence within the CRISPR vector itself. Thus, after expression begins, the CRISPR-Cas system will lead to its own destruction, but before destruction is complete it will have time to edit the genomic copies of the target gene (which, with a normal point mutation in a diploid cell, requires at most two edits). Simply, the self inactivating CRISPR-Cas system includes additional RNA. (i.e., guide RNA) that targets the coding sequence for the CRISPR enzyme itself or that targets one or more non-coding guide target sequences complementary to unique sequences present in one or more of the foll owing:

(a) within the promoter driving expression of the non-coding RNA elements, (b) within the promoter driving expression of the Cpfl effector protein gene, (c) within lOObp of the ATG translational start codon in the Cpfl effector protein coding sequence,

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PCT/US2016/038181 (d) within the inverted terminal repeat (iTR.) of a viral delivery vector, e.g., in the AAV genome. [00736] Furthermore, that RNA can be delivered via a vector, e.g., a separate vector or the same vector that is encoding the CRISPR complex. When provided by a separate vector, the CRISPR RNA that targets Cas expression can be administered sequentially or simultaneously. When administered sequentially, the CRISPR RNA that targets Cas expression is to be delivered after the CRISPR RNA that is intended for e.g, gene editing or gene engineering. This period may be a period of minutes (e.g. 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes). This period may be a period of hours (e.g. 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours). This period may be a period of days (e.g. 2 days, 3 days, 4 days, 7 days). This period may be a period of weeks (e.g. 2 weeks, 3 weeks, 4 weeks). This period may be a period of months (e.g. 2 months, 4 months, 8 months, 12 months). This period may be a period of years (2 years, 3 years, 4 years). In this fashion, the Cas enzyme associates with a first gRNA capable of hybridizing to a first target, such as a genomic locus or loci of interest and undertakes the function(s) desired of the CRISPR-Cas system (e.g., gene engineering); and subsequently the Cas enzyme may then associate with the second gRNA capable of hybridizing to the sequence comprising at least part of the Cas or CRISPR cassette. Where the guide RNA targets the sequences encoding expression of the Cas protein, the enzyme becomes impeded and the system becomes self inactivating. In the same manner, CRISPR RNA that targets Cas expression applied via, for example liposome, lipofection, particles, microvesicles as explained herein, may be administered sequentially or simultaneously. Similarly, self-inactivation may be used for inactivation of one or more guide RNA used to target one or more targets.

[00737] In some aspects, a single gRNA is provided that is capable of hybridization to a sequence downstream of a CRISPR enzyme start codon, whereby after a period of time there is a loss of the CRISPR enzyme expression. In some aspects, one or more gRNA(s) are provided that are capable of hybridization to one or more coding or non-coding regions of the polynucleotide encoding the CRISPR-Cas system, whereby after a period of time there is a inactivation of one or more, or in some cases all, of the CRISPR-Cas system. In some aspects of the system, and not to be limited by theory, the cell may comprise a plurality of CRISPR-Cas complexes, wherein a first subset of CRISPR complexes comprise a first guide RNA capable of targeting a genomic locus or loci to be edited, and a second subset of CRISPR complexes comprise at least one second guide RNA capable of targeting the polynucleotide encoding the

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CRISPR-Cas system, wherein the first subset of CRISPR-Cas complexes mediate editing of the targeted genomic locus or loci and the second subset of CRISPR complexes eventually inactivate the CRISPR-Cas system, thereby inactivating further CRISPR-Cas expression in the cell.

[00738] Thus the invention provides a CRISPR-Cas system comprising one or more vectors for delivery to a eukaryotic cell, wherein the vector(s) encode(s): (i) a CRISPR enzyme; (ii) a first guide RNA capable of hybridizing to a target sequence in the cell; (iii) a second guide RNA capable of hybridizing to one or more target sequence(s) in the vector which encodes the CRISPR enzyme, when expressed within the cell: the first guide RNA directs sequence-specific binding of a first CRISPR complex to the target sequence in the cell; the second guide RNA directs sequence-specific binding of a second CRISPR complex to the target sequence in the vector which encodes the CRISPR enzyme; the CRISPR complexes comprise a CRISPR enzyme bound to a guide RNA, such that a guide RNA can hybridize to its target sequence; and the second CRISPR complex inactivates the CRISPR-Cas system to prevent continued expression of the CRISPR enzyme by the cell.

[00739] The various coding sequences (CRISPR enzyme and guide RNAs) can be included on a single vector or on multiple vectors. For instance, it is possible to encode the enzyme on one vector and the various RNA sequences on another vector, or to encode the enzyme and one guide RNA on one vector, and the remaining guide RNA on another vector, or any other permutation. In general, a system using a total of one or two different vectors is preferred.

[00740] Where multiple vectors are used, it is possible to deliver them in unequal numbers, and ideally with an excess of a vector which encodes the first guide RNA relative to the second guide RNA, thereby assisting in delaying final inactivation of the CRISPR system until genome editing has had a chance to occur.

[00741] The first guide RNA can target any target sequence of interest within a genome, as described elsewhere herein. The second guide RNA targets a sequence within the vector which encodes the CRISPR Cpfl enzyme, and thereby inactivates the enzyme’s expression from that vector. Thus the target sequence in the vector must be capable of inactivating expression. Suitable target sequences can be, for instance, near to or within the translational start codon for the Cpflp coding sequence, in a non-coding sequence in the promoter driving expression of the non-coding RNA elements, within the promoter driving expression of the Cpflp gene, within lOObp of the ATG translational start codon in the Cas coding sequence, and/or within the

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PCT/US2016/038181 inverted terminal repeat (iTR) of a viral delivery' vector, e.g., in the AAV genome. A double stranded break near this region can induce a frame shift in the Cas coding sequence, causing a loss of protein expression. An alternative target sequence for the “self-inactivating” guide RNA would aim to edit/inactivate regulatory/ regions/sequences needed for the expression of the CRISPR-Cpfl system or for the stability of the vector. For instance, if the promoter for the Cas coding sequence is disrupted then transcription can be inhibited or prevented. Similarly, if a vector includes sequences for replication, maintenance or stability then it is possible to target these. For instance, in a AAV vector a useful target sequence is within the iTR. Other useful sequences to target can be promoter sequences, polyadenlyation sites, etc.

[00742] Furthermore, if the guide RNAs are expressed in array format, the “self-inactivating” guide RNAs that target both promoters simultaneously will result in the excision of the intervening nucleotides from within the CRISPR-Cas expression construct, effectively leading to its complete inactivation. Similarly, excision of the intervening nucleotides will result where the guide RNAs target both ITRs, or targets two or more other CRISPR-Cas components simultaneously. Self-inactivation as explained herein is applicable, in general, with CRISPR-Cas systems in order to provide regulation of the CRISPR-Cas. For example, self-inactivation as explained herein may be applied to the CRISPR repair of mutations, for example expansion disorders, as explained herein. As a result of this self-inactivation, CRISPR repair is only transiently active.

[00743] Addition of non-targeting nucleotides to the 5’ end (e.g. 1 --- 10 nucleotides, preferably 1 -- 5 nucleotides) of the “self-inactivating” guide RNA can be used to delay its processing and/or modify its efficiency as a means of ensuring editing at the targeted genomic locus prior to CRISPR-Cas shutdown.

[00744] In one aspect of the self-inactivating AAV-CRISPR-Cas system, plasmids that coexpress one or more guide RNA targeting genomic sequences of interest (e.g. 1-2, 1-5, 1-10, 1 15, 1-20, 1-30) may be established with “self-inactivating” guide RNAs that target an SpCas9 sequence at or near the engineered ATG start, site (e.g. within 5 nucleotides, within 15 nucleotides, within 30 nucleotides, within 50 nucleotides, within 100 nucleotides). A regulatory sequence in the U6 promoter region can also be targeted with an guide RNA. The U6-driven guide RNAs may be designed in an array format such that multiple guide RNA sequences can be simultaneously released. When first delivered into target tissue/cells (left cell) guide RNAs begin

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PCT/US2016/038181 to accumulate while Cas levels rise in the nucleus. Cas complexes with all of the guide RNAs to mediate genome editing and self-inactivation of the CRISPR-Cas plasmids.

[00745] One aspect of a self-inactivating CRISPR-Cas system is expression of singly or in tandam array format from 1 up to 4 or more different guide sequences; e.g. up to about 20 or about 30 guides sequences. Each individual self inactivating guide sequence may target a different target. Such may be processed from, e.g. one chimeric po!3 transcript. Pol3 promoters such as U6 or Hl promoters may be used. Pol2 promoters such as those mentioned throughout herein. Inverted terminal repeat (iTR.) sequences may flank the Pol3 promoter - guide RNA(s)Pol2 promoter- Cas.

[00746] One aspect of a tandem array transcript is that one or more guide(s) edit the one or more target(s) while one or more self inactivating guides inactivate the CRISPR-Cas system. Thus, for example, the described CRISPR-Cas system for repairing expansion disorders may be directly combined with the self-in activating CRISPR-Cas system described herein. Such a system may, for example, have two guides directed to the target region for repair as well as at least a third guide directed to self-inactivation of the CRISPR-Cas. Reference is made to Application Ser. No. PCT/US2014/069897, entitled “Compositions And Methods Of Use Of Crispr-Cas Systems In Nucleotide Repeat Disorders,” published Dec. 12, 2014 as WO/2015/089351.

[00747] The guideRNA may be a control guide. For example it may be engineered to target a nucleic acid sequence encoding the CRISPR Enzyme itself, as described in US2015232881 Al, the disclosure of which is hereby incorporated by reference. In some embodiments, a system or composition may be provided with just the guideRNA engineered to target the nucleic acid sequence encoding the CRISPR Enzyme. In addition, the system or composition may be provided with the guideRNA engineered to target the nucleic acid sequence encoding the CRISPR Enzyme, as well as nucleic acid sequence encoding the CRISPR Enzyme and, optionally a second guide RNA and, further optionally, a repair template. The second guideRNA may be the primary target of the CRISPR system or composition (such a therapeutic, diagnostic, knock out etc. as defined herein). In this way, the system or composition is self-inactivating. This is exemplified in relation to Cas9 in US2015232881 Al (also published as WO2015070083 (Al) referenced elsewhere herein, and may be extrapolated to Cpfl.

Enzymes according to the invention used in a multiplex (tandem) targeting approach

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PCT/US2016/038181 [00748] The inventors have shown that CRISPR enzymes as defined herein can employ more than one RNA guide without losing activity. This enables the use of the CRISPR enzymes, systems or complexes as defined herein for targeting multiple DNA targets, genes or gene loci, with a single enzyme, system or complex as defined herein. The guide RNAs may be tandemly arranged, optionally separated by a nucleotide sequence such as a direct repeat as defined herein. The position of the different guide RNAs is the tandem does not influence the activity. It is noted that the terms “CRISPR-Cas system”, “CRISP-Cas complex” “CRISPR complex” and “CRISPR system” are used interchangeably. Also the terms “CRISPR enzyme”, “Cas enzyme”, or “CRISPR-Cas enzyme”, can be used interchangeably. In preferred embodiments, said CRISPR enzyme, CRISP-Cas enzyme or Cas enzyme is Cpfl, or any one of the modified or mutated variants thereof described herein elsewhere.

[00749] In one aspect, the invention provides a non-naturally occurring or engineered CRISPR enzyme, preferably a class 2 CRISPR enzyme, preferably a Type V or ΑΊ CRISPR enzyme as described herein, such as without limitation Cpfl as described herein elsewhere, used for tandem or multiplex targeting. It is to be understood that any of the CRISPR (or CRISPR-Cas or Cas) enzymes, complexes, or systems according to the invention as described herein elsewhere may be used in such an approach. Any of the methods, products, compositions and uses as described herein elsewhere are equally applicable with the multiplex or tandem targeting approach further detailed below. By means of further guidance, the following particular aspects and embodiments are provided.

[00750] In one aspect, the invention provides for the use of a Cpfl enzyme, complex or system as defined herein for targeting multiple gene loci. In one embodiment, this can be established by using multiple (tandem or multiplex) guide RNA (gRNA) sequences.

[00751] In one aspect, the invention provides methods for using one or more elements of a Cpfl enzyme, complex or system as defined herein for tandem or multiplex targeting, wherein said CRISP system comprises multiple guide RNA sequences. Preferably, said gRNA sequences are separated by a nucleotide sequence, such as a direct repeat as defined herein elsewhere, [00752] The Cpfl enzyme, system or complex as defined herein provides an effective means for modifying multiple target polynucleotides. The Cpfl enzyme, system or complex as defined herein has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) one or more target polynucleotides in a multiplicity of cell types. As

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PCT/US2016/038181 such the Cpfl enzyme, system or complex as defined herein of the invention has a broad spectrum of applications in, e.g., gene therapy, drug screening, disease diagnosis, and prognosis, including targeting multiple gene loci within a single CRISPR system.

[00753] In one aspect, the invention provides a Cpfl enzyme, system or complex as defined herein, i.e. a Cpfl CRISPR-Cas complex having a Cpfl protein having at least one destabilization domain associated therewith, and multiple guide RNAs that target multiple nucleic acid molecules such as DNA molecules, whereby each of said multiple guide RNAs specifically targets its corresponding nucleic acid molecule, e.g., DNA molecule. Each nucleic acid molecule target, e.g., DNA molecule can encode a gene product or encompass a gene locus. Using multiple guide RNAs hence enables the targeting of multiple gene loci or multiple genes. In some embodiments the Cpfl enzyme may cleave the DNA molecule encoding the gene product. In some embodiments expression of the gene product is altered. The Cpfl protein and the guide RNAs do not naturally occur together. The invention comprehends the guide RNAs comprising tandemly arranged guide sequences. The invention further comprehends coding sequences for the Cpfl protein being codon optimized for expression in a eukaryotic cell. In a preferred embodiment the eukaryotic ceil is a mammalian ceil, a plant cell or a yeast cell and in a more preferred embodiment the mammalian cell is a human cell. Expression of the gene product may be decreased. The Cpfl enzyme may form part of a CRISPR system or complex, which further comprises tandemly arranged guide RNAs (gRNAs) comprising a series of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 25, 25, 30, or more than 30 guide sequences, each capable of specifically hybridizing to a target sequence in a genomic locus of interest in a cell. In some embodiments, the functional Cpfl CRISPR system or complex hinds to the multiple target sequences. In some embodiments, the functional CRISPR system or complex may edit the multiple target sequences, e.g., the target sequences may comprise a genomic locus, and in some embodiments there may be an alteration of gene expression, hi some embodiments, the functional CRISPR system or complex may comprise further functional domains. In some embodiments, the invention provides a method for altering or modifying expression of multiple gene products. The method may comprise introducing into a cell containing said target nucleic acids, e.g., DNA molecules, or containing and expressing target nucleic acid, e.g., DNA molecules; for instance, the target nucleic acids may encode gene products or provide for expression of gene products (e.g., regulatory sequences).

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PCT/US2016/038181 [00754] In preferred embodiments the CRISPR enzyme used for multiplex targeting is Cpfl, or the CRISPR system or complex comprises Cpfl. In some embodiments, the CRISPR enzyme used for multiplex targeting is AsCpfl, or the CRISPR system or complex used for multiplex targeting comprises an AsCpfl. In some embodiments, the CRISPR enzyme is an LbCpfl, or the CRISPR system or complex comprises LbCpfl. In some embodiments, the Cpfl enzyme used for multiplex targeting cleaves both strands of DNA to produce a double strand break (DSB). In some embodiments, the CRISPR enzyme used for multiplex targeting is a nickase. In some embodiments, the Cpfl enzyme used for multiplex targeting is a dual nickase. In some embodiments, the Cpfl enzyme used for multiplex targeting is a Cpfl enzyme such as a DD Cpfl enzyme as defined herein elsewhere.

[00755] In some general embodiments, the Cpfl enzyme used for multiplex targeting is associated with one or more functional domains. In some more specific embodiments, the CRISPR enzyme used for multiplex targeting is a deadCpfl as defined herein elsewhere.

[00756] In an aspect, the present invention provides a means for delivering the Cpfl enzyme, system or complex for use in multiple targeting as defined herein or the polynucleotides defined herein. Non-limiting examples of such deliver}' means are e.g. particle(s) delivering component(s) of the complex, vector(s) comprising the polynucleotide(s) discussed herein (e.g., encoding the CRISPR enzyme, providing the nucleotides encoding the CRISPR complex). In some embodiments, the vector may be a plasmid or a viral vector such as AAV, or lentivirus. Transient transfection with plasmids, e.g., into HEK cells may be advantageous, especially given the size limitations of AAV and that while Cpfl fits into AAV, one may reach an upper limit with additional guide RNAs.

[00757] Also provided is a model that constitutively expresses the Cpfl enzyme, complex or system as used herein for use in multiplex targeting. The organism may be transgenic and may have been transfected with the present vectors or may be the offspring of an organism so transfected. In a further aspect, the present invention provides compositions comprising the CRISPR enzyme, system and complex as defined herein or the polynucleotides or vectors described herein. Also provides are Cpfl CRISPR systems or complexes comprising multiple guide RNAs, preferably in a tandemly arranged format. Said different guide RNAs may be separated by nucleotide sequences such as direct repeats.

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PCT/US2016/038181 [00758] Also provided is a method of treating a subject, e.g., a subject in need thereof, comprising inducing gene editing by transforming the subject with the polynucleotide encoding the Cpfl CRISPR system or complex or any of polynucleotides or vectors described herein and administering them to the subject. A suitable repair template may also be provided, for example delivered by a vector comprising said repair template. Also provided is a method of treating a subject, e.g., a subject in need thereof, comprising inducing transcriptional activation or repression of multiple target gene loci by transforming the subject with the polynucleotides or vectors described herein, wherein said polynucleotide or vector encodes or comprises the Cpfl enzyme, complex or system comprising multiple guide RNAs, preferably tandemly arranged. Where any treatment is occurring ex vivo, for example in a cell culture, then it will be appreciated that the term ‘subject’ may be replaced by the phrase “cell or cell culture.” [00759] Compositions comprising Cpfl enzyme, complex or system comprising multiple guide RNAs, preferably tandemly arranged, or the polynucleotide or vector encoding or comprising said Cpfl enzyme, complex or system comprising multiple guide RNAs, preferably tandemly arranged, for use in the methods of treatment as defined herein elsewhere are also provided. A kit of parts may be provided including such compositions. Use of said composition in the manufacture of a medicament for such methods of treatment are also provided. Use of a Cpfl CRISPR system in screening is also provided by the present invention, eg., gain of function screens. Cells which are artificially forced to overexpress a gene are be able to down regulate the gene over time (re-establishing equilibrium) e.g, by negative feedback loops. By the time the screen starts the unregulated gene might be reduced again. Using an inducible Cpfl activator allows one to induce transcription right before the screen and therefore minimizes the chance of false negative hits. Accordingly, by use of the instant invention in screening, e.g., gain of function screens, the chance of false negative results may be minimized.

[00760] In one aspect, the invention provides an engineered, non-naturally occurring CRISPR system comprising a Cpfl protein and multiple guide RNAs that each specifically target a DNA molecule encoding a gene product in a cell, whereby the multiple guide RNAs each target their specific DNA molecule encoding the gene product and the Cpfl protein cleaves the target DNA molecule encoding the gene product, whereby expression of the gene product is altered; and, wherein the CRISPR protein and the guide RNAs do not naturally occur together. The invention comprehends the multiple guide RNAs comprising multiple guide sequences, preferably

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PCT/US2016/038181 separated by a nucleotide sequence such as a direct repeat. In an embodiment of the invention the CRISPR protein is a type V or VI CRISPR-Cas protein and in a more preferred embodiment the CRIPSR protein is a Cpfl protein. The invention further comprehends a Cpfl protein being codon optimized for expression in a eukaryotic cell. In a preferred embodiment the eukaryotic cell is a mammalian cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of the gene product is decreased. [00761] In another aspect, the invention provides an engineered, non-naturally occurring vector system comprising one or more vectors comprising a first regulatory element operably linked to the multiple Cpfl CRISPR system guide RNAs that each specifically target a DNA molecule encoding a gene product and a second regulatory element operably linked coding for a CRISPR protein. Both regulatory elements may be located on the same vector or on different vectors of the system. The multiple guide RNAs target the multiple DNA molecules encoding the multiple gene products in a cell and the CRISPR protein may cleave the multiple DNA molecules encoding the gene products (it may cleave one or both strands or have substantially no nuclease activity), whereby expression of the multiple gene products is altered, and, wherein the CRISPR protein and the multiple guide RNAs do not naturally occur together. In a preferred embodiment the CRISPR protein is Cpfl protein, optionally codon optimized for expression in a eukaryotic ceil. In a preferred embodiment the eukaryotic cell is a mammalian cell, a plant cell or a yeast cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of each of the multiple gene products is altered, preferably decreased.

[00762] In one aspect, the invention provides a vector system comprising one or more vectors. In some embodiments, the system comprises: (a) a first regulatory element operably linked to a direct repeat sequence and one or more insertion sites for inserting one or more guide sequences up- or downstream (whichever applicable) of the direct repeat sequence, wherein when expressed, the one or more guide sequence(s) direet(s) sequence-specific binding of the CRISPR complex to the one or more target sequence(s) in a eukaryotic cell, wherein the CRISPR complex comprises a Cpfl enzyme complexed with the one or more guide sequence(s) that is hybridized to the one or more target sequence(s), and (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme, preferably comprising at least one nuclear localization sequence and/or at least one NES, wherein components (a) and (b) are located on the

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PCT/US2016/038181 same or different vectors of the system. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a Cpfl CRISPR complex to a different target sequence in a eukaryotic cell. In some embodiments, the CRISPR complex comprises one or more nuclear localization sequences and/or one or more NES of sufficient strength to drive accumulation of said Cpfl CRISPR complex in a detectable amount in or out of the nucleus of a eukaryotic ceil. In some embodiments, the first regulatory element is a polymerase III promoter. In some embodiments, the second regulatory element is a polymerase II promoter. In some embodiments, each of the guide sequences is at least 16, 17, 18, 19, 20, 25 nucleotides, or between 16-30, or between 16-25, or between 16-20 nucleotides in length, [00763] Recombinant expression vectors can comprise the polynucleotides encoding the Cpfl enzyme, system or complex for use in multiple targeting as defined herein in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory elements, which may be selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to he expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory element(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

[00764] In some embodiments, a host cell is transiently or non-transiently transfected with one or more vectors comprising the polynucleotides encoding the Cpfl enzyme, system or complex for use in multiple targeting as defined herein. In some embodiments, a cell is transfected as it naturally occurs in a subject. In some embodiments, a cell that is transfected is taken from a subject. In some embodiments, the cell is derived from cells taken from a subject, such as a cell line. A wide variety of cell lines for tissue culture are known in the art and exemplidied herein elsewhere. Cell lines are available from a variety of sources known to those with skill in the art (see, e.g., the American Type Culture Collection (ATCC) (Manassus, Va.)). In some embodiments, a cell transfected with one or more vectors comprising the polynucleotides encoding the Cpfl enzyme, system or complex for use in multiple targeting as defined herein is used to establish a new cell line comprising one or more vector-derived

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PCT/US2016/038181 sequences. In some embodiments, a cell transiently transfected with the components of a Cpfl CRISPR system or complex for use in multiple targeting as described herein (such as by transient transfection of one or more vectors, or transfection with RNA), and modified through the activity of a Cpfl CRISPR system or complex, is used to establish a new cell line comprising cells containing the modification but lacking any other exogenous sequence. In some embodiments, cells transiently or non-transiently transfected with one or more vectors comprising the polynucleotides encoding the Cpfl enzyme, system or complex for use in multiple targeting as defined herein, or cell lines derived from such cells are used in assessing one or more test compounds.

[00765] The term “regulatory element” is as defined herein elsewhere.

[00766] Advantageous vectors include lentiviruses and adeno-associated viruses, and types of such vectors can also be selected for targeting particular types of cells.

[00767] In one aspect, the invention provides a eukaryotic host cell comprising (a) a first regulatory element operably linked to a direct repeat sequence and one or more insertion sites for inserting one or more guide RNA sequences up- or downstream (whichever applicable) of the direct repeat sequence, wherein when expressed, the guide sequence(s) direct(s) sequencespecific binding of the Cpfl CRISPR complex to the respective target sequence(s) in a eukaryotic cell, wherein the Cpfl CRISPR complex comprises a Cpfl enzyme complexed with the one or more guide sequence(s) that is hybridized to the respective target sequence(s); and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme comprising preferably at least one nuclear localization sequence and/or NES. In some embodiments, the host ceil comprises components (a) and (b). In some embodiments, component (a), component (b), or components (a) and (b) are stably integrated into a genome of the host eukaryotic ceil. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, and optionally separated by a direct repeat, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a Cpfl CRISPR complex to a different target sequence in a eukaryotic cell. In some embodiments, the Cpfl enzyme comprises one or more nuclear localization sequences and/or nuclear export sequences or NES of sufficient strength to drive accumulation of said CRISPR enzyme in a detectable amount in and/or out of the nucleus of a eukaryotic cell.

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PCT/US2016/038181 [00768] In some embodiments, the Cpfl enzyme is a type V or VI CRISPR system enzyme. In some embodiments, the Cpfl enzyme is a Cpfl enzyme. In some embodiments, the Cpfl enzyme is derived from Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW20I1 GWA2 33 10, Parcubacteria bacterium GW201I GWC2 44 17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, or Porphyromonas macacae Cpfl, and may include further alterations or mutations of the Cpfl as defined herein elsewhere, and can be a chimeric Cpfl. In some embodiments, the Cpfl enzyme is codon-optimized for expression in a eukaryotic cell. In some embodiments, the CRISPR enzyme directs cleavage of one or two strands at the location of the target sequence. In some embodiments, the first regulatory element is a polymerase III promoter. In some embodiments, the second regulatory' element is a polymerase II promoter. In some embodiments, the one or more guide sequence(s) is (are each) at least 16, 17, 18, 19, 20, 25 nucleotides, or between 16-30, or between 16-25, or between 16-20 nucleotides in length. When multiple guide RNAs are used, they are preferably separated by a direct repeat sequence. In an aspect, the invention provides a non-human eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments. In other aspects, the invention provides a eukaryotic organism, preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments. The organism in some embodiments of these aspects may be an animal; for example a mammal. Also, the organism may be an arthropod such as an insect. The organism also may be a plant. Further, the organism may be a fungus.

[00769] In one aspect, the invention provides a kit comprising one or more of the components described herein. In some embodiments, the kit comprises a vector system and instructions for using the kit. In some embodiments, the vector system comprises (a) a first regulatory element operably linked to a direct repeat sequence and one or more insertion sites for inserting one or more guide sequences up- or downstream (whichever applicable) of the direct repeat sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a Cpfl CRISPR complex to a target sequence in a eukaryotic cell, wherein the Cpfl CRISPR complex

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PCT/US2016/038181 comprises a Cpfl enzyme complexed with the guide sequence that is hybridized to the target sequence; and/or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said Cpfl enzyme comprising a nuclear localization sequence. In some embodiments, the kit comprises components (a) and (b) located on the same or different vectors of the system. In some embodiments, component (a) further comprises two or more guide sequences operably linked to the first regulatory element, wherein when expressed, each of the two or more guide sequences direct sequence specific binding of a CRISPR complex to a different target sequence in a eukaryotic cell. In some embodiments, the Cpfl enzyme comprises one or more nuclear localization sequences of sufficient strength to drive accumulation of said CRISPR enzyme in a detectable amount in the nucleus of a eukaryotic cell. In some embodiments, the CRISPR enzyme is a type V or VI CRISPR system enzyme. In some embodiments, the CRISPR enzyme is a Cpfl enzyme. In some embodiments, the Cpfl enzyme is derived from Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011 GWA2 33 JO, Parcubacteria bacterium GW2011 GWC2 44 17, Smithella. sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens, or Porphyromonas macacae Cpfl (e.g., modified to have or be associated with at least one DD), and may include further alteration or mutation of the Cpfl, and can be a chimeric Cpfl. In some embodiments, the DD-CRISPR enzyme is codon-optimized for expression in a eukaryotic cell. In some embodiments, the DDCRISPR enzyme directs cleavage of one or two strands at the location of the target sequence. In some embodiments, the DD-CRISPR enzyme lacks or substantially DNA strand cleavage activity (e.g., no more than 5% nuclease activity as compared with a wild type enzyme or enzyme not having the mutation or alteration that decreases nuclease activity). In some embodiments, the first regulatory element is a polymerase III promoter. In some embodiments, the second regulatory element is a polymerase II promoter. In some embodiments, the guide sequence is at least 16, 17, 18, 19, 20, 25 nucleotides, or between 16-30, or between 16-25, or between 16-20 nucleotides in length, [00770] In one aspect, the invention provides a method of modifying multiple target polynucleotides in a host cell such as a eukaryotic cell. In some embodiments, the method

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PCT/US2016/038181 comprises allowing a Cpfl CRISPR complex to bind to multiple target polynucleotides, e.g., to effect cleavage of said multiple target polynucleotides, thereby modifying multiple target polynucleotides, wherein the Cpfl CRISPR complex comprises a Cpfl enzyme complexed with multiple guide sequences each of the being hybridized to a specific target sequence within said target polynucleotide, wherein said multiple guide sequences are linked to a direct repeat sequence. In some embodiments, said cleavage comprises cleaving one or two strands at the location of each of the target sequence by said Cpfl enzyme. In some embodiments, said cleavage results in decreased transcription of the multiple target genes. In some embodiments, the method further comprises repairing one or more of said cleaved target polynucleotide by homologous recombination with an exogenous template polynucleotide, wherein said repair results in a mutation comprising an insertion, deletion, or substitution of one or more nucleotides of one or more of said target polynucleotides. In some embodiments, said mutation results in one or more amino acid changes in a protein expressed from a gene comprising one or more of the target sequence(s). In some embodiments, the method further comprises delivering one or more vectors to said eukaryotic cell, wherein the one or more vectors drive expression of one or more of: the Cpfl enzyme and the multiple guide RNA sequence linked to a direct repeat sequence. In some embodiments, said vectors are delivered to the eukaryotic cell in a subject. In some embodiments, said modifying takes place in said eukaryotic cell in a cell culture. In some embodiments, the method further comprises isolating said eukaryotic cell from a subject prior to said modifying. In some embodiments, the method further comprises returning said eukaryotic cell and/or cells derived therefrom to said subject.

[00771] In one aspect the invention provides a method of modifying expression of multiple polynucleotides in a eukaryotic cell. In some embodiments, the method comprises allowing a Cpfl CRISPR complex to bind to multiple polynucleotides such that said binding results in increased or decreased expression of said polynucleotides; wherein the Cpfl CRISPR complex comprises a Cpfl enzyme complexed with multiple guide sequences each specifically hybridized to its own target sequence within said polynucleotide, wherein said guide sequences are linked to a direct repeat sequence. In some embodiments, the method further comprises delivering one or more vectors to said eukaryotic cells, wherein the one or more vectors drive expression of one or more of: the Cpfl enzyme and the multiple guide sequences linked to the direct repeat sequences.

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PCT/US2016/038181 [00772] In one aspect, the invention provides a recombinant polynucleotide comprising multiple guide RNA sequences up- or downstream (whichever applicable) of a direct repeat sequence, wherein each of the guide sequences when expressed directs sequence-specific binding of a CpflCRISPR complex to its corresponding target sequence present in a eukaryotic cell, in some embodiments, the target sequence is a viral sequence present in a eukaryotic cell. In some embodiments, the target sequence is a proto-oncogene or an oncogene.

[00773] Aspects of the invention encompass a non-naturally occurring or engineered composition that may comprise a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a cell and a Cpfl enzyme as defined herein that may comprise at least one or more nuclear localization sequences.

[00774] An aspect of the invention emcompasses methods of modifying a genomic locus of interest to change gene expression in a cell by introducing into the cell any of the compositions decribed herein.

[00775] An aspect of the invention is that the above elements are comprised in a single composition or comprised in individual compositions. These compositions may advantageously be applied to a host to elicit a functional effect on the genomic level.

[00776] As used herein, the term “guide RNA” or “gRNA” has the leaning as used herein elsewhere and comprises any polynucleotide sequence having sufficient complementarity with a target nucleic acid sequence to hybridize with the target nucleic acid sequence and direct sequence-specific binding of a nucleic acid-targeting complex to the target nucleic acid sequence. Each gRNA may be designed to include multiple binding recognition sites (e.g., aptamers) specific to the same or different adapter protein. Each gRNA may he designed to bind to the promoter region -1000 - +1 nucleic acids upstream of the transcription start site (i.e. TSS), preferably -200 nucleic acids. This positioning improves functional domains which affect gene activiation (e.g., transcription activators) or gene inhibition (e.g., transcription repressors). The modified gRNA may be one or more modified gRNAs targeted to one or more target loci (e.g., at least 1 gRNA, at least 2 gRNA, at least 5 gRNA, at least 10 gRNA, at least 20 gRNA, at least 30 g RNA, at least 50 gRNA) comprised in a composition. Said multiple gRNA sequences can be tandemly arranged and are preferably separated by a direct repeat, [00777] Thus, gRNA, the CRISPR enzyme as defined herein may each individually be comprised in a composition and administered to a host individually or collectively. Alternatively,

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PCT/US2016/038181 these components may be provided in a single composition for administration to a host. Adminstration to a host may be performed via viral vectors known to the skilled person or described herein for delivery' to a host (e.g., lentiviral vector, adenoviral vector, AAV vector). As explained herein, use of different selection markers (e.g., for lentiviral gRNA selection) and concentration of gRNA (e.g., dependent on whether multiple gRNAs are used) may be advantageous for eliciting an improved effect. On the basis of this concept, several variations are appropriate to elicit a genomic locus event, including DNA cleavage, gene activation, or gene deactivation. Using the provided compositions, the person skilled in the art can advantageously and specifically target single or multiple loci with the same or different functional domains to elicit one or more genomic locus events. The compositions may be applied in a wide variety of methods for screening in libraries in cells and functional modeling in vivo (e.g., gene activation of lincRNA and indentification of function; gain-of-function modeling; loss-of-function modeling, the use the compositions of the invention to establish cel l lines and transgenic animals for optimization and screening purposes).

[00778] The current invention comprehends the use of the compositions of the current invention to establish and utilize conditional or inducible CRISPR transgenic cell /animals; see, e.g., Platt et al., Cell (2014), 159(2): 440-455, or PCT patent publications cited herein, such as WO 2014/093622 (PCT/US2013/074667). For example, ceils or animals such as non-human animals, e.g., vertebrates or mammals, such as rodents, e.g., mice, rats, or other laboratory or field animals, e.g., cats, dogs, sheep, etc., may be ‘knock-in’ whereby the animal conditionally or inducibly expresses Cpfl akin to Platt et al. The target cell or animal thus comprises the CRISRP enzyme (e.g., Cpfl) conditionally or inducibly (e.g., in the form of Cre dependent constructs), on expression of a vector introduced into the target cell, the vector expresses that which induces or gives rise to the condition of the CRISRP enzyme (e.g., Cpfl) expression in the target cell. By applying the teaching and compositions as defined herein with the known method of creating a CRISPR complex, inducible genomic events are also an aspect of the current invention. Examples of such inducible events have been described herein elsewhere.

[00779] In some embodiments, phenotypic alteration is preferably the result of genome modification when a genetic disease is targeted, especially in methods of therapy and preferably where a repair template is provided to correct or alter the phenotype.

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PCT/US2016/038181 [00780] In some embodiments diseases that may be targeted include those concerned with disease-causing splice defects.

[00781] In some embodiments, cellular targets include Hemopoietic Stem/Progenitor Cells (CD34+); Human T cells; and Eye (retinal cells) - for example photoreceptor precursor cells. [00782] In some embodiments Gene targets include: Human Beta Globin - HBB (for treating Sickle Cell Anemia, including by stimulating gene-conversion (using closely related HBD gene as an endogenous template)); CD3 (T-Cells); and CEP920 - retina (eye).

[00783] In some embodiments disease targets also include: cancer; Sickle Cell Anemia (based on a point mutation); HBV, HIV; Beta-Thalassemia; and ophthalmic or ocular disease - for example Leber Congenital Amaurosis (LCA)-causing Splice Defect.

In some embodiments delivery methods include: Cationic Lipid Mediated “direct” delivery of Enzyme-Guide complex (RiboNucleoProtein) and electroporation of plasmid DNA.

[00784] Methods, products and uses described herein may be used for non-therapeutic purposes. Furthermore, any of the methods described herein may be applied in vitro and ex vivo. [00785] In an aspect, provided is a non-naturally occurring or engineered composition comprising:

I. two or more CRISPR-Cas system polynucleotide sequences comprising (a) a first guide sequence capable of hybridizing to a first target sequence in a polynucleotide locus, (b) a second guide sequence capable of hybridizing to a second target sequence in a polynucleotide locus, (c) a direct repeat sequence, and

II. a Cpfl enzyme or a second polynucleotide sequence encoding it, wherein when transcribed, the first and the second guide sequences direct sequencespecific binding of a first and a second Cpfl CRISPR complex to the first and second target sequences respectively, wherein the first CRISPR complex comprises the Cpfl enzyme complexed with the first guide sequence that is hybridizable to the first target sequence, wherein the second CRISPR complex comprises the Cpfl enzyme complexed with the second guide sequence that is hybridizable to the second target sequence, and

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PCT/US2016/038181 wherein the first guide sequence directs cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directs cleavage of the other strand near the second target sequence inducing a double strand break, thereby modifying the organism or the non-human or non-animal organism. Similarly, compositions comprising more than two guide RNAs can be envisaged e.g. each specific for one target, and arranged tandemly in the composition or CRISPR system or complex as described herein.

[00786] In another embodiment, the Cpfl is delivered into the cell as a protein. In another and particularly preferred embodiment, the Cpfl is delivered into the cell as a protein or as a nucleotide sequence encoding it. Delivery to the cell as a protein may include deliver}' of a Ribonucleoprotein (RNP) complex, where the protein is complexed with the multiple guides. [00787] In an aspect, host cells and cell lines modified by or comprising the compositions, systems or modified enzymes of present invention are provided, including stem cells, and progeny thereof.

[00788] In an aspect, methods of cellular therapy are provided, where, for example, a single cell or a population of cells is sampled or cultured, wherein that cell or cells is or has been modified ex vivo as described herein, and is then re-introduced (sampled cells) or introduced (cultured cells) into the organism. Stem cells, whether embryonic or induce pluripotent or totipotent stem cells, are also particularly preferred in this regard. But, of course, in vivo embodiments are also envisaged.

[00789] Inventive methods can further comprise delivery of templates, such as repair templates, which may be dsODN or ssODN, see below. Delivery of templates may be via the cotemporaneous or separate from delivery of any or all the CRISPR enzyme or guide RNAs and via the same delivery mechanism or different. In some embodiments, it is preferred that the template is delivered together with the guide RNAs and, preferably, also the CRISPR enzyme. An example may be an AAV vector where the CRISPR enzyme is AsCpfl or LbCpfl.

[00790] Inventive methods can further comprise: (a) delivering to the cell a double-stranded oligodeoxynucleotide (dsODN) comprising overhangs complimentary to the overhangs created by said double strand break, wherein said dsODN is integrated into the locus of interest; or -(b) delivering to the cell a single-stranded oligodeoxynucleotide (ssODN), wherein said ssODN acts as a template for homology directed repair of said double strand break. Inventive methods can be for the prevention or treatment of disease in an individual, optionally wherein said disease is

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PCT/US2016/038181 caused by a defect in said locus of interest. Inventive methods can be conducted in vivo in the individual or ex vivo on a cell taken from the individual, optionally wherein said cell is returned to the individual.

[00791] The invention also comprehends products obtained from using CRISPR enzyme or Cas enzyme or Cpfl enzyme or CRISPR-CRISPR enzyme or CRISPR-Cas system or CRISPRCpfl system for use in tandem or multiple targeting as defined herein.

Kits [00792] In one aspect, the invention provides kits containing any one or more of the elements disclosed in the above methods and compositions. In some embodiments, the kit comprises a vector system as taught herein and instructions for using the kit. Elements may be provided individually or in combinations, and may be provided in any suitable container, such as a vial, a bottle, or a tube. The kits may include the gRNA and the unbound protector strand as described herein. The kits may include the gRNA with the protector strand bound to at least partially to the guide sequence (i.e. pgRNA). Thus the kits may include the pgRNA in the form of a partially double stranded nucleotide sequence as described here. In some embodiments, the kit includes instructions in one or more languages, for example in more than one language. The instructions may be specific to the applications and methods described herein.

[00793] In some embodiments, a kit comprises one or more reagents for use in a process utilizing one or more of the elements described herein. Reagents may be provided in any suitable container. For example, a kit may provide one or more reaction or storage buffers. Reagents may be provided in a form that is usable in a particular assay, or in a form that requires addition of one or more other components before use (e.g., in concentrate or lyophilized form). A buffer can be any buffer, including but not limited to a sodium carbonate buffer, a sodium bicarbonate buffer, a borate buffer, a Tris buffer, a MOPS buffer, a HEPES buffer, and combinations thereof. In some embodiments, the buffer is alkaline. In some embodiments, the buffer has a pH from about 7 to about 10. In some embodiments, the kit comprises one or more oligonucleotides corresponding to a guide sequence for insertion into a vector so as to operably link the guide sequence and a regulatory element. In some embodiments, the kit comprises a homologous recombination template polynucleotide. In some embodiments, the kit comprises one or more of the vectors and/or one or more of the polynucleotides described herein. The kit may ad vantageously allows to provide all elements of the systems of the invention.

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PCT/US2016/038181 [00794] In one aspect, the invention provides methods for using one or more elements of a CRISPR system. The CRISPR complex of the invention provides an effective means for modifying a target polynucleotide. The CRISPR complex of the invention has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target polynucleotide in a multiplicity of cell types. As such the CRISPR complex of the invention has a broad spectrum of applications in, e.g., gene therapy, drug screening, disease diagnosis, and prognosis. An exemplary CRISPR complex comprises a CRISPR effector protein complexed with a guide sequence hybridized to a target sequence within the target polynucleotide. In certain embodiments, a direct repeat sequence is linked to the guide sequence. [00795] In one embodiment, this invention provides a method of cleaving a target polynucleotide. The method comprises modifying a target polynucleotide using a CRISPR complex that binds to the target polynucleotide and effect cleavage of said target polynucleotide. Typically, the CRISPR complex of the invention, when introduced into a cell, creates a break (e.g., a single or a double strand break) in the genome sequence. For example, the method can be used to cleave a disease gene in a cell.

[00796] The break created by the CRISPR complex can be repaired by a repair processes such as the error prone non-homologous end joining (NHEJ) pathway or the high fidelity homology directed repair (HDR). During these repair process, an exogenous polynucleotide template can be introduced into the genome sequence. In some methods, the HDR process is used to modify genome sequence. For example, an exogenous polynucleotide template comprising a sequence to be integrated flanked by an upstream sequence and a downstream sequence is introduced into a ceil. The upstream and downstream sequences share sequence similarity with either side of the site of integration in the chromosome.

[00797] Where desired, a donor polynucleotide can be DNA, e.g., a DNA plasmid, a bacterial artificial chromosome (BAG), a yeast artificial chromosome (YAC), a viral vector, a linear piece of DNA, a PCR fragment, a naked nucleic acid, or a nucleic acid complexed with a delivery vehicle such as a liposome or poloxamer.

[00798] The exogenous polynucleotide template comprises a sequence to be integrated (e.g., a mutated gene). The sequence for integration may be a sequence endogenous or exogenous to the cell. Examples of a sequence to be integrated include polynucleotides encoding a protein or a non-coding RNA (e.g., a microRNA). Thus, the sequence for integration may be operably linked

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PCT/US2016/038181 to an appropriate control sequence or sequences. Alternatively, the sequence to be integrated may provide a regulatory function.

[00799] The upstream and downstream sequences in the exogenous polynucleotide template are selected to promote recombination between the chromosomal sequence of interest and the donor polynucleotide. The upstream sequence is a nucleic acid sequence that shares sequence similarity with the genome sequence upstream of the targeted site for integration. Similarly, the downstream sequence is a nucleic acid sequence that shares sequence similarity with the chromosomal sequence downstream of the targeted site of integration. The upstream and downstream sequences in the exogenous polynucleotide template can have 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with the targeted genome sequence. Preferably, the upstream and downstream sequences in the exogenous polynucleotide template have about 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the targeted genome sequence. In some methods, the upstream and downstream sequences in the exogenous polynucleotide template have about 99% or 100% sequence identity with the targeted genome sequence.

[00800] An upstream or downstream sequence may comprise from about 20 bp to about 2500 bp, for example, about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or 2500 bp. In some methods, the exemplary upstream or downstream sequence have about 200 bp to about 2000 bp, about 600 bp to about 1000 bp, or more particularly about 700 bp to about 1000 bp.

[00801] In some methods, the exogenous polynucleotide template may further comprise a marker. Such a marker may make it easy to screen for targeted integrations. Examples of suitable markers include restriction sites, fluorescent proteins, or selectable markers. The exogenous polynucleotide template of the invention can be constructed using recombinant techniques (see, for example, Sambrook et al., 2001 and Ausubel et al., 1996).

[00802] In an exemplary method for modifying a target polynucleotide by integrating an exogenous polynucleotide template, a double stranded break is introduced into the genome sequence by the CRISPR. complex, the break is repaired via homologous recombination an exogenous polynucleotide template such that the template is integrated into the genome. The presence of a double-stranded break facilitates integration of the template.

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PCT/US2016/038181 [00803] In other embodiments, this invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell. The method comprises increasing or decreasing expression of a target polynucleotide by using a CRISPR complex that binds to the polynucleotide.

[00804] In some methods, a target polynucleotide can be inactivated to effect the modification of the expression in a cell. For example, upon the binding of a CRISPR complex to a target sequence in a cell, the target polynucleotide is inactivated such that the sequence is not transcribed, the coded protein is not produced, or the sequence does not function as the wild-type sequence does. For example, a protein or microRNA coding sequence may be inactivated such that the protein is not produced.

[00805] In some methods, a control sequence can be inactivated such that it no longer functions as a control sequence. As used herein, “control sequence” refers to any nucleic acid sequence that effects the transcription, translation, or accessibility of a nucleic acid sequence. Examples of a control sequence include, a promoter, a transcription terminator, and an enhancer are control sequences. The inactivated target sequence may include a deletion mutation (i.e., deletion of one or more nucleotides), an insertion mutation (i.e., insertion of one or more nucleotides), or a nonsense mutation (i.e., substitution of a single nucleotide for another nucleotide such that a stop codon is introduced). In some methods, the inactivation of a target sequence results in “knockout” of the target sequence.

[00806] The invention provides a non-naturally occurring or engineered composition, or one or more polynucleotides encoding components of said composition, or vector or delivery systems comprising one or more polynucleotides encoding components of said composition for use in a modifying a target cell in vivo, ex vivo or in vitro and, may be conducted in a manner alters the cell such that once modified the progeny or cell line of the CRISPR modified cell retains the altered phenotype. The modified cells and progeny may be part of a multi-cellular organism such as a plant or animal with ex vivo or in vivo application of CRISPR system to desired cell types. The CRISPR invention may be a therapeutic method of treatment. The therapeutic method of treatment may comprise gene or genome editing, or gene therapy.

[00807] In one aspect, the invention provides an engineered, non-naturally occurring CRISPR-Cas system comprising a catalytically inactivate Cas protein described herein,

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PCT/US2016/038181 prefereably an inactivate Cpfl (dCpfl), and use this system in detection methods such as fluorescence in situ hybridization (FISH). dCpfl which lacks the ability to produce DNA doublestrand breaks may be fused with a marker, such as fluorescent protein, such as the enhanced green fluorescent protein (eEGFP) and co-expressed with small guide RNAs to target pericentric, centric and teleomeric repeats in vivo. The dCpfl system can be used to visualize both repetitive sequences and individual genes in the human genome. Such new applications of labelled dCpfl CRISPR-cas systems may be important in imaging cells and studying the functional nuclear architecture, especially in cases with a small nucleus volume or complex 3-D structures. (Chen B, Gilbert LA, Cimini BA, Schnitzbauer J, Zhang W, Li GW, Park J, Blackburn EH, Weissman JS, Qi LS, Huang B. 2013. Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Ceil 155(7):1479-91. doi: 10.1016/j cell.2013.12.001.) [00808] In one aspect, the invention provides for methods of modifying a target polynucleotide in a eukaryotic cell, which may be in vivo, ex vivo or in vitro. In some embodiments, the method comprises sampling a cell or population of cells from a human or nonhuman animal, and modifying the cell or cells. Culturing may occur at any stage ex vivo. The cell or cells may even be re-introduced into the non-human animal or plant. For re-introduced cells it is particularly preferred that the cells are stem cells.

[00809] In some embodiments, the method comprises allowing a CRISPR complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized or hybridizable to a target sequence within said target polynucleotide.

[00810] In one aspect, the invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell. In some embodiments, the method comprises allowing a CRISPR complex to bind to the polynucleotide such that said binding results in increased or decreased expression of said polynucleotide, wherein the CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized or hybridizable to a target sequence within said polynucleotide. Similar considerations and conditions apply as above for methods of modifying a target polynucleotide. In fact, these sampling, culturing and re-introduction options apply across the aspects of the present invention.

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PCT/US2016/038181 [00811] Indeed, in any aspect of the invention, the CRISPR complex may comprise a CRISPR enzyme complexed with a guide sequence hybridized or hybridizable to a target sequence. Similar considerations and conditions apply as above for methods of modifying a target polynucleotide, [00812] Thus in any of the non-naturally-occurring CRISPR enzymes described herein comprise at least one modification and whereby the enzyme has certain improved capabilities. In particular, any of the enzymes are capable of forming a CRISPR complex with a guide RNA. When such a complex forms, the guide RNA is capable of binding to a target polynucleotide sequence and the enzyme is capable of modifying a target locus. In addition, the enzyme in the CRISPR complex has reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme.

[00813] In addition, the modified CRISPR emzymes described herein encompass enzymes whereby in the CRISPR complex the enzyme has increased capability of modifying the one or more target loci as compared to an unmodified enzyme. Such function may be provided separate to or provided in combination with the above-described function of reduced capability of modifying one or more off-target loci. Any such enzymes may be provided with any of the further modifications to the CRISPR enzyme as described herein, such as in combination with any activity provided by one or more associated heterologous functional domains, any further mutations to reduce nuclease activity and the like.

[00814] In advantageous embodiments of the invention, the modified CRISPR emzyme is provided with reduced capability of modifying one or more off-target loci as compared to an unmodified enzyme and increased capability of modifying the one or more target loci as compared to an unmodified enzyme. In combination with further modifications to the enzyme, significantly enhanced specificity may be achieved. For example, combination of such advantageous embodiments with one or more additional mutations is provided wherein the one or more additional mutations are in one or more catalytically active domains. Such further catalytic mutations may confer nickase functionality as described in detail elsewhere herein. In such enzymes, enhanced specificity may be achieved due to an improved specificity in terms of enzyme activity, [00815] Modifications to reduce off-target effects and/or enhance on-target effects as described above may be made to amino acid residues located in a positively-charged

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PCT/US2016/038181 region/groove situated between the RuvC-ΠΙ and HNH domains. It will be appreciated that any of the functional effects described above may be achieved by modification of amino acids within the aforementioned groove but also by modification of amino acids adjacent to or outside of that groove.

[00816] Additional functionalities which may be engineered into modified CRISPR enzymes as described herein include the following, 1. modified CRISPR. enzymes that disrupt DNA:protein interactions without affecting protein tertiary or secondary structure. This includes residues that contact any part, of the RNA:DNA duplex. 2. modified CRISPR enzymes that weaken intra-protein interactions holding Cpfl in conformation essential for nuclease cutting in response to DNA binding (on or off target). For example: a modification that mildly inhibits, but still allows, the nuclease conformation of the HNH domain (positioned at the scissile phosphate). 3. modified CRISPR enzymes that strengthen intra-protein interactions holding Cpfl in a conformation inhibiting nuclease activity in response to DNA binding (on or off targets). For example: a modification that stabilizes the HNH domain in a conformation away from the scissile phosphate. Any such additional functional enhancement may be provided in combination with any other modification to the CRISPR enzyme as described in detail elsewhere herein.

[00817] Any of the herein described improved functionalities may be made to any CRISPR enzyme, such as a Cpfl enzyme. However, it will be appreciated that any of the functionalities described herein may be engineered into Cpfl enzymes from other orthologs, including chimeric enzymes comprising fragments from multiple orthologs.

Nucleic acids, amino acids and proteins, Regulatory sequences, Vectors, etc.

[00818] The invention uses nucleic acids to bind target DNA sequences. This is advantageous as nucleic acids are much easier and cheaper to produce than proteins, and the specificity can be varied according to the length of the stretch where homology is sought. Complex 3-D positioning of multiple fingers, for example is not required. The terms “polynucleotide”, “nucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene ??7

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PCT/US2016/038181 fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. The term also encompasses nucleic-acid-like structures with synthetic backbones, see, e.g,, Eckstein, 1991; Baserga et al., 1992; Milligan, 1993; WO 97/03211; WO 96/39154; Mata, 1997; Strauss-Soukup, 1997; and Samstag, 1996. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. As used herein the term “wild type” is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms. A “wild type” can be a base line. As used herein the term “variant” should be taken to mean the exhibition of qualities that have a pattern that deviates from what occurs in nature. The terms “non-naturally occurring” or “engineered” are used interchangeably and indicate the involvement of the hand of man. The terms, when referring to nucleic acid molecules or polypeptides mean that the nucleic acid molecule or the polypeptide is at least substantially free from at least one other component with which they are naturally associated in nature and as found in nature. “Complementarity” refers to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick base pairing or other non-traditional types. A percent complementarity indicates the percentage of residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. “Substantially complementary” as used herein refers to a degree of complementarity that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% over a region of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, or more nucleotides, or refers to two nucleic acids that hybridize under stringent

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PCT/US2016/038181 conditions. As used herein, “stringent conditions” for hybridization refer to conditions under which a nucleic acid having complementarity to a target sequence predominantly hybridizes with the target sequence, and substantially does not hybridize to non-target sequences. Stringent conditions are generally sequence-dependent, and vary depending on a number of factors. In general, the longer the sequence, the higher the temperature at which the sequence specifically hybridizes to its target sequence. Non-limiting examples of stringent conditions are described in detail in Tijssen (1993), Laboratory Techniques In Biochemistry And Molecular BiologyHybridization With Nucleic Acid Probes Part I, Second Chapter “Overview of principles of hybridization and the strategy of nucleic acid probe assay”, Elsevier, N.Y. Where reference is made to a polynucleotide sequence, then complementary or partially complementary sequences are also envisaged. These are preferably capable of hybridising to the reference sequence under highly stringent conditions. Generally, in order to maximize the hybridization rate, relatively low-stringency hybridization conditions are selected; about 20 to 25° C lower than the thermal melting point (T_m ). The T_m is the temperature at which 50% of specific target sequence hybridizes to a perfectly complementary probe in solution at a defined ionic strength and pH. Generally, in order to require at least about 85% nucleotide complementarity of hybridized sequences, highly stringent washing conditions are selected to be about 5 to 15° C lower than the T_m. In order to require at least about 70% nucleotide complementarity of hybridized sequences, moderately-stringent washing conditions are selected to be about 15 to 30° C lower than the T_m. Highly permissive (very low stringency) washing conditions may be as low as 50° C below the T_m , allowing a high level of mis-matching between hybridized sequences. Those skilled in the art wili recognize that other physical and chemical parameters in the hybridization and wash stages can also be altered to affect the outcome of a detectable hybridization signal from a specific level of homology between target and probe sequences. Preferred highly stringent conditions comprise incubation in 50% formamide, 5><SSC, and 1% SDS at 42° C, or incubation in 5xSSC and 1% SDS at 65° C, with wash in 0.2xSSC and 0.1% SDS at 65° C. “Hybridization” refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues. The hydrogen bonding may occur by Watson Crick base pairing, Hoogstein binding, or in any other sequence specific manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi stranded complex, a single self-hybridizing strand, or any

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PCT/US2016/038181 combination of these. A hybridization reaction may constitute a step in a more extensive process, such as the initiation of PCR, or the cleavage of a polynucleotide by an enzyme. A sequence capable of hybridizing with a given sequence is referred to as the “complement” of the given sequence. As used herein, the term “genomic locus” or “locus” (plural loci) is the specific location of a gene or DNA sequence on a chromosome. A “gene” refers to stretches of DNA or RNA that encode a polypeptide or an RNA chain that has functional role to play in an organism and hence is the molecular unit of heredity in living organisms. For the purpose of this invention it may be considered that genes include regions which regulate the production of the gene product, whether or not such regulatory⁷ sequences are adjacent to coding and/or transcribed sequences. Accordingly, a gene includes, but is not necessarily limited to, promoter sequences, terminators, translational regulatory sequences such as ribosome binding sites and internal ribosome entry sites, enhancers, silencers, insulators, boundary⁷ elements, replication origins, matrix attachment sites and locus control regions. As used herein, “expression of a genomic locus” or “gene expression” is the process by which information from a gene is used in the synthesis of a functional gene product. The products of gene expression are often proteins, but in non-protein coding genes such as rRNA genes or tRNA genes, the product is functional RNA. The process of gene expression is used by all known life - eukaryotes (including multicellular organisms), prokaryotes (bacteria and archaea) and viruses to generate functional products to survive. As used herein expression of a gene or nucleic acid encompasses not only cellular gene expression, but also the transcription and translation of nucleic acid(s) in cloning systems and in any other context. As used herein, “expression” also refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and mRNA or other RNA transcript) and/or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As

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PCT/US2016/038181 used herein the term “amino acid” includes natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics. As used herein, the term “domain” or “protein domain” refers to a part of a protein sequence that may exist and function independently of the rest of the protein chain. As described in aspects of the invention, sequence identity is related to sequence homology. Homology comparisons may be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs may calculate percent (%) homology between two or more sequences and may also calculate the sequence identity shared by two or more amino acid or nucleic acid sequences.

[00819] In aspects of the invention the term “guide RNA”, refers to the polynucleotide sequence comprising a putative or identified crRNA sequence or guide sequence, [00820] As used herein the term “wild type” is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms. A “wild type” can be a base line.

[00821] As used herein the term “variant” should be taken to mean the exhibition of qualities that have a pattern that deviates from what occurs in nature.

[00822] The terms “non-naturally occurring” or “engineered” are used interchangeably and indicate the involvement of the hand of man. The terms, when referring to nucleic acid molecules or polypeptides mean that the nucleic acid molecule or the polypeptide is at least substantially free from at least one other component with which they are naturally associated in nature and as found in nature. In all aspects and embodiments, whether they include these terms or not, it will be understood that, preferably, the may he optional and thus preferably included or not preferably not included. Furthermore, the terms “non-naturally occurring” and “engineered” may be used interchangeably and so can therefore be used alone or in combination and one or other may replace mention of both together. In particular, “engineered” is preferred in place of “non-naturally occurring” or “non-naturally occurring and/or engineered.” [00823] Sequence homologies may be generated by any of a number of computer programs known in the art, for example BLAST or FASTA, etc. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, U.S.A, Devereux et al., 1984, Nucleic Acids Research 12:387). Examples of other software than may perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel

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PCT/US2016/038181 et al., 1999 ibid - Chapter 18), FASTA (Atschul et al., 1990, J. Mol. Biol., 403-410) and the GENEWORKS suite of comparison tools. Both BLAST and FASTA are available for offline and online searching (see Ausubel et al., 1999 ibid, pages 7-58 to 7-60). However it is preferred to use the GCG Bestfit program. Percentage (%) sequence homology may be calculated over contiguous sequences, i.e., one sequence is aligned with the other sequence and each amino acid or nucleotide in one sequence is directly compared with the corresponding amino acid or nucleotide in the other sequence, one residue at a time. This is called an “ungapped” alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues. Although this is a very simple and consistent method, it fails to take into consideration that, for example, in an otherwise identical pair of sequences, one insertion or deletion may cause the following amino acid residues to be put out of alignment, thus potentially resulting in a large reduction in % homology when a global alignment is performed. Consequently, most sequence comparison methods are designed to produce optimal alignments that take into consideration possible insertions and deletions without unduly penalizing the overall homology or identity score. This is achieved by inserting “gaps” in the sequence alignment to try to maximize local homology or identity. However, these more complex methods assign “gap penalties” to each gap that occurs in the alignment so that, for the same number of identical amino acids, a sequence alignment with as few gaps as possible - reflecting higher relatedness between the two compared sequences - may achieve a higher score than one with many gaps. “Affinity gap costs” are typically used that charge a relatively high cost for the existence of a gap and a smaller penalty for each subsequent residue in the gap. This is the most commonly used gap scoring system. High gap penalties may, of course, produce optimized alignments with fewer gaps. Most alignment programs allow the gap penalties to be modified. However, it is preferred to use the default values when using such software for sequence compari sons. For example, when using the GCG Wisconsin Bestfit package the default gap penalty for amino acid sequences is -12 for a gap and -4 for each extension. Calculation of maximum % homology therefore first requires the production of an optimal alignment, taking into consideration gap penalties. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (Devereux et al., 1984 Nuc. Acids Research 12 p387). Examples of other software than may perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel et al., 1999 Short Protocols in Molecular Biology, 4^m Ed. -- Chapter 18), FASTA (Altschul et al., 1990 J. Mol.

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Biol. 403-410) and the GENEWORKS suite of comparison tools. Both BLAST and PASTA are available for offline and online searching (see Ausubel et al., 1999, Short Protocols in Molecular Biology, pages 7-58 to 7-60). However, for some applications, it is preferred to use the GCG Bestfit program. A new tool, called BLAST 2 Sequences is also available for comparing protein and nucleotide sequences (see FEMS Microbiol Lett. 1999 174(2): 247-50; FELLS Microbiol Lett. 1999 177(1): 187-8 and the websi te of the National Center for Biotechnology information at the website of the National Institutes for Health). Although the final % homology may be measured in terms of identity, the alignment process itself is typically not based on an all-ornothing pair comparison. Instead, a scaled similarity score matrix is generally used that assigns scores to each pair-wise comparison based on chemical similarity or evolutionary distance. An example of such a matrix commonly used is the BLOSUM62 matrix - the default matrix for the BLAST suite of programs. GCG Wisconsin programs generally use either the public default values or a custom symbol comparison table, if supplied (see user manual for further details). For some applications, it is preferred to use the public default values for the GCG package, or in the case of other software, the default matrix, such as BLOSUM62. Alternatively, percentage homologies may be calculated using the multiple alignment feature in DNASIS^lM (Hitachi Software), based on an algorithm, analogous to CLUSTAL (Higgins DG & Sharp PM (1988), Gene 73(1), 237-244). Once the software has produced an optimal alignment, it is possible to calculate % homology, preferably % sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result. The sequences may also have deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent substance. Deliberate amino acid substitutions may be made on the basis of similarity in amino acid properties (such as polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues) and it is therefore useful to group amino acids together in functional groups. Amino acids may be grouped together based on the properties of their side chains alone. However, it is more useful to include mutation data as wed The sets of amino acids thus derived are likely to be conserved for structural reasons. These sets may be described in the form of a Venn diagram (Livingstone C.D. and Barton G.J. (1993) “Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation” Comput. Appl. Biosci. 9: 745-756) (Taylor W.R. (1986) “The classification of amino acid conservation” J. Theor. Biol. 119, 205-218). Conservative substitutions may be

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PCT/US2016/038181 made, for example according to the table below which describes a generally accepted Venn diagram grouping of amino acids.

Set	Sub-set
Hydrophobic	F W ¥ Η K ΜIL V A G C	Aromatic	F W Y H
Aliphatic	IL V
Polar	WYHKREDCSTNQ	Charged	HKRED
Positively charged	Η K R
Negatively charged	E D
Small	V C A G S P T N D	Tiny	A G S

[00824] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals Include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.

[00825] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations, amelioration of a disease, symptom, disorder, or pathological condition, reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[00826] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested.

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PCT/US2016/038181 [00827] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will provide an image for detection by any one of the imaging methods described herein. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to he imaged, and the physical delivery system in which it is carried.

[00828] Several aspects of the invention relate to vector systems comprising one or more vectors, or vectors as such. Vectors can be designed for expression of CRISPR transcripts (e.g. nucleic acid transcripts, proteins, or enzymes) in prokaryotic or eukaryotic cells. For example, CRISPR transcripts can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[00829] Embodiments of the invention include sequences (both polynucleotide or polypeptide) which may comprise homologous substitution (substitution and replacement are both used herein to mean the interchange of an existing amino acid residue or nucleotide, with an alternative residue or nucleotide) that may occur i.e., like-for-like substitution in the case of amino acids such as basic for basic, acidic for acidic, polar for polar, etc. Non-homologous substitution may also occur i.e., from one class of residue to another or alternatively involving the inclusion of unnatural amino acids such as ornithine (hereinafter referred to as Z), diaminobutyric acid ornithine (hereinafter referred to as B), norleucine ornithine (hereinafter referred to as O), pyriylalanine, thienylalanine, naphthylalanine and phenylglycine. Variant amino acid sequences may include suitable spacer groups that may be inserted between any two amino acid residues of the sequence including alkyl groups such as methyl, ethyl or propyl groups in addition to amino acid spacers such as glycine or β-alanine residues. A further form of

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PCT/US2016/038181 variation, which involves the presence of one or more amino acid residues in peptoid form, may be well understood by those skilled in the art. For the avoidance of doubt, “the peptoid form” is used to refer to variant amino acid residues wherein the cc-carbon substituent group is on the residue’s nitrogen atom rather than the cc-carbon. Processes for preparing peptides in the peptoid form are known in the art, for example Simon RJ et al., PANS (1992) 89(20), 9367-9371 and Horwell DC, Trends Biotechnol. (1995) 13(4), 132-134.

[00830] Homology modelling: Corresponding residues in other Cpfl orthologs can be identified by the methods of Zhang et al., 2012 (Nature; 490(7421): 556-60) and Chen et ah, 2015 (PLoS Comput Biol; 11(5): el004248)—a computational protein-protein interaction (PPI) method to predict interactions mediated by domain-motif interfaces. PrePPI (Predicting PPI), a structure based PPI prediction method, combines structural evidence with non-structural evidence using a Bayesian statistical framework. The method involves taking a pair a query proteins and using structural alignment to identify structural representatives that correspond to either their experimentally determined structures or homology models. Structural alignment is further used to identify both close and remote structural neighbours by considering global and local geometric relationships. Whenever two neighbors of the structural representatives form a complex reported in the Protein Data Bank, this defines a template for modelling the interaction between the two query proteins. Models of the complex are created by superimposing the representative structures on their corresponding structural neighbour in the template. This approach is further described in Dey et ah, 2013 (Prot Sci; 22: 359-66).

[00831] For purpose of this invention, amplification means any method employing a primer and a polymerase capable of replicating a target sequence with reasonable fidelity. Amplification may be carried out by natural or recombinant DNA polymerases such as TaqGold™, T7 DNA polymerase, Klenow fragment of E.coli DNA polymerase, and reverse transcriptase. A preferred amplification method is PCR.

[00832] In certain aspects the invention involves vectors. A used herein, a “vector” is a tool that allows or facilitates the transfer of an entity from one environment to another. It is a replicon, such as a plasmid, phage, or cosmid, into which another DNA segment may be inserted so as to bring about the replication of the inserted segment. Generally, a vector is capable of replication when associated with the proper control elements. In general, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been

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PCT/US2016/038181 linked. Vectors include, but are not limited to, nucleic acid molecules that are single-stranded, double-stranded, or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g. circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art. One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments can be inserted, such as by standard molecular cloning techniques. Another type of vector is a viral vector, wherein virally-derived DNA or RNA sequences are present in the vector for packaging into a virus (e.g. retroviruses, replication defective retroviruses, adenoviruses, replication defective adenoviruses, and adeno-associated viruses (AAVs)). Viral vectors also include polynucleotides carried by a virus for transfection into a host cell. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g. bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operativelylinked. Such vectors are referred to herein as “expression vectors.” Common expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.

[00833] Recombinant expression vectors can comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory elements, which may be selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory element(s) in a manner that allows for expression of the nucleotide sequence (e.g. in an in vitro transeription/translation system or in a host cell when the vector is introduced into the host cell). With regards to recombination and cloning methods, mention is made of U.S. patent application 10/815,730, published September 2, 2004 as US 2004-0171156 Al, the contents of which are herein incorporated by reference in their entirety.

[00834] Aspects of the invention relate to bicistronic vectors for guide RNA and (optionally modified or mutated) CRISPR enzymes (e.g. Cpfl). Bicistronic expression vectors for guide RNA and (optionally modified or mutated) CRISPR enzymes are preferred. In general and

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PCT/US2016/038181 particularly in this embodiment (optionally modified or mutated) CRISPR enzymes are preferably driven by the CBh promoter. The RNA may preferably be driven by a Pol III promoter, such as a U6 promoter. Ideally the two are combined.

[00835] In some embodiments, a loop in the guide RNA is provided. This may be a stem loop or a tetra loop. The loop is preferably GAAA, but it is not limited to this sequence or indeed to being only 4bp in length. Indeed, preferred loop forming sequences for use in hairpin structures are four nucleotides in length, and most preferably have the sequence GAAA. However, longer or shorter loop sequences may be used, as may alternative sequences. The sequences preferably include a nucleotide triplet (for example, AAA), and an additional nucleotide (for example C or G). Examples of loop forming sequences include CAAA. and AAAG. In practicing any of the methods disclosed herein, a suitable vector can be introduced to a cell or an embryo via one or more methods known in the art, including without limitation, microinjection, electroporation, sonoporation, biofistics, calcium phosphate-mediated transfection, cationic transfection, liposome transfection, dendrimer transfection, heat shock transfection, nucleofection transfection, magnetofection, lipofection, impalefection, optical transfection, proprietary agentenhanced uptake of nucleic acids, and delivery via liposomes, immunoliposomes, virosomes, or artificial virions. In some methods, the vector is introduced into an embryo by microinjection. The vector or vectors may be microinjected into the nucleus or the cytoplasm of the embryo. In some methods, the vector or vectors may be introduced into a cell by nucleofection.

[00836] The term “regulatory element” is intended to include promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g. transcription termination signals, such as polyadenyiation signals and poly-U sequences). Such regulatory elements are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory elements include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences), A tissue-specific promoter may direct expression primarily in a desired tissue of interest, such as muscle, neuron, bone, skin, blood, specific organs (e.g, liver, pancreas), or particular cell types (e.g, lymphocytes). Regulatory elements may also direct expression in a temporal-dependent manner, such as in a cell-cycle dependent or developmental stage-dependent manner, which may or may not also be tissue or cell-type

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PCT/US2016/038181 specific. In some embodiments, a vector comprises one or more ροί III promoter (e.g. 1, 2, 3, 4, 5, or more pol III promoters), one or more pol II promoters (e.g. 1, 2, 3, 4, 5, or more pol II promoters), one or more pol I promoters (e.g. I, 2, 3, 4, 5, or more pol I promoters), or combinations thereof. Examples of pol III promoters include, but are not limited to, U6 and Hl promoters. Examples of pol II promoters include, but are not limited to, the retroviral Rous sarcoma vims (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) [see, e.g., Boshart et al, Cell, 41:521-530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EFla promoter. Also encompassed by the term “regulatory element” are enhancer elements, such as WPRE; CMV enhancers; the R-U5’ segment in LTR of HTLV-I (Moi, Cell. Biol., Vol. 8(1), p. 466-472, 1988); SV40 enhancer; and the intron sequence between exons 2 and 3 of rabbit β-globin (Proc. Natl. Acad. Sci. USA., Vol. 78(3), p, 1527-31, 1981). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression desired, etc. A vector can be introduced into host cells to thereby produce transcripts, proteins, or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., clustered regularly interspersed short palindromic repeats (CRISPR) transcripts, proteins, enzymes, mutant forms thereof, fusion proteins thereof, etc.). With regards to regulatory sequences, mention is made of U.S. patent application 10/491,026, the contents of which are incorporated by reference herein in their entirety. With regards to promoters, mention is made of PCT publication WO 2011/028929 and U.S. application 12/511,940, the contents of which are incorporated by reference herein in their entirety.

[00837] Vectors can be designed for expression of CRISPR transcripts (e.g. nucleic acid transcripts, proteins, or enzymes) in prokaryotic or eukaryotic cells. For example, CRISPR transcripts can be expressed in bacterial cells such as Escherichia coli, insect ceils (using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory' sequences and T7 polymerase.

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PCT/US2016/038181 [00838] Vectors may be introduced and propagated in a prokaryote or prokaryotic cell. In some embodiments, a prokaryote is used to amplify copies of a vector to be introduced into a eukaryotic cell or as an intermediate vector in the production of a vector to be introduced into a eukaryotic cell (e.g. amplifying a plasmid as part of a viral vector packaging system). In some embodiments, a prokaryote is used to amplify copies of a vector and express one or more nucleic acids, such as to provide a source of one or more proteins for deliver}/ to a host cell or host organism. Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, such as to the amino terminus of the recombinant protein. Such fusion vectors may serve one or more purposes, such as; (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Example fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, NJ.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al,, (1988) Gene 69:301-315) and pET lid (Studier et al,, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89). In some embodiments, a vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSecl (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kuijan and Herskowitz, 1982. Cell 30: 933943), pJRY88 (Schultz et al., 1987. Gene 54: 1 13-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.). In some embodiments, a vector drives protein expression in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the

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PCT/US2016/038181 pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

[00839] In some embodiments, a vector is capable of driving expression of one or more sequences in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987, EMBO J. 6: 187-195), When used in mammalian cells, the expression vector’s control functions are typically provided by one or more regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, simian virus 40, and others disclosed herein and known in the art. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed,, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

[00840] In some embodiments, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissuespecific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Baneiji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell NN 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentallyregulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Grass, 1990, Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546). With regards to these prokaryotic and eukaryotic vectors, mention is made of U.S. Patent 6,750,059, the contents of which are incorporated by reference herein in their entirety. Other embodiments of the invention may relate to the use of viral vectors, with regards to which mention is made of U.S. Patent application 13/092,085, the contents of which are incorporated by reference herein in their entirety. Tissue-specific regulatory elements are

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PCT/US2016/038181 known in the art and in this regard, mention is made of U.S. Patent 7,776,321, the contents of which are incorporated by reference herein in their entirety. In some embodiments, a regulatory⁷ element is operably linked to one or more elements of a CRISPR system so as to drive expression of the one or more elements of the CRISPR system. In general, CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats), also known as SPIDRs (SPacer Interspersed Direct Repeats), constitute a family of DNA loci that are usually specific to a particular bacterial species. The CRISPR locus comprises a distinct class of interspersed short sequence repeats (SSRs) that were recognized in E. coli (Ishino et al., J. Bacteriol., 169:5429-5433 [1987]; and Nakata et al., J. Bacteriol., 171:3553-3556 [1989]), and associated genes. Similar interspersed SSRs have been identified in Haloferax mediterranei, Streptococcus pyogenes, Anabaena, and Mycobacterium tuberculosis (See, Groenen et al,, Mol. Microbiol., 10:1057-1065 [1993]; Hoe et al., Emerg. Infect. Dis., 5:254-263 [ 1999]; Masepohl et al., Biochim. Biophys. Acta 1307:26-30 [1996]; and Mojica et al., Mol. Microbiol., 17:85-93 [1995]), The CRISPR loci typically differ from other SSRs by the structure of the repeats, which have been termed short regularly spaced repeats (SRSRs) (Janssen et al., OMICS J. Integ. Biol., 6:23-33 [2002]; and Mojica et al., Mol. Microbiol., 36:244-246 [2000]). In general, the repeats are short elements that occur in clusters that are regularly spaced by unique intervening sequences with a substantially constant length (Mojica et al., [2000], supra). Although the repeat sequences are highly conserved between strains, the number of interspersed repeats and the sequences of the spacer regions typically differ from strain to strain (van Embden et al., J. Bacteriol,, 182:2393-2401 [2000]). CRISPR loci have been identified in more than 40 prokaryotes (See e.g., Jansen et al., Mol. Microbiol., 43:1565-1575 [2002]; and Mojica et ah, [2005]) including, but not limited to Aeropyrum, Pyrobaculum, Sulfolobus, Archaeoglobus, Halocarcula, Methanobacterium, Methanococcus, Methanosarcina, Methanopyrus, Pyrococcus, Picrophilus, Thermoplasma, Corynebacterium, Mycobacterium, Streptomyces, Aquifex, Porphyromonas, Chlorobium, Thermus, Bacillus, Listeria, Staphylococcus, Clostridium, Thermoanaerobacter, Mycoplasma, Fusobacterium, Azarcus, Chromobacterium, Neisseria, Nitrosomonas, Desulfovibrio, Geobacter, Myxococcus, Campylobacter, Wolinella, Acinetobacter, Erwinia, Escherichia, Legionella, Methylococcus, Pasteurella, Photobacterium, Salmonella, Xanthomonas, Yersinia, Treponema, and Thermotoga. [00841] In general, “nucleic acid-targeting system” as used in the present application refers collectively to transcripts and other elements involved in the expression of or directing the

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PCT/US2016/038181 activity of nucleic acid-targeting CRISPR-associated (“Cas”) genes (also referred to herein as an effector protein), including sequences encoding a nucleic acid-targeting Cas (effector) protein and a guide RNA or other sequences and transcripts from a nucleic acid-targeting CRISPR locus. In some embodiments, one or more elements of a nucleic acid-targeting system are derived from a Type V/Type VI nucleic acid-targeting CRISPR system. In some embodiments, one or more elements of a nucleic acid-targeting system is derived from a particular organism comprising an endogenous nucleic acid-targeting CRISPR system. In general, a nucleic acid-targeting system is characterized by elements that promote the formation of a nucleic acid-targeting complex at the site of a target sequence. In the context of formation of a nucleic acid-targeting complex, “target sequence” refers to a sequence to which a guide sequence is designed to have complementarity, where hybridization between a target sequence and a guide RNA promotes the formation of a DNA or RNA-targeting complex. Full complementarity is not necessarily required, provided there is sufficient complementarity to cause hybridization and promote formation of a nucleic acid-targeting complex. A target sequence may comprise RNA polynucleotides. In some embodiments, a target sequence is located in the nucleus or cytoplasm of a cell. In some embodiments, the target sequence may be within an organelle of a eukaryotic cell, for example, mitochondrion or chloroplast. A sequence or template that may be used for recombination into the targeted locus comprising the target sequences is referred to as an “editing template” or “editing RNA” or “editing sequence”. In aspects of the invention, an exogenous template RNA may he referred to as an editing template. In an aspect of the invention the recombination is homologous recombination.

[00842] Typically, in the context of an endogenous nucleic acid-targeting system, formation of a nucleic acid-targeting complex (comprising a guide RNA hybridized to a target sequence and complexed with one or more nucleic acid-targeting effector proteins) results in cleavage of one or both RNA strands in or near (e.g. within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the target sequence. In some embodiments, one or more vectors driving expression of one or more elements of a nucleic acid-targeting system are introduced into a host cell such that expression of the elements of the nucleic acid-targeting system direct formation of a nucleic acid-targeting complex at one or more target sites. For example, a nucleic acid-targeting effector protein and a guide RNA could each be operably linked to separate regulatory elements on separate vectors. Alternatively, two or more of the elements expressed from the same or

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PCT/US2016/038181 different regulator)/ elements, may be combined in a single vector, with one or more additional vectors providing any components of the nucleic acid-targeting system not included in the first vector, nucleic acid-targeting system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5’ with respect to (“upstream” of) or 3’ with respect to (“downstream” of) a second element. The coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In some embodiments, a single promoter drives expression of a transcript encoding a nucleic acid-targeting effector protein and a guide RNA embedded within one or more intron sequences (e.g. each in a different intron, two or more in at least one intron, or all in a single intron). In some embodiments, the nucleic acidtargeting effector protein and guide RNA are operably linked to and expressed from the same promoter.

[00843] In general, a guide sequence is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific binding of a nucleic acid-targeting complex to the target sequence. In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g. the Burrows Wheeler Aligner), ClustalW, Clustal X, BEAT, Novoalign (Novocraft Technologies, ELAND (Illumina, San Diego, CA), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). In some embodiments, a guide sequence is about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In some embodiments, a guide sequence is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. The ability of a guide sequence to direct sequence-specific binding of a nucleic acid-targeting complex to a target sequence may be assessed by any suitable assay. For example, the components of a nucleic acid-targeting system sufficient to form a nucleic acid-targeting complex, including the guide sequence to be tested, may be provided to a host cell having the corresponding target

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PCT/US2016/038181 sequence, such as by transfection with vectors encoding the components of the nucleic acidtargeting CRISPR sequence, followed by an assessment of preferential cleavage within or in the vicinity of the target sequence, such as by Surveyor assay as described herein. Similarly, cleavage of a target polynucleotide sequence (or a sequence in the vicinity thereof) may be evaluated in a test tube by providing the target sequence, components of a nucleic acid-targeting complex, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at or in the vicinity of the target sequence between the test and control guide sequence reactions. Other assays are possible, and will occur to those skilled in the art.

[00844] A guide sequence may be selected to target any target sequence. In some embodiments, the target sequence is a sequence within a gene transcript or mRNA.

[00845] In some embodiments, the target sequence is a sequence within a genome of a cell. [00846] In some embodiments, a guide sequence is selected to reduce the degree of secondary structure within the guide sequence. Secondary structure may be determined by any suitable polynucleotide folding algorithm. Some programs are based on calculating the minimal Gibbs free energy. An example of one such algorithm is mFold, as described by Zuker and Stiegler (Nucleic Acids Res. 9 (1981), 133-148). Another example folding algorithm is the online webserver RNAfold, developed at Institute for Theoretical Chemistry at the University of Vienna, using the centroid structure prediction algorithm (see e.g. A.R. Gruber et al., 2008, Cell 106(1); 23-24; and PA Carr and GM Church, 2009, Nature Biotechnology 27(12): 1151-62). Further algorithms may be found in U.S. application Serial No. TBA (attorney docket 44790.11.2022, Broad Reference BI-2013/004A); incorporated herein by reference.

[00847] In some embodiments, a recombination template is also provided. A recombination template may be a component of another vector as described herein, contained in a separate vector, or provided as a separate polynucleotide. In some embodiments, a recombination template is designed to serve as a template in homologous recombination, such as within or near a target sequence nicked or cleaved by a nucleic acid-targeting effector protein as a part of a nucleic acid-targeting complex. A template polynucleotide may be of any suitable length, such as about or more than about 10, 15, 20, 25, 50, 75, 100, 150, 200, 500, 1000, or more nucleotides in length. In some embodiments, the template polynucleotide is complementary'· to a portion of a polynucleotide comprising the target sequence. When optimally aligned, a template

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PCT/US2016/038181 polynucleotide might overlap with one or more nucleotides of a target sequences (e.g. about or more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or more nucleotides). In some embodiments, when a template sequence and a polynucleotide comprising a target sequence are optimally aligned, the nearest nucleotide of the template polynucleotide is within about 1, 5, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 1000, 5000, 10000, or more nucleotides from the target sequence, [00848] In some embodiments, the nucleic acid-targeting effector protein is part of a fusion protein comprising one or more heterologous protein domains (e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more domains in addition to the nucleic acid-targeting effector protein). In some embodiments, the CRISPR effector protein is part of a fusion protein comprising one or more heterologous protein domains (e.g. about or more than about I, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more domains in addition to the CRISPR enzyme). A CRISPR enzyme fusion protein may comprise any additional protein sequence, and optionally a linker sequence between any two domains. Examples of protein domains that may be fused to a CRISPR enzyme include, without limitation, epitope tags, reporter gene sequences, and protein domains having one or more of the following activities: methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, RNA cleavage activity and nucleic acid binding activity. Non-limiting examples of epitope tags include histidine (His) tags, V5 tags, FLAG tags, influenza hemagglutinin (HA) tags, Myc tags, VSV-G tags, and thioredoxin (Trx) tags. Examples of reporter genes include, but are not limited to, glutathione-S-transferase (GST), horseradish peroxidase (HRP), chloramphenicol acetyltransferase (CAT) beta-galactosidase, betaglucuronidase, luciferase, green fluorescent protein (GFP), HcRed, DsRed, cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and autofluorescent proteins including blue fluorescent protein (BFP). A CRISPR enzyme may be fused to a gene sequence encoding a protein or a fragment of a protein that bind DNA molecules or bind other cellular molecules, including but not limited to maltose binding protein (MBP), S-tag, Lex A DNA binding domain (DBD) fusions, GAL4 DNA binding domain fusions, and herpes simplex vims (HSV) BP 16 protein fusions. Additional domains that may form part of a fusion protein comprising a CRISPR enzyme are described in US20110059502, incorporated herein by reference. In some embodiments, a tagged CRISPR enzyme is used to identify the location of a target sequence.

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PCT/US2016/038181 [00849] In some embodiments, a CRISPR enzyme may form a component of an inducible system. The inducible nature of the system would allow for spatiotemporal control of gene editing or gene expression using a form of energy. The form of energy may include but is not limited to electromagnetic radiation, sound energy, chemical energy and thermal energy. Examples of inducible system include tetracycline inducible promoters (Tet-On or Tet-Off), small molecule two-hybrid transcription activations systems (FKBP, ABA, etc), or light inducible systems (Phytochrome, LOV domains, or cryptochrome).In one embodiment, the CRISPR enzyme may be a part of a Light Inducible Transcriptional Effector (LITE) to direct changes in transcriptional activity in a sequence-specific manner. The components of a light may include a CRISPR enzyme, a light-responsive cytochrome heterodimer (e.g. from Arabidopsis thaliana), and a transcriptional activation/repression domain. Further examples of inducible DNA binding proteins and methods for their use are provided in US 61/736465 and US 61/721,283 and WO 2014/018423 and US8889418, US8895308, US20140186919, US20140242700,

US20140273234, US20140335620, WO2014093635, which is hereby incorporated by reference in its entirety.

[00850] Delivery [00851] In some aspects, the invention provides methods comprising delivering one or more polynucleotides, such as or one or more vectors as described herein, one or more transcripts thereof, and/or one or proteins transcribed therefrom, to a host cell. In some aspects, the invention further provides cells produced by such methods, and organisms (such as animals, plants, or fungi) comprising or produced from such cells. In some embodiments, a nucleic acidtargeting effector protein in combination with (and optionally complexed with) a guide RNA is delivered to a cell. Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding components of a nucleic acid-targeting system to cells in culture, or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery⁷ to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Feigner, TIBTECH 11:211-217 (1993), Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon,

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TIBTECH 11:167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10):1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology, Doerfler and Bohm (eds) (1995), and Yu et al., Gene Therapy 1:13-26 (1994).

[00852] Methods of non-viral delivery of nucleic acids include lipofection, nucleofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91/17424; WO 91/16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration).

[00853] The preparation of lipidmucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787).

[00854] The use of RNA or DNA viral based systems for the deliver}'· of nucleic acids takes advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo). Conventional viral based systems could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues.

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PCT/US2016/038181 [00855] The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et ak, J. Virol. 66:2731-2739 (1992); Johann et ak, J. Virol. 66:1635-1640 (1992); Sommnerfelt et ak, Virol. 176:58-59 (1990); Wilson et ak, J. Virol. 63:2374-2378 (1989), Miller et ak, J, Virok 65:2220-2224 (1991); PCT/US94/05700).In applications where transient expression is preferred, adenoviral based systems may be used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system. Adeno-associated virus (“AAV”) vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et ak. Virology 160:38-47 (1987); U.S. Pat, No, 4,797,368; WO 93/24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest. 94:1351 (1994). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No. 5,173,414; Tratschin et ak, Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin, et ak, Mol. Cell. Biol. 4:2072-2081 (1984), Hermonat & Muzyczka, PNAS 81:64666470 (1984); and Samulski et ak, J. Virol. 63:03822-3828 (1989).

options for DNA/RNA or DNA/DNA or RNA/RNA or protein/RNA [00856] In some embodiments, the components of the CRISPR system may be delivered in various form, such as combinations of DNA/RNA or RNA/RNA or protein RNA. For example, the Cpfl may be delivered as a DNA-coding polynucleotide or an RNA—coding polynucleotide or as a protein. The guide may be delivered may be delivered as a DNA-coding polynucleotide or an RNA. All possible combinations are envisioned, including mixed forms of delivery.

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PCT/US2016/038181 [00857] In some embodiments, all such combinations (DNA/RNA or DNA/DNA or RNA/RNA or protein/RNA).

[00858] In some embodiment, when the Cpfl is delivered in protein form, it is possible to preassemble same with one or more guide/s. nanodews [00859] Further, the CRISPR system may he delivered using nanoclews, for example as described in Sun W et al, Cocoon-like seif-degradable DNA nanoclew for anticancer drug delivery., J Am Chem Soc. 2014 Oct 22; 136(42): 14722-5. doi: 10.1021/ja5088Q24, Epub 2014 Oct 13. ; or in Sun W et al, Self-Assembled DNA Nanoclews for the Efficient Delivery of CR1SPR-Cas9 for Genome Editing., Angew Chem Int Ed Engl. 2015 Oct 5,54(41):12029-33. doi: 10.1002/ani e, 2015 0603 0. Epub 2015 Aug 27..

[00860] The practice of the present invention employs, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See Sambrook, Fritsch and Maniatis, MOLECULAR CLONING: A LABORATORY MANUAL, 2nd edition (1989); CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel, et al. eds., (1987)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M.J. MacPherson, B.D. Hanies and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R.I. Freshney, ed. (1987)).

Models of Genetic and Epigenetic Conditions [00861] A method of the invention may be used to create a plant, an animal or cell that may be used to model and/or study genetic or epitgenetic conditions of interest, such as a through a model of mutations of interest or a disease model. As used herein, “disease” refers to a disease, disorder, or indication in a subject. For example, a method of the invention may be used to create an animal or cell that comprises a modification in one or more nucleic acid sequences associated with a disease, or a plant, animal or cell In which the expression of one or more nucleic acid sequences associated with a disease are altered. Such a nucleic acid sequence may encode a disease associated protein sequence or may be a disease associated control sequence. Accordingly, it is understood that in embodiments of the invention, a plant, subject, patient, organism or ceil can be a non-human subject, patient, organism or cell. Thus, the invention

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PCT/US2016/038181 provides a plant, animal or cell, produced by the present methods, or a progeny thereof. The progeny may be a clone of the produced plant or animal, or may result from sexual reproduction by crossing with other individuals of the same species to introgress further desirable traits into their offspring. The cell may be in vivo or ex vivo in the cases of multicellular organisms, particularly animals or plants. In the instance where the cell is in cultured, a cell line may be established if appropriate culturing conditions are met and preferably if the cell is suitably adapted for this purpose (for instance a stem cell). Bacterial cell lines produced by the invention are also envisaged. Hence, cell lines are also envisaged.

[00862] In some methods, the disease model can be used to study the effects of mutations on the animal or cell and development and/or progression of the disease using measures commonly used in the study of the disease. Alternatively, such a disease model is useful for studying the effect of a pharmaceutically active compound on the disease.

[00863] In some methods, the disease model can be used to assess the efficacy of a potential gene therapy strategy. That is, a disease-associated gene or polynucleotide can be modified such that the disease development and/or progression is inhibited or reduced. In particular, the method comprises modifying a disease-associated gene or polynucleotide such that an altered protein is produced and, as a result, the animal or cell has an altered response. Accordingly, in some methods, a genetically modified animal may be compared with an animal predisposed to development of the disease such that the effect of the gene therapy event may be assessed.

[00864] In another embodiment, this invention provides a method of developing a biologically active agent that modulates a cell signaling event associated with a disease gene. The method comprises contacting a test compound with a cell comprising one or more vectors that drive expression of one or more of a CRISPR enzyme, and a direct repeat sequence linked to a guide sequence; and detecting a change in a readout that is indicative of a reduction or an augmentation of a cell signaling event associated with, e.g., a mutation in a disease gene contained in the cell. [00865] A cell model or animal model can be constructed in combination with the method of the invention for screening a cellular function change. Such a model may be used to study the effects of a genome sequence modified by the CRISPR complex of the invention on a cellular function of interest. For example, a cellular function model may be used to study the effect of a modified genome sequence on intracellular signaling or extracellular signaling. Alternatively, a cellular function model may be used to study the effects of a modified genome sequence on

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PCT/US2016/038181 sensory perception. In some such models, one or more genome sequences associated with a signaling biochemical pathway in the model are modified.

[00866] Several disease models have been specifically investigated. These include de novo autism risk genes CHD8, KATNAL2, and SCN2A; and the syndromic autism (Angelman Syndrome) gene UBE3A. These genes and resulting autism models are of course preferred, but serve to show the broad applicability of the invention across genes and corresponding models. An altered expression of one or more genome sequences associated with a signalling biochemical pathway can be determined by assaying for a difference in the mRNA level s of the corresponding genes between the test model cell and a control cell, when they are contacted with a candidate agent. Alternatively, the differential expression of the sequences associated with a signaling biochemical pathway is determined by detecting a difference in the level of the encoded polypeptide or gene product.

[00867] To assay for an agent-induced alteration in the level of mRNA transcripts or corresponding polynucleotides, nucleic acid contained in a sample is first extracted according to standard methods in the art. For instance, mRNA can be isolated using various lytic enzymes or chemical solutions according to the procedures set forth in Sambrook et al. (1989), or extracted by nucleic-acid-binding resins following the accompanying instructions provided by the manufacturers. The mRNA contained in the extracted nucleic acid sample is then detected by amplification procedures or conventional hybridization assays (e.g. Northern blot analysis) according to methods widely known in the art or based on the methods exemplified herein. [00868] For purpose of this invention, amplification means any method employing a primer and a polymerase capable of replicating a target sequence with reasonable fidelity. Amplification may be carried out by natural or recombinant DNA polymerases such as TaqGold™, T7 DNA polymerase, Klenow fragment of E.coli DNA polymerase, and reverse transcriptase. A preferred amplification method is PCR. In particular, the isolated RNA can be subjected to a reverse transcription assay that is coupled with a quantitative polymerase chain reaction (RT-PCR) in order to quantify the expression level of a sequence associated with a signaling biochemical pathway.

[00869] Detection of the gene expression level can be conducted in real time in an amplification assay. In one aspect, the amplified products can be directly visualized with fluorescent DNA-binding agents including but not limited to DNA intercalators and DNA groove

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PCT/US2016/038181 binders. Because the amount of the intercalators incorporated into the double-stranded DNA molecules is typically proportional to the amount of the amplified DNA products, one can conveniently determine the amount of the amplified products by quantifying the fluorescence of the intercalated dye using conventional optical systems in the art, DNA-binding dye suitable for this application include SYBR green, SYBR blue, DAPI, propidium iodine, Hoeste, SYBR gold, ethidium bromide, acridines, proflavine, acridine orange, acrifiavine, fluorcoumanin, ellipticine, daunomycin, chloroquine, distamycin D, chromomycin, homidium, mithramycin, ruthenium polypyridyls, anthramycin, and the like.

[00870] In another aspect, other fluorescent labels such as sequence specific probes can be employed in the amplification reaction to facilitate the detection and quantification of the amplified products. Probe-based quantitative amplification relies on the sequence-specific detection of a desired amplified product. It utilizes fluorescent, target-specific probes (e.g., TaqMan® probes) resulting in increased specificity and sensitivity. Methods for performing probe-based quantitative amplification are well established in the art and are taught in U.S. Patent No. 5,210,015.

[00871] In yet another aspect, conventional hybridization assays using hybridization probes that share sequence homology with sequences associated with a signaling biochemical pathway can be performed. Typically, probes are allowed to form stable complexes with the sequences associated with a signaling biochemical pathway contained within the biological sample derived from the test subject in a hybridization reaction. It will be appreciated by one of skill in the art that where antisense is used as the probe nucleic acid, the target polynucleotides provided in the sample are chosen to be complementary to sequences of the antisense nucleic acids. Conversely, where the nucleotide probe is a sense nucleic acid, the target polynucleotide is selected to be complementary to sequences of the sense nucleic acid.

[00872] Hybridization can be performed under conditions of various stringency. Suitable hybridization conditions for the practice of the present invention are such that the recognition interaction between the probe and sequences associated with a signaling biochemical pathway is both sufficiently specific and sufficiently stable. Conditions that increase the stringency of a hybridization reaction are widely known and published in the art. See, for example, (Sambrook, et al., (1989); Nonradioactive In Situ Hybridization Application Manual, Boehringer Mannheim, second edition). The hybridization assay can be formed using probes immobilized on any solid

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PCT/US2016/038181 support, including but are not limited to nitrocellulose, glass, silicon, and a variety of gene arrays. A preferred hybridization assay is conducted on high-density gene chips as described in U.S. Patent No. 5,445,934.

[00873] For a convenient detection of the probe-target complexes formed during the hybridization assay, the nucleotide probes are conjugated to a detectable label. Detectable labels suitable for use in the present invention include any composition detectable by photochemical, biochemical, spectroscopic, immunochemical, electrical, optical or chemical means. A wide variety of appropriate detectable labels are known in the art, which include fluorescent or chemiluminescent labels, radioactive isotope labels, enzymatic or other ligands. In preferred embodiments, one will likely desire to employ a fluorescent label or an enzyme tag, such as digoxigenin, β-galactosidase, urease, alkaline phosphatase or peroxidase, avidin/hiotin complex. [00874] The detection methods used to detect or quantify the hybridization intensity will typically depend upon the label selected above. For example, radiolabels may be detected using photographic film or a phosphoimager. Fluorescent markers may be detected and quantified using a photodetector to detect emitted light. Enzymatic labels are typically detected by providing the enzyme with a substrate and measuring the reaction product produced by the action of the enzyme on the substrate; and finally colorimetric label s are detected by simply visualizing the colored label.

[00875] An agent-induced change in expression of sequences associated with a signalling biochemical pathway can also he determined by examining the corresponding gene products. Determining the protein level typically involves a) contacting the protein contained in a biological sample with an agent that specifically bind to a protein associated with a signalling biochemical pathway; and (b) identifying any agent:protein complex so formed. In one aspect of this embodiment, the agent that specifically binds a protein associated with a signalling biochemical pathway is an antibody, preferably a monoclonal antibody.

[00876] The reaction is performed by contacting the agent with a sample of the proteins associated with a signaling biochemical pathway derived from the test samples under conditions that will allow' a complex to form between the agent and the proteins associated with a signalling biochemical pathway. The formation of the complex can be detected directly or indirectly according to standard procedures in the art. In the direct detection method, the agents are supplied with a detectable label and unreacted agents may be removed from the complex; the

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PCT/US2016/038181 amount of remaining label thereby indicating the amount of complex formed. For such method, it is preferable to select labels that remain attached to the agents even during stringent washing conditions. It is preferable that the label does not interfere with the binding reaction. In the alternative, an indirect detection procedure may use an agent that contains a label introduced either chemically or enzymatically. A desirable label generally does not interfere with binding or the stability of the resulting agentpolypeptide complex. However, the label is typically designed to be accessible to an antibody for an effective binding and hence generating a detectable signal. [00877] A wide variety of labels suitable for detecting protein levels are known in the art. Non-limiting examples include radioisotopes, enzymes, colloidal metals, fluorescent compounds, bioluminescent compounds, and chemiluminescent compounds.

[00878] The amount of agent:polypeptide complexes formed during the binding reaction can be quantified by standard quantitative assays. As illustrated above, the formation of agent:polypeptide complex can be measured directly by the amount of label remained at the site of binding. In an alternative, the protein associated with a signaling biochemical pathway is tested for its ability to compete with a labeled analog for binding sites on the specific agent. In this competitive assay, the amount of label captured is inversely proportional to the amount of protein sequences associated with a signaling biochemical pathway present in a test sample. [00879] A number of techniques for protein analysis based on the general principles outlined above are available in the art. They include but are not limited to radioimmunoassays, ELISA (enzyme linked immunoradiometric assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays (using e.g., colloidal gold, enzyme or radioisotope labels), western blot analysis, immunoprecipitation assays, immunofluorescent assays, and SDS-PAGE.

[00880] Antibodies that specifically recognize or bind to proteins associated with a signalling biochemical pathway are preferable for conducting the aforementioned protein analyses. Where desired, antibodies that recognize a specific type of post-translational modifications (e.g., signaling biochemical pathway inducible modifications) can be used. Post-translational modifications include but are not limited to glycosylation, lipidation, acetylation, and phosphorylation. These antibodies may be purchased from commercial vendors. For example, anti-phosphotyrosine antibodies that specifically recognize tyrosine-phosphorylated proteins are available from a number of vendors including Invitrogen and Perkin Elmer. Antiphosphotyrosine antibodies are particularly useful in detecting proteins that are differentially

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PCT/US2016/038181 phosphorylated on their tyrosine residues in response to an ER stress. Such proteins include but are not limited to eukaryotic translation initiation factor 2 alpha (eIF-2a). Alternatively, these antibodies can be generated using conventional polyclonal or monoclonal antibody technologies by immunizing a host animal or an antibody-producing cell with a target protein that exhibits the desired post-translational modification.

[00881] In practicing the subject method, it may be desirable to discern the expression pattern of an protein associated with a signaling biochemical pathway in different bodily tissue, in different cell types, and/or in different subcellular structures. These studies can be performed with the use of tissue-specific, cell-specific or subcellular structure specific antibodies capable of binding to protein markers that are preferentially expressed in certain tissues, cell types, or subcellular structures.

[00882] An altered expression of a gene associated with a signaling biochemical pathway can also be determined by examining a change in activity of the gene product relative to a control cell. The assay for an agent-induced change in the activity of a protein associated with a signaling biochemical pathway will dependent on the biological activity and/or the signal transduction pathway that is under investigation. For example, where the protein is a kinase, a change in its ability to phosphorylate the downstream substrate(s) can be determined by a variety of assays known in the art. Representative assays include but are not limited to immunoblotting and immunoprecipitation with antibodies such as anti-phosphotyrosine antibodies that recognize phosphorylated proteins. In addition, kinase activity can be detected by high throughput chemiluminescent assays such as AlphaScreen™ (available from Perkin Elmer) and eTag™ assay (Chan-Hui, etal. (2003) Clinical Immunology 111: 162-174).

[00883] Where the protein associated with a signaling biochemical pathway is part of a signaling cascade leading to a fluctuation of intracellular pH condition, pH sensitive molecules such as fluorescent pH dyes can be used as the reporter molecules. In another example where the protein associated with a signaling biochemical pathway is an ion channel, fluctuations in membrane potential and/or intracellular ion concentration can be monitored. A number of commercial kits and high-throughput devices are particularly suited for a rapid and robust screening for modulators of ion channels. Representative instruments include FLIPRTM (Molecular Devices, Inc.) and VIPR (Aurora Biosciences). These instruments are capable of

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PCT/US2016/038181 detecting reactions in over 1000 sample wells of a microplate simultaneously, and providing real-time measurement and functional data within a second or even a minisecond.

[00884] In practicing any of the methods disclosed herein, a suitable vector can be introduced to a cell or an embryo via one or more methods known in the art, including without limitation, microinjection, electroporation, sonoporation, biolistics, calcium phosphate-mediated transfection, cationic transfection, liposome transfection, dendrimer transfection, heat shock transfection, nucleofection transfection, magnetofection, lipofection, impalefection, optical transfection, proprietary agent-enhanced uptake of nucleic acids, and delivery via liposomes, immunoliposomes, virosomes, or artificial virions. In some methods, the vector is introduced into an embryo by microinjection. The vector or vectors may be microinjected into the nucleus or the cytoplasm of the embryo. In some methods, the vector or vectors may be introduced into a cell by nucleofection.

[00885] The target polynucleotide of a CRISPR complex can be any polynucleotide endogenous or exogenous to the eukaryotic cell. For example, the target polynucleotide can be a polynucleotide residing in the nucl eus of the eukaryotic cell. The target polynucleotide can be a sequence coding a gene product (e.g., a protein) or a non-coding sequence (e.g., a regulatory⁷ polynucleotide or a junk DNA).

[00886] Examples of target polynucleotides include a sequence associated with a signalling biochemical pathway, e.g., a signaling biochemical pathway-associated gene or polynucleotide. Examples of target polynucleotides include a disease associated gene or polynucleotide. A “disease-associated” gene or polynucleotide refers to any gene or polynucleotide which is yielding transcription or translation products at an abnormal level or in an abnormal form in cells derived from a disease-affected tissues compared with tissues or cells of a non disease control. It may be a gene that becomes expressed at an abnormally high level; it may be a gene that becomes expressed at an abnormally low level, where the altered expression correlates with the occurrence and/or progression of the disease. A disease-associated gene also refers to a gene possessing mutation(s) or genetic variation that is directly responsible or is in linkage disequilibrium with a gene(s) that is responsible for the etiology of a disease. The transcribed or translated products may be known or unknown, and may be at a normal or abnormal level. [00887] The target polynucleotide of a CRISPR complex can be any polynucleotide endogenous or exogenous to the eukaryotic cell. For example, the target polynucleotide can be a

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PCT/US2016/038181 polynucleotide residing in the nucleus of the eukaryotic cell. The target polynucleotide can be a sequence coding a gene product (e.g., a protein) or a non-coding sequence (e.g., a regulatory’ polynucleotide or a junk DNA). Without wishing to be bound by theory, it is believed that the target sequence should be associated with a PAM (protospacer adjacent motif); that is, a short sequence recognized by the CRISPR complex. The precise sequence and length requirements for the PAM differ depending on the CRISPR enzyme used, but PAMs are typically 2-5 base pair sequences adjacent the protospacer (that is, the target sequence) Examples of PAM sequences are given in the examples section below', and the skilled person will be able to identify further PAM sequences for use with a given CRISPR enzyme. Further, engineering of the PAM Interacting (PI) domain may allow programing of PAM specificity, improve target site recognition fidelity, and increase the versatility of the Cas, e.g. Cas9, genome engineering platform. Cas proteins, such as Cas9 proteins may be engineered to alter their PAM specificity, for example as described in Kleinstiver BP et al. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature. 2015 Jul 23;523(7561):481-5. doi: 10.1038/natureI4592.

[00888] The target polynucleotide of a CRISPR complex may include a number of diseaseassociated genes and polynucleotides as well as signaling biochemical pathway-associated genes and polynucleotides as listed in US provisional patent applications 61/736,527 and 61/748,427 having Broad reference BI-2011/008/WSGR Docket No. 44063-701.101 and ΒΪ2011/008/WSGR Docket No. 44063-701.102 respectively, both entitled SYSTEMS METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION filed on December 12, 2012 and January 2, 2013, respectively, and PCT Application PCT/US2013/074667, entitled DELIVERY, ENGINEERING AND OPTIMIZATION OF SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION AND THERAPEUTIC APPLICATIONS, filed December 12, 2013, the contents of all of which are herein incorporated by reference in their entirety.

[00889] Examples of target polynucleotides include a sequence associated with a signalling biochemical pathway, e.g., a signaling biochemical pathway-associated gene or polynucleotide. Examples of target polynucleotides include a disease associated gene or polynucleotide. A “disease-associated” gene or polynucleotide refers to any gene or polynucleotide which is yielding transcription or translation products at an abnormal level or in an abnormal form in cells derived from a disease-affected tissues compared with tissues or ceils of a non disease control. It may be a gene that becomes expressed at an abnormally high level; it may be a gene that

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PCT/US2016/038181 becomes expressed at an abnormally low level, where the altered expression correlates with the occurrence and/or progression of the disease. A disease-associated gene also refers to a gene possessing mutation(s) or genetic variation that is directly responsible or is in linkage disequilibrium with a gene(s) that is responsible for the etiology of a disease. The transcribed or translated products may be known or unknown, and may be at a normal or abnormal level. Genome Wide Knock-out Screening [00890] The CRISPR proteins and systems described herein can be used to perform efficient and cost effective functional genomic screens. Such screens can utilize CRISPR effector protein based genome wide libraries. Such screens and libraries can provide for determining the function of genes, cellular pathways genes are involved in, and how any alteration in gene expression can result in a particular biological process. An advantage of the present invention is that the CRISPR system avoids off-target binding and its resulting side effects. This is achieved using systems arranged to have a high degree of sequence specificity for the target DNA, In preferred embodiments of the invention, the CRISPR effector protein complexes are Cpfl effector protein complexes.

[00891] In embodiments of the invention, a genome wide library may comprise a plurality of Cpfl guide RNAs, as described herein, comprising guide sequences that are capable of targeting a plurality of target sequences in a plurality of genomic loci in a population of eukaryotic cells. The population of cells may be a population of embryonic stem (ES) cells. The target sequence in the genomic locus may be a non-coding sequence. The non-coding sequence may be an intron, regulatory sequence, splice site, 3’ UTR, 5’ UTR, or polyadenylation signal. Gene function of one or more gene products may be altered by said targeting. The targeting may result in a knockout of gene function. The targeting of a gene product may comprise more than one guide RNA. A gene product may be targeted by 2, 3, 4, 5, 6, 7, 8, 9, or 10 guide RNAs, preferably 3 to 4 per gene. Off-target modifications may be minimized by exploiting the staggered double strand breaks generated by Cpfl effector protein complexes or by utilizing methods analogous to those used in CRISPR-Cas9 systems (See, e.g., DNA targeting specificity of RNA-guided Cas9 nucleases. Hsu, P., Scott, D., Weinstein, J., Ran, FA., Konermann, S., Agarwala, V., Li, Y., Fine, E., Wu, X., Shalem, 0., Cradick, TJ,, Marraffini, LA., Bao, G., & Zhang, F. Nat Biotechnol doi:10.1038/nbt.2647 (2013)), incorporated herein by reference. The targeting may be of about 100 or more sequences. The targeting may be of about 1000 or more sequences. The targeting

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PCT/US2016/038181 may be of about 20,000 or more sequences. The targeting may be of the entire genome. The targeting may be of a panel of target sequences focused on a relevant or desirable pathway. The pathway may be an immune pathway. The pathway may be a cell division pathway.

[00892] One aspect of the invention comprehends a genome wide library that may comprise a plurality of Cpfl guide RNAs that may comprise guide sequences that are capable of targeting a plurality of target sequences in a plurality of genomic loci, wherein said targeting results in a knockout/knockdown of gene function. This library may potentially comprise guide RNAs that target each and every gene in the genome of an organism.

[00893] In some embodiments of the invention the organism or subject is a eukaryote (including mammal including human) or a non-human eukaryote or a non-human animal or a non-human mammal. In some embodiments, the organism or subject is a non-human animal, and may be an arthropod, for example, an insect, or may be a nematode. In some methods of the invention the organism or subject is a plant. In some methods of the invention the organism or subject is a mammal or a non-human mammal. A non-human mammal may be for example a rodent (preferably a mouse or a rat), an ungulate, or a primate. In some methods of the invention the organism or subject is algae, including microalgae, or is a fungus.

[00894] The knockout/knockdown of gene function may comprise: introducing into each cell in the population of cells a vector system of one or more vectors comprising an engineered, nonnaturally occurring Cpfl effector protein system comprising I. a Cpfl effector protein, and II. one or more guide RNAs, wherein components 1 and II may be same or on different vectors of the system, integrating components I and II into each cell, wherein the guide sequence targets a unique gene in each cell, wherein the Cpfl effector protein is operably linked to a regulatory element, wherein when transcribed, the guide RNA comprising the guide sequence directs sequence-specific binding of the Cpfl effector protein system to a target sequence corresponding to the genomic loci of the unique gene, inducing cleavage of the genomic loci by the Cpfl effector protein, and confirming different knockout/knockdown mutations in a plurality of unique genes in each cell of the population of cells thereby generating a gene knockout/knockdown cell library⁷. The invention comprehends that the population of cells is a population of eukaryotic cells, and in a preferred embodiment, the population of cells is a population of embryonic stem (ES) cells.

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PCT/US2016/038181 [00895] The one or more vectors may be plasmid vectors. The vector may be a single vector comprising a Cpfl effector protein, a gRNA, and optionally, a selection marker into target cells. Not being bound by a theory, the ability to simultaneously deliver a Cpfl effector protein and gRNA through a single vector enables application to any cell type of interest, without the need to first generate cell lines that express the Cpfl effector protein. The regulator)' element may be an inducible promoter. The inducible promoter may be a doxycycline inducible promoter. In some methods of the invention the expression of the guide sequence is under the control of the T7 promoter and is driven by the expression of T7 polymerase. The confirming of different knockout/knockdown mutations may be by whole exome sequencing. The knockout/knockdown mutation may be achieved in 100 or more unique genes. The knockout/knockdown mutation may be achieved in 1000 or more unique genes. The knockout/knockdown mutation may he achieved in 20,000 or more unique genes. The knockout/knockdown mutation may be achieved in the entire genome. The knockout/knockdown of gene function may be achieved in a plurality of unique genes which function in a particular physiological pathway or condition. The pathway or condition may be an immune pathway or condition. The pathway or condition may be a cell division pathway or condition.

[00896] The invention also provides kits that comprise the genome wide libraries mentioned herein. The kit may comprise a single container comprising vectors or plasmids comprising the library' of the invention. The kit may also comprise a panel comprising a selection of unique Cpfl effector protein system guide RNAs comprising guide sequences from the library of the invention, wherein the selection is indicative of a particular physiological condition. The invention comprehends that the targeting is of about 100 or more sequences, about 1000 or more sequences or about 20,000 or more sequences or the entire genome. Furthermore, a panel of target sequences may be focused on a relevant or desirable pathway, such as an immune pathway or cell division.

[00897] In an additional aspect of the invention, the Cpfl effector protein may comprise one or more mutations and may be used as a generic DNA binding protein with or without fusion to a functional domain. The mutations may be artificially introduced mutations or gain- or loss-offunction mutations. The mutations have been characterized as described herein. In one aspect of the invention, the functional domain may be a transcriptional activation domain, which may be VP64. In other aspects of the invention, the functional domain may be a transcriptional repressor

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PCT/US2016/038181 domain, which may be KRAB or SID4X. Other aspects of the invention relate to the mutated Cpfl effector protein being fused to domains which include but are not limited to a transcriptional activator, repressor, a recombinase, a transposase, a histone remodeler, a demethylase, a DNA methyltransferase, a cryptochrome, a light inducible/controllable domain or a chemically inducible/controllable domain. Some methods of the invention can include inducing expression of targeted genes. In one embodiment, inducing expression by targeting a plurality of target sequences in a plurality of genomic loci in a population of eukaryotic cells is by use of a functional domain.

[00898] Useful in the practice of the instant invention utilizing Cpfl effector protein complexes are methods used in CRISPR-Cas9 systems and reference is made to:

[00899] Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells. Shalem, 0,, Sanjana, NE., Hartenian, E., Shi, X., Scott, DA., Mikkelson, T., Heckl, D., Ebert, BE., Root, DE., Doench, JG., Zhang, F. Science Dec 12. (2013). [Epub ahead of print]; Published in final edited form as: Science. 2014 Jan 3; 343(6166): 84--87.

[00900] Shalem et al. involves a new way to interrogate gene function on a genome-wide scale. Their studies showed that deliver)' of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeted 18,080 genes with 64,751 unique guide sequences enabled both negative and positive selection screening in human cells. First, the authors showed use of the GeCKO library' to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, the authors screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic that inhibits mutant protein kinase BRAE. Their studies showed that the highest-ranking candidates included previously validated genes NF1 and MED 12 as well as novel hitsNF2, CUL3, TADA2B, and TADA1. The authors observed a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, and thus demonstrated the promise of genome-scale screening with Cas9.

[00901] Reference is also made to US patent publication number US20140357530; and PCT Patent Publication WO2014093701, hereby incorporated herein by reference. Reference is also made to N1H Press Release of Oct. 22, 2015 entitled, “Researchers identify potential alternative to CRISPR-Cas genome editing tools: New Cas enzymes shed light on evolution of CRISPR-Cas systems, which is incorporated by reference.

Functional Alteration and Screening

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PCT/US2016/038181 [00902] In another aspect, the present invention provides for a method of functional evaluation and screening of genes. The use of the CRISPR system of the present invention to precisely deliver functional domains, to activate or repress genes or to alter epigenetic state by precisely altering the methylation site on a a specific locus of interest, can be with one or more guide RNAs applied to a single cell or population of cells or with a library’ applied to genome in a pool of cells ex vivo or in vivo comprising the administration or expression of a library comprising a plurality of guide RNAs (gRNAs) and wherein the screening further comprises use of a Cpfl effector protein, wherein the CRISPR complex comprising the Cpfl effector protein is modified to comprise a heterologous functional domain. In an aspect the invention provides a method for screening a genome comprising the administration to a host or expression in a host in vivo of a library'. In an aspect the invention provides a method as herein discussed further comprising an activator administered to the host or expressed in the host. In an aspect the invention provides a method as herein discussed wherein the activator is attached to a Cpfl effector protein. In an aspect the invention provides a method as herein discussed wherein the activator is attached to the N terminus or the C terminus of the Cpfl effector protein. In an aspect the invention provides a method as herein discussed wherein the activator is attached to a gRNA loop. In an aspect the invention provides a method as herein discussed further comprising a repressor administered to the host or expressed in the host, in an aspect the invention provides a method as herein discussed, wherein the screening comprises affecting and detecting gene activation, gene inhibition, or cleavage in the locus.

[00903] In an aspect, the invention provides efficient on-target activity and minimizes off target activity. In an aspect, the invention provides efficient on-target cleavage by Cpfl effector protein and minimizes off-target cleavage by the Cpfl effector protein. In an aspect, the invention provides guide specific binding of Cpfl effector protein at a gene locus without DNA cleavage. Accordingly, in an aspect, the invention provides target-specific gene regulation. In an aspect, the invention provides guide specific binding of Cpfl effector protein at a gene locus without DNA cleavage. Accordingly, in an aspect, the invention provides for cleavage at one gene locus and gene regulation at a different gene locus using a single Cpfl effector protein. In an aspect, the invention provides orthogonal activation and/or inhibition and/or cleavage of multiple targets using one or more Cpfl effector protein and/or enzyme.

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PCT/US2016/038181 [00904] In an aspect the invention provides a method as herein discussed, wherein the host is a eukaryotic cell. In an aspect the invention provides a method as herein discussed, wherein the host is a mammalian cell. In an aspect the invention provides a method as herein discussed, wherein the host is a non-human eukaryote. In an aspect the invention provides a method as herein discussed, wherein the non-human eukaryote is a non-human mammal. In an aspect the invention provides a method as herein discussed, wherein the non-human mammal is a mouse. An aspect the invention provides a method as herein discussed comprising the delivery of the Cpfl effector protein complexes or component(s) thereof or nucleic acid molecule(s) coding therefor, wherein said nucleic acid molecule(s) are operatively linked to regulatory sequence(s) and expressed in vivo. In an aspect the invention provides a method as herein discussed wherein the expressing in vivo is via a lentivirus, an adenovirus, or an AAV, In an aspect the invention provides a method as herein discussed wherein the delivery is via a particle, a nanoparticle, a lipid or a cell penetrating peptide (CPP).

[00905] In an aspect the invention provides a pair of CRISPR complexes comprising Cpfl effector protein, each comprising a guide RNA (gRNA) comprising a guide sequence capable of hybridizing to a target sequence in a genomic locus of interest in a ceil, wherein at least one loop of each gRNA is modified by the insertion of distinct RNA sequence(s) that bind to one or more adaptor proteins, and wherein the adaptor protein is associated with one or more functional domains, wherein each gRNA of each Cpfl effector protein complex comprises a functional domain having a DNA cleavage activity. In an aspect the invention provides paired Cpfl effector protein complexes as herein-discussed, wherein the DNA cleavage activity is due to a Fokl nuclease.

[00906] In an aspect the invention provides a method for cutting a target sequence in a genomic locus of interest comprising delivery to a cell of the Cpfl effector protein complexes or component(s) thereof or nucleic acid molecule(s) coding therefor, wherein said nucleic acid molecule(s) are operatively linked to regulatory sequence(s) and expressed in vivo. In an aspect the invention provides a method as herein-discussed wherein the delivery⁷ is via a lentivirus, an adenovirus, or an AAV. In an aspect the invention provides a method as herein-discussed or paired Cpfl effector protein complexes as herein-discussed wherein the target sequence for a first complex of the pair is on a first strand of double stranded DNA and the target sequence for a second complex of the pair is on a second strand of double stranded DNA. In an aspect the

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PCT/US2016/038181 invention provides a method as herein-discussed or paired Cpfl effector protein complexes as herein-discussed wherein the target sequences of the first and second complexes are in proximity to each other such that the DNA is cut in a manner that facilitates homology directed repair. In an aspect a herein method can further include introducing into the cell template DNA. In an aspect a herein method or herein paired Cpfl effector protein complexes can involve wherein each Cpfl effector protein complex has a Cpfl effector enzyme that is mutated such that it has no more than about 5% of the nuclease activity of the Cpfl effector enzyme that is not mutated. [00907] In an aspect the invention provides a library, method or complex as herein-discussed wherein the gRNA is modified to have at least one non-coding functional loop, e.g., wherein the at least one non-coding functional loop is repressive, for instance, wherein the at least one noncoding functional loop comprises Alu.

[00908] In one aspect, the invention provides a method for altering or modifying expression of a gene product. The said method may comprise introducing into a cell containing and expressing a DNA molecule encoding the gene product an engineered, non-naturally occurring CRISPR system comprising a Cpfl effector protein and guide RNA that targets the DNA molecule, whereby the guide RNA targets the DNA molecule encoding the gene product and the Cpfl effector protein cleaves the DNA molecule encoding the gene product, whereby expression of the gene product is altered; and, wherein the Cpfl effector protein and the guide RNA do not naturally occur together. The invention comprehends the guide RNA comprising a guide sequence linked to a direct repeat sequence. The invention further comprehends the Cpfl effector protein being codon optimized for expression in a Eukaryotic cell. In a preferred embodiment the Eukaryotic ceil is a mammalian cell and in a more preferred embodiment the mammalian cell is a human cell. In a further embodiment of the invention, the expression of the gene product is decreased.

[00909] In some embodiments, one or more functional domains are associated with the Cpfl effector protein. In some embodiments, one or more functional domains are associated with an adaptor protein, for example as used with the modified guides of Konnerman et al. (Nature 517, 583-588, 29 January 2015). In some embodiments, one or more functional domains are associated with an dead gRNA (dRNA). In some embodiments, a dRNA complex with active Cpfl effector protein directs gene regulation by a functional domain at on gene locus while an gRNA directs DNA cleavage by the active Cpfl effector protein at another locus, for example as

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PCT/US2016/038181 described analogously in CRISPR-Cas9 systems by Dahlman et al., ‘Orthogonal gene control with a catalytically active Cas9 nuclease’ (in press). In some embodiments, dRNAs are selected to maximize selectivity of regulation for a gene locus of interest compared to off-target regulation. In some embodiments, dRNAs are selected to maximize target gene regulation and minimize target cleavage [00910] For the purposes of the following discussion, reference to a functional domain could be a functional domain associated with the Cpfl effector protein or a functional domain associated with the adaptor protein.

[00911] In the practice of the invention, loops of the gRNA may be extended, without colliding with the Cpfl protein by the insertion of distinct RNA loop(s) or disctinct sequence(s) that may recruit adaptor proteins that can bind to the distinct RNA loop(s) or distinct sequence(s). The adaptor proteins may include but are not limited to orthogonal RNA-binding protein / aptamer combinations that exist within the diversity of bacteriophage coat proteins. A list of such coat proteins includes, but is not limited to: Qp, F2, GA, fr, JP501, M12, R17, BZ13, JP34, JP500, KU1, MU, MX1, TW18, VK, SP, FI, ID2, NL95, TW19, AP205, φθ?5, ([>Cb8r, <|Cbl2r, 4>Cb23r, 7s and PRR1. These adaptor proteins or orthogonal RNA binding proteins can further reciuit effector proteins or fusions which comprise one or more functional domains. In some embodiments, the functional domain may be selected from the group consisting of: transposase domain, integrase domain, recombinase domain, resolvase domain, invertase domain, protease domain, DNA methyltransferase domain, DNA hydroxylmethylase domain, DNA demethylase domain, histone acetylase domain, histone deacetylases domain, nuclease domain, repressor domain, activator domain, nuclear-localization signal domains, transcriptionregulatory protein (or transcription complex recruiting) domain, cellular uptake activity associated domain, nucleic acid binding domain, antibody presentation domain, histone modifying enzymes, recruiter of histone modifying enzymes; inhibitor of histone modifying enzymes, histone methyltransferase, histone demethylase, histone kinase, histone phosphatase, histone ribosylase, histone deribosylase, histone ubiquitinase, histone deubiquitinase, histone biotinase and histone tail protease. In some preferred embodiments, the functional domain is a transcriptional activation domain, such as, without limitation, VP64, p65, MyoDl, HSF1, RTA, SET7/9 or a histone acetyltransferase. In some embodiments, the functional domain is a transcription repression domain, preferably KRAB. In some embodiments, the transcription

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PCT/US2016/038181 repression domain is SID, or concatemers of SID (eg SID4X). In some embodiments, the functional domain is an epigenetic modifying domain, such that an epigenetic modifying enzyme is provided. In some embodiments, the functional domain is an activation domain, which may be the P65 activation domain.

[00912] In some embodiments, the one or more functional domains is an NLS (Nuclear Localization Sequence) or an NES (Nuclear Export Signal), In some embodiments, the one or more functional domains is a transcriptional activation domain comprises VP64, p65, MyoDl, HSF1, RTA, SET7/9 and a histone acetyltransferase. Other references herein to activation (or activator) domains in respect of those associated with the CRISPR enzyme include any known transcriptional activation domain and specifically VP64, p65, MyoDl, HSFi, RTA, SET7/9 or a histone acetyltransferase.

[00913] In some embodiments, the one or more functional domains is a transcriptional repressor domain. In some embodiments, the transcriptional repressor domain is a KRAB domain. In some embodiments, the transcriptional repressor domain is a NuE domain, NcoR domain, SID domain or a SID4X domain.

[00914] In some embodiments, the one or more functional domains have one or more activities comprising methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, RNA cleavage activity, DNA cleavage activity, DNA integration activity or nucleic acid binding activity.

[00915] Histone modifying domains are also preferred in some embodiments. Exemplary histone modifying domains are discussed below. Transposase domains, HR (Homologous Recombination) machinery domains, recombinase domains, and/or integrase domains are also preferred as the present functional domains. In some embodiments, DNA integration activity includes HR machinery domains, integrase domains, recombinase domains and/or transposase domains. Histone acetyltransferases are preferred in some embodiments.

[00916] In some embodiments, the DNA cleavage activity is due to a nuclease. In some embodiments, the nuclease comprises a Fokl nuclease. See, “Dimeric CRISPR RNA-guided Fold nucleases for highly specific genome editing”, Shengdar Q. Tsai, Nicolas Wyvekens, Cyd Khayter, Jennifer A. Foden, Vishal Thapar, Deepak Reyon, Mathew J. Goodwin, Martin J. Aryee, J. Keith Joung Nature Biotechnology 32(6): 569-77 (2014), relates to dimeric RNA267

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PCT/US2016/038181 guided FokI Nucleases that recognize extended sequences and can edit endogenous genes with high efficiencies in human cells.

[00917] In some embodiments, the one or more functional domains is attached to the Cpfl effector protein so that upon binding to the sgRNA and target the functional domain is in a spatial orientation allowing for the functional domain to function in its attributed function. [00918] In some embodiments, the one or more functional domains is attached to the adaptor protein so that upon binding of the Cpfl effector protein to the gRNA and target, the functional domain is in a spatial orientation allowing for the functional domain to function in its attributed function.

[00919] In an aspect the invention provides a composition as herein discussed wherein the one or more functional domains is attached to the Cpfl effector protein or adaptor protein via a linker, optionally a GlySer linker, as discussed herein.

[00920] Endogenous transcriptional repression is often mediated by chromatin modifying enzymes such as histone methyltransferases (HMTs) and deacetylases (HDACs). Repressive histone effector domains are known and an exemplar)/ list is provided below. In the exemplary table, preference was given to proteins and functional truncations of small size to facilitate efficient viral packaging (for instance via AAV). In general, however, the domains may include HDACs, histone methyltransferases (HMTs), and histone acetyltransferase (HAT) inhibitors, as well as HD AC and HMT recruiting proteins. The functional domain may be or include, in some embodiments, HDAC Effector Domains, HDAC Recruiter Effector Domains, Histone Methyltransferase (HMT) Effector Domains, Histone Methyl transferase (HMT) Recruiter Effector Domains, or Histone Acetyltransferase Inhibitor Effector Domains.

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HDAC Effector Domains

Subtype/ Complex	Name	Substrate (If known)	Modification (if known)	Organism	Full size (aa)	Selected truncation (aa)	Final size (aa)	Catalytic domain
HDAC 1	HDACS	-	-	X. laevis	325	1-325	325	1-272: HDAC
HDAC 1	RPD3	-	-	S. cerews/ae	433	19-340	322 (Vannier)	19-331: HDAC
HDAC IV	MessLol	-	*	M. /of/	300	1-300 (Gregorettl)	300	-
HDAC IV	HDAC11			H. sapiens	347	1-347 (Gao)	347	14-326: HDAC
HD2	HDT1	-	-	A. thaliana	245	1-211 (Wu)	211	-
SIRT!	S1RT3	H3K9Ac H4K16AC H3K56Ac		H. sapiens	399	143-399 (Scher)	257	126-382: SIRT
SIRT 1	HST2	-	-	C, albicans	331	1-331 (Hnisz)	331	-
SIRTI	CsbB	-	-	E. coli (K12)	242	1-242 (Landry)	242	-
SIRT 1	HST2	-	-	S. cerevisiae	357	8-298 (Wilson)	291	-
SIRT II!	SSRT5	H4K8AC H4K16AC		H. sapiens	310	37-310 (Gertz)	274	41-309: SIRT
SIRT!!!	Sir2A	-	*	P. falciparum	273	1-273 (Zhu)	273	19-273: SIRT
SIRT IV	SSRT6	H3K9AC H3K56AC		H. sapiens	355	1-289 (Tennen)	289	35-274: SIRT

[00921] Accordingly, the repressor domains of the present invention may be selected from histone methyltransferases (HMTs), histone deaeetylases (HDACs), histone acetyltransferase (HAT) inhibitors, as well as HDAC and HMT recruiting proteins.

[00922] The HDAC domain may be any of those in the table above, namely: HDACS, RPD3, MesoLo4, HDAC11, HDTI, SIRT3, HST2, CobB, HST2, SIRT5, Sir2A, or S1RT6.

[00923] In some embodiment, the functional domain may be a HDAC Recruiter Effector Domain, Preferred examples include those in the Table below, namely MeCP2, MBD2b, Sin3a, NcoR, SALE 1, RCOR1. NcoR is exemplified in the present Examples and, although preferred, it is envisaged that others in the class will also be useful.

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Table of HD AC Recruiter Effector Domains

Subtype/ Complex	Name	Substrate (if known)	Modification (if known)	Organism	Full size (aa)	Selected truncation (aa)	Final size (aa)	Catalytic domain
Sin3a	MeCP2			R. norvegicus	492	207-492 (Nan)	286
Sin3a	MBD2b	-	-	H. sapiens	262	45-262 (Boeke)	218	-
Sin3a	Sm3a			H. sapiens	1273	524-851 (Laherty)	328	627-829: HDAC1 interaction
NcoR	NcoR			H. sapiens	2440	420-488 (Zhang)	69
NuRD	SALL1			M. musculus	1322	1-93 (Lauberth)	93	-
CoREST	RCOR1	-	-	H. sapiens	482	81-300 (Gu, Ouyang)	220	-

[00924] In some embodiment, the functional domain may be a Methyltransferase (HMT)

Effector Domain. Preferred examples include those in the Table below, namely NUE, vSET, EHMT2/G9A, SUV39H1, dim-5, KYP, SUVR4, SET4, SET1, SETD8, and TgSETS. NUE is exemplified in the present Examples and, although preferred, it is envisaged that others in the class will also be useful.

fable of Histone Methyltransferase (HMT) Effector Domains

Subtype/ Complex	Name	Substrat e (if known)	Modification (if known)	Organism	Full size (aa)	Selected truncation (aa)	Final size (aa)	Catalytic domain
SET	NUE	H2B, H3, H4		C. trachomatis	2Ϊ9	1-219 (Pennini)	219	-
SET	vSET	-	H3K27me3	P. bursaria chlorella virus	119	1-119 (Mujtaba)	119	4-112: SET2
SUV39 family	EHMT2 /G9A	H1.4K2, H3K9, H3K27	H3K9me1/2 H1K25me1	M. musculus	1263	969-1263 (Tachibana)	295	1025-1233: preSET, SET, posts ET
SUV39	SUV39 H1		H3K9me2/3	H. sapiens	412	79-412 (Snowden)	334	172-412: preSET, SET, posts ET
Suvar3-9	dim-5	*	H3K9me3	N. crassa	331	1-331 (Rathert)	331	77-331: preSET, SET, postSET
Suvar3-9 (SUVH subfamily)	KYP		H3K9me1/2	A. thaliana	624	335-601	267 (Jackso n)
Suvar3-9 (SUVR subfamily)	SUVR4	H3K9me 1	H3K9me2/3	A. thaiiana	492	180-492	313 (Thorst ensen)	192-462: preSET, SET, postSET
Suvar4-20	SET4		H4K20me3	C. eiegans	288	1-288 (Vielle)	288	-
SETS	SET1	-	H4K20mei	C. eiegans	242	1-242 (Celle)	242	-
SETS	SETD8		H4K20me1	H. sapiens	393	185-393	209 (uouiur e)	256-382: SET
SETS	TgSET		H4K20me1/	T. gondii	1893	1590-1893	304	1749-1884: SET

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| 1 8 1 | 2/3 | J | (Saute!) j	j
[00925] In some embodiment, the functional domain may be a Histone Met	lyltransferase

(HMT) Recruiter Effector Domain. Preferred examples include those in the Table below, namely Hpla, PHF19, andNIPPl.

[00926] Table of Histone Methyltransferase (HMT) Recruiter Effector Domains

Subtype/ Complex	Name	Substrate (if known)	Modification (if known)	Organism	Full size (aa)	Selected truncation (aa)	Final size (aa)	Catalytic domain
-	Hp1a	-	H3K9me3	M. musculus	191	73-191	119 (Hathaway)	121-179: chromoshadow
	PHF19		H3K27me3	H. sapiens	580	(1-250) + GGSG linker + (500-580)	335 (Ballare)	163-250: PHD2
-	NIPP1	-	H3K27me3	H. sapiens	351	1-329 (Jin)	329	310-329: EED

[00927] In some embodiment, the functional domain may be Histone Acetyltransferase

Inhibitor Effector Domain. Preferred examples include SET/TAF-Ιβ listed in the Table below.

[00928] Table of Histone Acetyltransferase Inhibitor Effector Domains

Subtype/ Complex	Name	Substrate (if known)	Modification (if known)	Organism	Full size (aa)	Selected truncation (aa)	Final size (aa)	Catalytic domain
-	SET/TAF-1p	-	-	M. musculus	289	1-289 (Cervoni)	289	-

[00929] It is also preferred to target endogenous (regulatory) control elements (such as enhancers and silencers) in addition to a promoter or promoter-proximal elements. Thus, the invention can also be used to target endogenous control elements (including enhancers and silencers) in addition to targeting of the promoter. These control elements can be located upstream and downstream of the transcriptional start site (TSS), starting from 200bp from the TSS to lOOkb away. Targeting of known control elements can be used to activate or repress the gene of interest. In some cases, a single control element can influence the transcription of multiple target genes. Targeting of a single control element could therefore be used to control the transcription of multiple genes simultaneously.

[00930] Targeting of putative control elements on the other hand (e.g. by tiling the region of the putative control element as well as 200bp up to 1 OOkB around the element) can be used as a means to verify such elements (by measuring the transcription of the gene of interest) or to detect novel control elements (e.g. by tiling lOOkb upstream and downstream of the TSS of the gene of interest). In addition, targeting of putative control elements can be useful in the context of

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PCT/US2016/038181 understanding genetic causes of disease. Many mutations and common SNP variants associated with disease phenotypes are located outside coding regions. Targeting of such regions with either the activation or repression systems described herein can be followed by readout of transcription of either a) a set of putative targets (e.g, a set of genes located in closest proximity to the control element) or b) whole-transcriptome readout by e.g. RNAseq or microarray. This would allow' for the identification of likely candidate genes involved in the disease phenotype. Such candidate genes could be useful as novel drug targets.

[00931] Histone acetyltransferase (HAT) inhibitors are mentioned herein. However, an alternative in some embodiments is for the one or more functional domains to comprise an acetyltransferase, preferably a histone acetyltransferase. These are useful in the field of epigenomics, for example in methods of interrogating the epigenome. Methods of interrogating the epigenome may include, for example, targeting epigenomic sequences. Targeting epigenomic sequences may include the guide being directed to an epigenomic target sequence. Epigenomic target sequence may include, in some embodiments, include a promoter, silencer or an enhancer sequence.

[00932] Use of a functional domain linked to a Cpfl effector protein as described herein, preferably a dead- Cpfl effector protein, more preferably a dead-FnCpfl effector protein, to target epigenomic sequences can be used to activate or repress promoters, silencer or enhancers. [00933] Examples of acetyltransferases are known but may include, in some embodiments, histone acetyltransferases. In some embodiments, the histone acetyltransferase may comprise the catalytic core of the human acetyltransferase p300 (Gerbasch & Reddy, Nature Biotech 6th April 2015).

[00934] In some preferred embodiments, the functional domain is linked to a dead- Cpfl effector protein to target and activate epigenomic sequences such as promoters or enhancers. One or more guides directed to such promoters or enhancers may also be provided to direct the binding of the CRISPR enzyme to such promoters or enhancers.

[00935] The term “associated with” is used here in relation to the association of the functional domain to the Cpfl effector protein or the adaptor protein. It is used in respect of how one molecule ‘associates’ with respect to another, for example between an adaptor protein and a functional domain, or between the Cpfl effector protein and a functional domain. In the case of such protein-protein interactions, this association may be viewed in terms of recognition in the

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PCT/US2016/038181 way an antibody recognizes an epitope. Alternatively, one protein may be associated with another protein via a fusion of the two, for instance one subunit being fused to another subunit. Fusion typically occurs by addition of the amino acid sequence of one to that of the other, for instance via splicing together of the nucleotide sequences that encode each protein or subunit. Alternatively, this may essentially be viewed as binding between two molecules or direct linkage, such as a fusion protein. In any event, the fusion protein may include a linker between the two subunits of interest (i.e. between the enzyme and the functional domain or between the adaptor protein and the functional domain). Thus, in some embodiments, the Cpfl effector protein or adaptor protein is associated with a functional domain by binding thereto. In other embodiments, the Cpfl effector protein or adaptor protein is associated with a functional domain because the two are fused together, optionally via an intermediate linker.

[00936] Attachment of a functional domain or fusion protein can be via a linker, e.g., a flexible glycine-serine (GlyGlyGlySer) or (GGGSfy or a rigid alpha-helical linker such as (Ala(GluAlaAlaAlaLys)Ala). Linkers such as (GGGGS)3 are preferably used herein to separate protein or peptide domains. (GGGGSfy is preferable because it is a relatively long tinker (15 amino acids). The glycine residues are the most flexible and the serine residues enhance the chance that the linker is on the outside of the protein. (GGGGSjc, (GGGGS)q or (GGGGS))₂ may preferably be used as alternatives. Other preferred alternatives are (GGGGS)i, (GGGGS)₂, (GGGGSk (GGGGSk (GGGGS)₇, (GGGGSk (GGGGS)w, or (GGGGS)u. Alternative linkers are available, but highly flexible linkers are thought to work best to allow for maximum opportunity for the 2 parts of the Cpfl to come together and thus reconstitute Cpfl activity. One alternative is that the NLS of nucleoplasmin can be used as a linker. For example, a linker can also be used between the Cpfl and any functional domain. Again, a (GGGGSfy linker may be used here (or the 6, 9, or 12 repeat versions therefore) or the NLS of nucleoplasmin can be used as a linker between Cpfl and the functional domain.

Saturating Mutagenesis [00937] The Cpfl effector protein system(s) described herein can be used to perform saturating or deep scanning mutagenesis of genomic loci in conjunction with a cellular phenotype—for instance, for determining critical minimal features and discrete vulnerabilities of functional elements required for gene expression, drug resistance, and reversal of disease. By saturating or deep scanning mutagenesis is meant that every or essentially every DNA base is cut

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PCT/US2016/038181 within the genomic loci. A library⁷ of Cpfl effector protein guide RNAs may be introduced into a population of cells. The library may be introduced, such that each cell receives a single guide RNA (gRNA). In the case where the library⁷ is introduced by transduction of a viral vector, as described herein, a low multiplicity of infection (MOI) is used. The library may include gRNAs targeting every sequence upstream of a (protospacer adjacent motif) (PAM) sequence in a genomic locus. The library may include at least 100 non-overlapping genomic sequences upstream of a PAM sequence for every⁷ 1000 base pairs within the genomic locus. The library⁷ may include gRNAs targeting sequences upstream of at least one different PAM sequence. The Cpfl effector protein systems may include more than one Cpfl protein. Any Cpfl effector protein as described herein, including orthologues or engineered Cpfl effector proteins that recognize different PAM sequences may be used. The frequency of off target sites for a gRNA may be less than 500. Off target scores may be generated to select gRNAs with the lowest off target sites. Any phenotype determined to be associated with cutting at a gRNA target site may be confirmed by using gRNAs targeting the same site in a single experiment. Validation of a target site may also be performed by using a modified Cpfl effector protein, as described herein, and two gRNAs targeting the genomic site of interest. Not being bound by a theory', a target site is a hue hit if the change in phenotype is observed in validation experiments.

[00938] The genomic loci may include at least one continuous genomic region. The at least one continuous genomic region may comprise up to the entire genome. The at least one continuous genomic region may comprise a functional element of the genome. The functional element may be within a non-coding region, coding gene, intronic region, promoter, or enhancer. The at least one continuous genomic region may comprise at least 1 kb, preferably at least 50 kb of genomic DNA. The at least one continuous genomic region may comprise a transcription factor binding site. The at least one continuous genomic region may comprise a region of DNase I hypersensitivity. The at least one continuous genomic region may comprise a transcription enhancer or repressor element. The at least one continuous genomic region may comprise a site enriched for an epigenetic signature. The at least one continuous genomic DNA region may comprise an epigenetic insulator. The at least one continuous genomic region may comprise two or more continuous genomic regions that physically interact. Genomic regions that interact may be determined by ‘4C technology’. 4C technology allows the screening of the entire genome in an unbiased manner for DNA segments that physically interact with a DNA fragment of choice,

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PCT/US2016/038181 as is described in Zhao et al. ((2006) Nat Genet 38, 1341-7) and in U.S. patent 8,642,295, both incorporated herein by reference in its entirety. The epigenetic signature may be histone acetylation, histone methylation, histone ubiquitination, histone phosphorylation, DNA methylation, or a lack thereof.

[00939] The Cpfl effector protein system(s) for saturating or deep scanning mutagenesis can be used in a population of cells. The Cpfl effector protein system(s) can be used in eukaryotic cells, including but not limited to mammalian and plant cells. The population of cells may be prokaryotic cells. The population of eukaryotic cells may be a population of embryonic stem (ES) cells, neuronal ceils, epithelial cells, immune cells, endocrine cells, muscle cells, erythrocytes, lymphocytes, plant cells, or yeast cells.

[00940] In one aspect, the present invention provides for a method of screening for functional elements associated with a change in a phenotype. The library may be introduced into a population of cells that are adapted to contain a Cpfl effector protein. The cells may be sorted into at least two groups based on the phenotype. The phenotype may be expression of a gene, cell growth, or cell viability. The relative representation of the guide RNAs present in each group are determined, whereby genomic sites associated with the change in phenotype are determined by the representation of guide RNAs present in each group. The change in phenotype may be a change in expression of a gene of interest. The gene of interest may be upregulated, downregulated, or knocked out. The cells may be sorted into a high expression group and a low expression group. The population of cells may include a reporter construct that Is used to determine the phenotype. The reporter construct may include a detectable marker. Cells may be sorted by use of the detectable marker, [00941] In another aspect, the present invention provides for a method of screening for genomic sites associated with resistance to a chemical compound. The chemical compound may be a drug or pesticide. The library may be introduced into a population of cells that are adapted to contain a Cpf l effector protein, wherein each cell of the population contains no more than one guide RNA; the population of cells are treated with the chemical compound; and the representation of guide RNAs are determined after treatment with the chemical compound at a later time point as compared to an early time point, whereby genomic sites associated with resistance to the chemical compound are determined by enrichment of guide RNAs. Representation of gRNAs may be determined by deep sequencing methods.

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PCT/US2016/038181 [00942] Useful In the practice of the instant invention utilizing Cpfl effector protein complexes are methods used in CRISPR-Cas9 systems and reference is made to the article entitled BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Canver, M.C., Smith,E.C., Sher, F., Pinelio, L., Sanjana, N.E., Shalem, 0., Chen, D.D., Schupp, P.G., Vinjamur, D.S., Garcia, S.P., Luc, S., Kurita, R., Nakamura, Fujiwara, Maeda, T., Yuan, G, Zhang, F., Orkin, S.H., & Bauer, D.E. D01:10,1038/naturel5521, published online September 16, 2015, the article is herein incorporated by reference and discussed briefly below: [00943] Canver et al. involves novel pooled CRISPR-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse BCL11A erythroid enhancers previously identified as an enhancer associated with fetal hemoglobin (HbF) level and whose mouse ortholog is necessary for erythroid BCL11A expression. This approach revealed critical minimal features and discrete vulnerabilities of these enhancers. Through editing of primary human progenitors and mouse transgenesis, the authors validated the BCL11A erythroid enhancer as a target for HbF reinduction. The authors generated a detailed enhancer map that informs therapeutic genome editing.

Method of Using Cpfl Systems to Modify a Cell or Oganism [00944] The invention in some embodiments comprehends a method of modifying an cell or organism. The cell may he a prokaryotic cell or a eukaryotic cell. The cell may be a mammalian cell. The mammalian cell many be a non-human primate, bovine, porcine, rodent or mouse cell. The cell may be a non-mammalian eukaryotic cell such as poultry, fish or shrimp. The cell may also be a plant cell. The plant cell may be of a crop plant such as cassava, corn, sorghum, wheat, or rice. The plant cell may also be of an algae, tree or vegetable. The modification introduced to the cell by the present invention may be such that the cell and progeny of the cell are altered for improved production of biologic products such as an antibody, starch, alcohol or other desired cellular output. The modification introduced to the cell by the present invention may be such that the cell and progeny of the cell include an alteration that changes the biologic product produced. [00945] The system may comprise one or more different vectors. In an aspect of the invention, the Cas protein is codon optimized for expression the desired cell type, preferentially a eukaryotic cell, preferably a mammalian cell or a human cell.

[00946] Packaging cells are typically used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and ψ2 cells or PA317 cells,

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PCT/US2016/038181 which package retrovirus. Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAN genes, namely rep and cap, but lacking ITR sequences. The cell line may also be infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV.

Delivery [00947] The invention involves at least one component of the CRISPR complex, e.g., RNA, delivered via at least one nanoparticle complex. In some aspects, the invention provides methods comprising delivering one or more polynucleotides, such as or one or more vectors as described herein, one or more transcripts thereof, and/or one or proteins transcribed therefrom, to a host cell. In some aspects, the invention further provides cells produced by such methods, and animals comprising or produced from such cells. In some embodiments, a CRISPR enzyme in combination with (and optionally complexed with) a guide sequence is delivered to a cell. Conventional viral and non-viral based gene transfer methods can he used to introduce nucleic acids in mammalian cells or target tissues. Such methods can he used to administer nucleic acids encoding components of a CRISPR system to cells in culture, or in a host organism. Non-viral vector delivery⁷ systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery⁷ vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Feigner, TIBTECH 11:211217 (1993); Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon, TIBTECH 11:167-175 (1993), Miller, Nature 357:455-460 (1992); Van Biunt, Biotechnology 6(10):1149-1154 (1988);

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Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995), Kremer & Perricaudet, British Medical Bulletin 51(1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology Doerfler and Bohm (eds) (1995); and Yu et al., Gene Therapy 1:13-26 (1994). [00948] Methods of non-viral delivery of nucleic acids include lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91/17424, WO 91/16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration), [00949] The preparation of lipidmucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Tlier. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994), Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787).

[00950] The use of RNA or DNA viral based systems for the delivery of nucleic acids take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo). Conventional viral based systems could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues.

[00951] The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers.

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Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia vims (GaLV), Simian Immuno deficiency vims (SIV), human immuno deficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992), Johann et al., J. Virol. 66:1635-1640 (1992); Sommnerfelt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol. 65:2220-2224 (1991); PCT/US94/05700).

[00952] In another embodiment, Cocal vesiculovirus envelope pseudotyped retroviral vector particles are contemplated (see, e.g., US Patent Publication No. 20120164118 assigned to the Fred Hutchinson Cancer Research Center). Cocal vims is in the Vesiculovirus genus, and is a causative agent of vesicular stomatitis in mammals. Cocal vims was originally isolated from mites in Trinidad (Jonkers et al., Am. J. Vet. Res. 25:236-242 (1964)), and infections have been identified in Trinidad, Brazil, and Argentina from insects, cattle, and horses. Many of the vesiculoviruses that infect mammals have been isolated from naturally infected arthropods, suggesting that they are vector-borne. Antibodies to vesiculoviruses are common among people living in rural areas where the viruses are endemic and laboratory-acquired; infections in humans usually result in influenza-like symptoms. The Cocal vims envelope glycoprotein shares 71,5% identity at the amino acid level with VSV-G Indiana, and phylogenetic comparison of the envelope gene of vesiculoviruses shows that Cocal virus is serologically distinct from, but most closely related to, VSV-G Indiana strains among the vesiculoviruses. Jonkers et al., Am. J. Vet. Res. 25:236-242 (1964) and Travassos da Rosa et al., Am. J. Tropical Med. & Hygiene 33:9991006 (1984). The Cocal vesiculovirus envelope pseudotyped retroviral vector particles may include for example, lentiviral, alpharetroviral, betaretroviral, gammaretroviral, deltaretroviral, and epsilonretrovirai vector particles that may comprise retroviral Gag, Pol, and/or one or more accessory' protein(s) and a Cocal vesiculovirus envelope protein. Within certain aspects of these embodiments, the Gag, Pol, and accessory/ proteins are lentiviral and/or gammaretroviral.The invention provides AAV that contains or consists essentially of an exogenous nucleic acid molecule encoding a CRISPR system, e.g., a plurality of cassettes comprising or consisting a

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PCT/US2016/038181 first cassette comprising or consisting essentially of a promoter, a nucleic acid molecule encoding a CRISPR-associated (Cas) protein (putative nuclease or helicase proteins), e.g., Cpfl and a terminator, and a two, or more, advantageously up to the packaging size limit of the vector, e.g., in total (including the first cassette) five, cassettes comprising or consisting essentially of a promoter, nucleic acid molecule encoding guide RNA (gRNA) and a terminator (e.g., each cassette schematically represented as Promoter-gRN A1-terminator, Promoter-gRN A2-terminator ... Promoter-gRNA(N)-terminator (where N is a number that can be inserted that is at an upper limit of the packaging size limit of the vector), or two or more individual rAAVs, each containing one or more than one cassette of a CRISPR system, e.g., a first rAAV containing the first cassette comprising or consisting essentially of a promoter, a nucleic acid molecule encoding Cas, e.g,, Cas (Cpfl) and a terminator, and a second rAAV containing a plurality, four, cassettes comprising or consisting essentially of a promoter, nucleic acid molecule encoding guide RNA (gRNA) and a terminator (e.g., each cassette schematically represented as PromotergRNAl-terminator, Promoter-gRNA2-terminator ... Promoter-gRNA(N)-terminator (where N is a number that can be inserted that is at an upper limit of the packaging size limit of the vector). As rAAV is a DNA vims, the nucleic acid molecules in the herein discussion concerning AAV or rAAV are advantageously DNA. The promoter is in some embodiments advantageously human Synapsin I promoter (hSyn). Additional methods for the deliver}' of nucleic acids to cells are known to those skilled in the art. See, for example, US20030087817, incorporated herein by reference.

[00953] In some embodiments, a host cell is transiently or non-transiently transfected with one or more vectors described herein. In some embodiments, a cell is transfected as it naturally occurs in a subject. In some embodiments, a cell that is transfected is taken from a subject. In some embodiments, the cell is derived from cells taken from a subject, such as a cell line. A wide variety of cell lines for tissue culture are known in the art. Examples of cell lines include, but are not limited to, C816I, CCRF-CEM, MOLT, mIMCD-3, NHDF, HeLa-S3, Huhl, Huh4, Huh7, HUVEC, HASMC, HEKn, HEKa, MiaPaCell, Panel, PC-3, TF1, CTLL-2, C1R, Rat6, CV1, RPTE, AIO, T24, J82, A375, ARH-77, Calul, SW480, SW620, SKOV3, SK-UT, CaCo2, P388D1, SEM-K2, WEHI-231, HB56, ΊΊΒ55, Jurkat, J45.01, LRMB, Bcl-1, BC-3, IC21, DLD2, Raw264.7, NRK, NRK-52E, MRC5, MEF, Hep G2, HeLa B, HeLa T4, COS, COS-1, COS-6, COS-M6A, BS-C-1 monkey kidney epithelial, BALE/ 3T3 mouse embryo fibroblast, 3T3 Swiss,

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3T3-L1, 132-d5 human fetal fibroblasts, 10.1 mouse fibroblasts, 293-T, 3T3, 721, 9L, A2780, A2780ADR, A2780eis, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1 cells, BEAS2B, bEnd.3, BHK-21, BR 293, BxPC3, C3H-10T1/2, C6/36, Cal-27, CHO, CHO-7, CHO-IR, CHO-K1, CHO-K2, CHO-T, CHO Dhfr -/-, COR-L23, COR-L23/CPR, COR-L23/5010, CORL23/R23, COS-7, COV-434, CML Tl, CMT, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6/AR1, EMT6/AR10.0, FM3, Hl299, H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, HT-29, Jurkat, JY cells, K562 cells, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel 1-48, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB435, MDCK II, MDCK II, MOR/0.2R, MONO-MAC 6, MTD-IA, MvEnd. NCI-H69/CPR, NCI-H69/LX10, NCI-H69/LX20, NCI-H69/LX4, NIH-3T3, NALM-1, NW-145, OPCN / OPCT cell lines, Peer, PNT-1A/PNT 2, RenCa, RIN-5F, RMA/RMAS, Saos-2 cells, Sf-9, SkBr3, T2, T-47D, T84, THP1 cell line, U373, U87, U937, VCaP, Vero cells, WM39, WT-49, X63, YAC-1, YAR, and transgenic varieties thereof. Cell lines are available from a variety of sources known to those with skill in the art (see, e.g., the American Type Culture Collection (ATCC) (Manassus, Va.)). In some embodiments, a cell transfected with one or more vectors described herein is used to establish a new cell line comprising one or more vector-derived sequences. In some embodiments, a ceil transiently transfected with the components of a CRISPR system as described herein (such as by transient transfection of one or more vectors, or transfection with RNA), and modified through the activity of a CRISPR complex, is used to establish a new cell line comprising cells containing the modification but lacking any other exogenous sequence. In some embodiments, cells transiently or non-transiently transfected with one or more vectors described herein, or cell lines derived from such cells are used in assessing one or more test compounds.

[00954] In some embodiments, one or more vectors described herein are used to produce a non-human transgenic animal or transgenic plant. In some embodiments, the transgenic animal is a mammal, such as a mouse, rat, or rabbit. Methods for producing transgenic animals and plants are known in the art, and generally begin with a method of cell transfection, such as described herein. In another embodiment, a fluid delivery device with an array of needles (see, e.g., US Patent Publication No. 20110230839 assigned to the Fred Hutchinson Cancer Research Center) may be contemplated for delivery of CRISPR Cas to solid tissue. A device of US Patent Publication No. 20110230839 for delivery of a fluid to a solid tissue may comprise a plurality of

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PCT/US2016/038181 needles arranged in an array, a plurality of reservoirs, each in fluid communication with a respective one of the plurality of needles; and a plurality of actuators operatively coupled to respective ones of the plurality of reservoirs and configured to control a fluid pressure within the reservoir. In certain embodiments each of the plurality of actuators may comprise one of a plurality of plungers, a first end of each of the plurality of plungers being received in a respective one of the plurality of reservoirs, and in certain further embodiments the plungers of the plurality of plungers are operatively coupled together at respective second ends so as to be simultaneously depressable. Certain still further embodiments may comprise a plunger driver configured to depress all of the plurality of plungers at a selectively variable rate. In other embodiments each of the plurality of actuators may comprise one of a plurality of fluid transmission lines having first and second ends, a first end of each of the plurality of fluid transmission lines being coupled to a respective one of the plurality of reservoirs. In other embodiments the device may comprise a fluid pressure source, and each of the plurality of actuators comprises a fluid coupling between the fluid pressure source and a respective one of the plurality of reservoirs. In further embodiments the fluid pressure source may comprise at least one of a compressor, a vacuum accumulator, a peristaltic pump, a master cylinder, a microfluidic pump, and a valve. In another embodiment, each of the plurality of needles may comprise a plurality of ports distributed along its length.

[00955] In one aspect, the invention provides for methods of modifying a target polynucleotide in a eukaryotic cell. In some embodiments, the method comprises allowing a nucleic acid-targeting complex to bind to the target polynucleotide to effect cleavage of said target polynucleotide thereby modifying the target polynucleotide, wherein the nucleic acidtargeting complex comprises a nucleic acid-targeting effector protein complexed with a guide RNA hybridized to a target sequence within said target polynucleotide.

[00956] In one aspect, the invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell. In some embodiments, the method comprises allowing a nucleic acid-targeting complex to bind to the polynucleotide such that said binding results in increased or decreased expression of said polynucleotide; wherein the nucleic acid-targeting complex comprises a nucleic acid-targeting effector protein complexed with a guide RNA. hybridized to a target sequence within said polynucleotide.

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PCT/US2016/038181 [00957] CRISPR complex components may be delivered by conjugation or association with transport moieties (adapted for example from approaches disclosed in US Patent Nos. 8,106,022; 8,313,772). Nucleic acid delivery strategies may for example be used to improve delivery of guide RNA, or messenger RNAs or coding DNAs encoding CRISPR complex components. For example, RNAs may incorporate modified RNA nucleotides to improve stability, reduce immunostimulation, and/or improve specificity (see Deleavey, Glen F. et al., 2012, Chemistry & Biology , Volume 19 , Issue 8 , 937 - 954; Zalipsky, 1995, Advanced Drug Delivery Reviews 16: 157-182; Caliceti and Veronese, 2003, Advanced Drug Delivery Reviews 55: 1261-1277). Various constructs have been described that may be used to modify nucleic acids, such as gRNAs, for more efficient delivery, such as reversible charge-neutralizing phosphotriester backbone modifications that may be adapted to modify gRNAs so as to be more hydrophobic and non-anionic, thereby improving cell entry (Meade BR et al., 2014, Nature Biotechnology 32,1256-1261). In further alternative embodiments, selected RNA motifs may be useful for mediating cellular transfection (Magalhaes M., et al., Molecular Therapy (2012); 20 3, 616-624). Similarly, aptamers may be adapted for deliver)/ of CRISPR complex components, for example by appending aptamers to gRNAs (Tan W. et al., 2011, Trends in Biotechnology, December 2011, Vol. 29, No. 12).

[00958] In some embodiments, conjugation of triantennary N-acetyl galactosamine (GalNAc) to oligonucleotide components may be used to improve deliver)/, for example delivery to select cell types, for example hepatocytes (see WO2014118272 incorporated herein by reference; Nair, JK et al., 2014, Journal of the American Chemical Society 136 (49), 16958-16961). This may beis considered to be a sugar-based particle and further details on other particle delivery systems and/or formulations are provided herein. GalNAc can therefore be considered to be a particle in the sense of the other particles described herein, such that general uses and other considerations, for instance deliver)⁷ of said particles, apply to GalNAc particles as well . A solution-phase conjugation strategy may for example be used to attach triantennary GalNAc clusters (mol. wt. ~2000) activated as PFP (pentafluorophenyl) esters onto 5'-hexylamino modified oligonucleotides (5'-HA ASOs, mol. wt. -8000 Da; Ostergaard et al., Bioconjugate Chem., 2015, 26 (8), pp 1451-1455). Similarly, poly(acrylate) polymers have been described for in vivo nucleic acid deliver)/ (see WO2013158141 incorporated herein by reference). In further alternative embodiments, pre-mixing CRISPR nanoparticles (or protein complexes) with

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PCT/US2016/038181 naturally occurring serum proteins may be used in order to improve delivery/ (Akinc A et al, 2010, Molecular Therapy vol. 18 no. 7, 1357-1364).

[00959] Screening techniques are available to identify delivery enhancers, for example byscreening chemical libraries (Gilleron J, et al., 2015, Nucl. Acids Res. 43 (16): 7984-8001), Approaches have also been described for assessing the efficiency of delivery vehicles, such as lipid nanoparticles, which may be employed to identify effective delivery vehicles for CRISPR components (see Sahay G. et al., 2013, Nature Biotechnology 31, 653-658).

[00960] In some embodiments, delivery of protein CRISPR components may be facilitated with the addition of functional peptides to the protein, such as peptides that change protein hydrophobicity, for example so as to improve in vivo functionality. CRISPR component proteins may similarly be modified to facilitate subsequent chemical reactions. For example, amino acids may be added to a protein that have a group that undergoes click chemistry (Nikic I. et al., 2015, Nature Protocols 10,780--791). In embodiments of this kind, the click chemical group may then be used to add a wide variety of alternative structures, such as poly(ethylene glycol) for stability, cell penetrating peptides, RNA aptamers, lipids, or carbohydrates such as GalNAc. In further alternatives, a CRISPR component protein may be modified to adapt the protein for cell entry⁷ (see Svensen et al., 2012, Trends in Pharmacological Sciences, Vol. 33, No. 4), for example by adding cell penetrating peptides to the protein (see Kauffman, W. Berkeley et al., 2015, Trends in Biochemical Sciences , Volume 40 , Issue 12,749 - 764; Koren and Torchilin, 2012, Trends in Molecular Medicine, Vol. 18, No. 7). In further alternative embodiment, patients or subjects may be pre-treated with compounds or formulations that facilitate the later delivery of CRISPR components.

[00961] The Cpfl effector protein system(s) (e.g., single or multiplexed) can be used in conjunction w⁷ith recent advances in crop genomics. The systems described herein can be used to perform efficient and cost effective plant gene or genome interrogation or editing or manipulation—for instance, for rapid investigation and/or selection and/or interrogations and/or comparison and/or manipulations and/or transformation of plant genes or genomes; e.g., to create, identify, develop, optimize, or confer trait(s) or characteristic(s) to plant(s) or to transform a plant genome. There can accordingly be improved production of plants, new⁷ plants with new combinations of traits or characteristics or new⁷ plants with enhanced traits. The Cpfl

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PCT/US2016/038181 effector protein system(s) can be used with regard to plants in Site-Directed Integration (SDI) or Gene Editing (GE) or any Near Reverse Breeding (NRB) or Reverse Breeding (RB) techniques. Aspects of utilizing the herein described Cpfl effector protein systems may be analogous to the use of the CRISPR-Cas (e.g. CRISPR-Cas9) system in plants, and mention is made of the University of Arizona website “CRISPR-PLANT” (http://www.genome.arizona.edu/crispr/) (supported by Penn State and AGI). Emodiments of the invention can be used in genome editing in plants or where RNAi or similar genome editing techniques have been used previously; see, e.g., Nekrasov, “Plant genome editing made easy: targeted mutagenesis in model and crop plants using the CRISPR-Cas system,” Plant Methods 2013, 9:39 (doi:10.1186/1746-4811-9-39); Brooks, “Efficient gene editing in tomato in the first generation using the CRISPR-Cas9 system,” Plant Physiology September 2014 pp 114,247577, Shan, “Targeted genome modification of crop plants using a CRISPR-Cas system,” Nature Biotechnology 31, 686-688 (2013), Feng, “Efficient genome editing in plants using a CRISPR/Cas system,” Cell Research (2013) 23:1229--1232. doi:10.1038/cr.2013.114; published online 20 August 2013; Xie, “RNAguided genome editing in plants using a CRISPR-Cas system,” Mol Plant. 2013 Nov;6(6): 197583. doi: 10.1093/mp/sstll9. Epub 2013 Aug 17; Xu, “Gene targeting using the Agrobacterium tumefaciens-mediated CRISPR-Cas system in rice,” Rice 2014, 7:5 (2014), Zhou et al., “Exploiting SNPs for biallelic CRISPR mutations in the outcrossing woody perennial Populus reveals 4-coumarate: CoA ligase specificity and Redundancy,” New Phytologist (2015) (Forum) 1-4 (available online only at www.newphytoiogist.com); Caliando et al, “Targeted DNA degradation using a CRISPR device stably carried in the host genome, NATURE COMMUNICATIONS 6:6989, DOI: 10.1038/ncomms7989, www.nature.com/naturecommunications DOI: 10.1038/ncomms7989; US Patent No. 6,603,061 Agrobacterium-Mediated Plant Transformation Method; US Patent No. 7,868,149 - Plant Genome Sequences and Uses Thereof and US 2009/0100536 - Transgenic Plants with Enhanced Agronomic Traits, all the contents and disclosure of each of which are herein incorporated by reference in their entirety. In the practice of the invention, the contents and disclosure of Morrell et al “Crop genomics: advances and applications,” Nat Rev Genet. 2011 Dec 29;13(2):85-96; each of which is incorporated by reference herein including as to how herein embodiments may be used as to plants. Accordingly, reference herein to animal cells may also apply, mutatis mutandis, to plant cells unless otherwise apparent, and, the enzymes herein having reduced off285

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PCT/US2016/038181 target effects and systems employing such enzymes can be used in plant applciations, Including those mentioned herein.

Application of Cpfl-CRISPR system to plants and yeast

Definitions:

[00962] In general, the term “plant” relates to any various photosynthetic, eukaryotic, unicellular or multicellular organism of the kingdom Plantae characteristically growing by cell division, containing chloroplasts, and having cell walls comprised of cellulose. The term plant encompasses monocotyledonous and dicotyledonous plants. Specifically, the plants are intended to comprise without limitation angiosperm and gymnosperm plants such as acacia, alfalfa, amaranth, apple, apricot, artichoke, ash tree, asparagus, avocado, banana, barley, beans, beet, birch, beech, blackberry, blueberry, broccoli, Brussel’s sprouts, cabbage, canola, cantaloupe, carrot, cassava, cauliflower, cedar, a cereal, celery, chestnut, cherry, Chinese cabbage, citrus, clementine, clover, coffee, corn, cotton, cowpea, cucumber, cypress, eggplant, elm, endive, eucalyptus, fennel, figs, fir, geranium, grape, grapefruit, groundnuts, ground cherry, gum hemlock, hickory, kale, kiwifruit, kohlrabi, larch, lettuce, leek, lemon, lime, locust, pine, maidenhair, maize, mango, maple, melon, millet, mushroom, mustard, nuts, oak, oats, oil palm, okra, onion, orange, an ornamental plant or flower or tree, papaya, palm, parsley, parsnip, pea, peach, peanut, pear, peat, pepper, persimmon, pigeon pea, pine, pineapple, plantain, plum, pomegranate, potato, pumpkin, radicchio, radish, rapeseed, raspberry⁷, rice, rye, sorghum, safflower, sallow, soybean, spinach, spruce, squash, strawberry⁷, sugar beet, sugarcane, sunflower, sweet potato, sweet corn, tangerine, tea, tobacco, tomato, trees, triticale, turf grasses, turnips, vine, walnut, watercress, watermelon, wheat, yams, yew, and zucchini. The term plant also encompasses Algae, which are mainly photoautotrophs unified primarily by their lack of roots, leaves and other organs that characterize higher plants.

[00963] The methods for genome editing using the Cpfl system as described herein can be used to confer desired traits on essentially any plant. A wide variety of plants and plant cell systems may be engineered for the desired physiological and agronomic characteristics described herein using the nucleic acid constructs of the present disclosure and the various transformation methods mentioned above. In preferred embodiments, target plants and plant cells for engineering include, but are not limited to, those monocotyledonous and dicotyledonous plants, such as crops including grain crops (e.g., wheat, maize, rice, millet, barley), fruit crops (e.g.,

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PCT/US2016/038181 tomato, apple, pear, strawberry, orange), forage crops (e.g., alfalfa), root vegetable crops (e.g., carrot, potato, sugar beets, yam), leafy vegetable crops (e.g., lettuce, spinach); flowering plants (e.g., petunia, rose, chrysanthemum), conifers and pine trees (e.g., pine fir, spruce); plants used in phytoremediation (e.g., heavy metal accumulating plants); oil crops (e.g., sunflower, rape seed) and plants used for experimental purposes (e.g., Arabidopsis). Thus, the methods and CRISPR-Cas systems can be used over a broad range of plants, such as for example with dicotyledonous plants belonging to the orders Magniolales, Illiciales, Laurales, Piperales, Aristochiales, Nymphaeales, Ranunculales, Papeverales, Sarraceniaceae, Trochodendrales, Hamamelidales, Eucomiales, Leitneriales, Myricales, Fagales, Casuarinales, Cary ophyll ales, Batales, Polygon ales, Plumbaginales, Dilleniales, Theales, Malvales, Urucales, Lecythidales, Violaies, Salicales, Capparaies, Erieales, Diapensales, Ebenales, Primulales, Rosales, Fabaies, Podostemales, Haloragales, Myrtales, Cornales, Proteales, San tales, Rafflesiales, Celastrales, Euphorbiales, Rhamnales, Sapindaies, Juglandales, Geraniales, Polygalales, Umbel!ales, Gentianales, Polernoniales, Lamiales, Plantaginales, Scrophulariales, Campanulales, Rubiales, Dipsacales, and Asterales: the methods and CRISPR-Cas systems can be used with monocotyledonous plants such as those belonging to the orders Alismatales, Hvdrochari tales, Najadales, Triuridales, Commeiinales, Eriocaulales, Rationales, Poales, Juncal es, Cyperales, Typhales, Bromeliales, Zingiberales, Arecales, Cyclanthales, Pandanales, Arales, Lilliales, and Orchid ales, or with plants belonging to Gyninosperrnae, e.g those belonging to the orders Finales, Ginkgoales, Cycadales, Araucaria!es, Cupressales and Gnetales.

[00964] The Cpfl CRISPR systems and methods of use described herein can be used over a broad range of plant species, included in the non-limitative list of dicot, monocot or gymnosperm genera hereunder: Aitropa. Alseodaphne, Anacardium, Arachis, Beilschmiedia, Brassica, Carthamus, Cocculus, Croton, Cucumis, Citrus, Citrullus, Capsicum, Catharanthus, Cocos, Coffea, Cucurbita, Daucus, Duguetia, Eschscholzia, Ficus, Fragaria, Glaucium, Glycine, Gossypiurn. Helianthus, Hevea, Hyoscyamus, Lactuca, Landoipluci. Limmt, Litsea, Lycopersicon, Lupinus, Manihot, Majorana, Mains, Medicago, Hicotiana, Olea, Parthenium, Papaver, Persea, Phaseolus, Pisiacia, Pi sum, Pyrus, Prunus, Raphanus, Ricinus, Senecio, Sinomenintn, Stephania, Sinapis, Solatium, Theobroma, Trifolium, Tri gone Ua, Vici a, Vinca. Vilis, and Cigna; and the genera Allium, Andropogon, Aragrostis, Asparagus, Avena, Cynodon, Elaeis, Fesiuca, Festulolium, Heterocallis, Hordeum, Lemna. Lolium, Musa, Oryza, Panicum, Pannesetum,

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Phleunt, Poa, Secale, Sorghum, Triticum, Sea, Abies, Cunninghamia, Ephedra, Picea, Pinus, and Pseudotsuga.

[00965] The Cpfl CRISPR systems and methods of use can also be used over a broad range of algae or algae ceils; including for example algea selected from several eukaryotic phyla, including the Rhodophyta (red algae), Chlorophyta (green algae), Phaeophyta (brown algae), Bacillariophyta (diatoms), Eustigmatophyta. and dinofiagellates as well as the prokaryotic phylum Cyanobacteria (blue-green algae). The term algae includes for example algae selected from : Amphora, Anabaena, Anikstrodesmis, Botryococcus, Chaetoceros, Chlamydomonas, Chlorella, C’hlorococcum, Cyclotella, Cylindrotheca, Dunaliella, Emiliana, Euglena, Heraatococcus, Isochrysis, Monochrysis, Monoraphidium, Nannochloris, Nannnochloropsis, Navicula, Nephrochloris, Nephroselmis, Nitzschia, Nodularia, Nostoc, Oochromonas, Oocystis, Oscillartoria, Pavlova, Phaeodactyium, Playtmonas, Pleurochrysis, Porhyra, Pseudoanabaena, Pyramimonas, Stichococcus, Synechococcus, Synechocystis, Tetraselmis, Thalassiosira, and Triehodesmium.

[00966] A part of a plant, i.e., a plant tissue may be treated according to the methods of the present invention to produce an improved plant. Plant tissue also encompasses plant cells.The term “plant cell” as used herein refers to individual units of a living plant, either in an intact whole plant or in an isolated form grown in in vitro tissue cultures, on media or agar, in suspension in a growth media or buffer or as a part of higher organized unites, such as, for example, plant tissue, a plant organ, or a whole plant.

[00967] A “protoplast” refers to a plant cell that has had its protective cell wall completely or partially removed using, for example, mechanical or enzymatic means resulting in an intact biochemical competent unit of living plant that can reform their cell wall, proliferate and regenerate grow into a whole plant under proper growing conditions, [00968] The term transformation broadly refers to the process by which a plant host is genetically modified by the introduction of DNA by means οΐ Agro bacteria or one of a variety of chemical or physical methods. As used herein, the term plant host refers to plants, including any cells, tissues, organs, or progeny of the plants. Many suitable plant tissues or plant cells can be transformed and include, but are not limited to, protoplasts, somatic embryos, pollen, leaves, seedlings, stems, calli, stolons, microtubers, and shoots. A plant tissue also refers to any clone of

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[00969] The term transformed as used herein, refers to a cell, tissue, organ, or organism into which a foreign DNA molecule, such as a construct, has been introduced. The introduced DNA molecule may be integrated into the genomic DNA of the recipient cell, tissue, organ, or organism such that the introduced DNA molecule is transmitted to the subsequent progeny. In these embodiments, the transformed or “transgenic” cell or plant may also include progeny of the cell or plant and progeny produced from a breeding program employing such a transformed plant as a parent in a cross and exhibiting an altered phenotype resulting from the presence of the introduced DNA molecule. Preferably, the transgenic plant is fertile and capable of transmitting the introduced DNA to progeny through sexual reproduction.

[00970] The term “progeny”, such as the progeny of a transgenic plant, is one that is born of, begotten by, or derived from a plant or the transgenic plant. The introduced DNA molecule may also be transiently introduced into the recipient cell such that the introduced DNA molecule is not inherited by subsequent progeny and thus not considered “transgenic”. Accordingly, as used herein, a “non-transgenic” plant or plant cell is a plant which does not contain a foreign DNA stably integrated into its genome.

[00971] The term “plant promoter” as used herein is a promoter capable of initiating transcription in plant cells, whether or not its origin is a plant cell. Exemplary⁷ suitable plant promoters include, but are not limited to, those that are obtained from plants, plant viruses, and bacteria such as Agrobacterium or Rhizobium which comprise genes expressed in plant cells. [00972] As used herein, a fungal cell refers to any type of eukaryotic cell within the kingdom of fungi. Phyla within the kingdom of fungi include Ascomycota, Basidiomycota, Blastocladiomycota, Chytridiomycota, Glomeromycota, Microsporidia, and Neocallimastigomycota. Fungal cells may include yeasts, molds, and filamentous fungi. In some embodiments, the fungal cell is a yeast cell.

[00973] As used herein, the term yeast cell refers to any fungal cell within the phyla Ascomycota and Basidiomycota. Yeast cells may include budding yeast cells, fission yeast cells, and mold cells. Without being limited to these organisms, many types of yeast used in laboratory and industrial settings are part of the phylum Ascomycota. In some embodiments, the yeast cell is an S. cerervisiae, Kluyveromyces marxianus, or Issatchenkia orientalis cell. Other yeast cells

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PCT/US2016/038181 may include without limitation Candida spp. (e.g., Candida albicans), Yarrowia spp. (e.g., Yarrowia lipolytica), Pichia spp. (e.g., Pichia pastoris), Kluyveromyces spp. (e.g., Kluyveromyces lactis and Kluyveromyces marxianus), Neurospora spp. (e.g., Neurospora crassa), Fusarium spp, (e.g., Fusarium oxysporum), and Issatchenkia spp. (e.g., Issatchenkia orientalis, a.k.a. Pichia kudriavzevii and Candida acidothermophilum). In some embodiments, the fungal cell is a filamentous fungal cell. As used herein, the term filamentous fungal cell refers to any type of fungal cell that grows in filaments, i.e., hyphae or mycelia. Examples of filamentous fungal cells may include without limitation Aspergillus spp. (e.g., Aspergillus niger), Trichoderma spp. (e.g., Trichoderma reesei), Rhizopus spp. (e.g., Rhizopus oryzae), and Mortierella spp. (e.g., Mortierella isabellina).

[00974] In some embodiments, the fungal cell is an industrial strain. As used herein, industrial strain refers to any strain of fungal cell used in or isolated from an industrial process, e.g., production of a product on a commercial or industrial scale. Industrial strain may refer to a fungal species that is typically used in an industrial process, or it may refer to an isolate of a fungal species that may be also used for non-industrial purposes (e.g., laboratory research). Examples of industrial processes may include fermentation (e.g., in production of food or beverage products), distillation, biofuel production, production of a compound, and production of a polypeptide. Examples of industrial strains may include, without limitation, JAY270 and ATCC4124.

[00975] In some embodiments, the fungal cell is a polyploid cell. As used herein, a polyploid cell may refer to any cell whose genome is present in more than one copy. A polyploid cell may refer to a type of cell that is naturally found In a polyploid state, or it may refer to a cell that has been induced to exist in a polyploid state (e.g., through specific regulation, alteration, inactivation, activation, or modification of meiosis, cytokinesis, or DNA replication). A polyploid cell may refer to a cell whose entire genome is polyploid, or it may refer to a cell that is polyploid in a particular genomic locus of interest. Without wishing to be bound to theory, it is thought that the abundance of guideRNA may more often be a rate-limiting component in genome engineering of polyploid cells than in haploid cells, and thus the methods using the Cpfl CRISPRS system described herein may take advantage of using a certain fungal cel l type.

[00976] In some embodiments, the fungal cell is a diploid cell. As used herein, a diploid cell may refer to any cell whose genome Is present In two copies. A diploid cell may refer to a type

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PCT/US2016/038181 of cell that is naturally found in a diploid state, or it may refer to a cell that has been induced to exist in a diploid state (e.g., through specific regulation, alteration, inactivation, activation, or modification of meiosis, cytokinesis, or DNA replication). For example, the S. cerevisiae strain S228C may be maintained in a haploid or diploid state. A diploid cell may refer to a cell whose entire genome is diploid, or it may refer to a cell that is diploid in a particular genomic locus of interest. In some embodiments, the fungal cell is a haploid cell. As used herein, a haploid cell may refer to any cell whose genome is present in one copy. A haploid cell may refer to a type of cell that is naturally found in a haploid state, or it may refer to a cell that has been induced to exist in a haploid state (e.g., through specific regulation, alteration, inactivation, activation, or modification of meiosis, cytokinesis, or DNA replication). For example, the S. cerevisiae strain S228C may be maintained in a haploid or diploid state. A haploid cell may refer to a cell whose entire genome is haploid, or it may refer to a cell that is haploid in a particular genomic locus of interest.

[00977] As used herein, a yeast expression vector refers to a nucleic acid that contains one or more sequences encoding an RNA and/or polypeptide and may further contain any desired elements that control the expression of the nucleic acid(s), as well as any elements that enable the replication and maintenance of the expression vector inside the yeast cell. Many suitable yeast expression vectors and features thereof are known in the art; for example, various vectors and techniques are illustrated in in Yeast Protocols, 2nd edition, Xiao, W., ed. (Humana Press, New York, 2007) and Buckholz, R.G. and Gleeson, M.A. (1991) Biotechnology (NY) 9(11): 1067-72. Yeast vectors may contain, without limitation, a centromeric (CEN) sequence, an autonomous replication sequence (ARS), a promoter, such as an RNA Polymerase III promoter, operably linked to a sequence or gene of interest, a terminator such as an RNA polymerase III terminator, an origin of replication, and a marker gene (e.g., auxotrophic, antibiotic, or other selectable markers). Examples of expression vectors for use in yeast may include plasmids, yeast artificial chromosomes, 2μ plasmids, yeast integrative plasmids, yeast replicative plasmids, shuttle vectors, and episomal plasmids.

Stable integration of Cpfl CRISP system components in the genome of plants and plant cells [00978] In particular embodiments, it is envisaged that the polynucleotides encoding the components of the Cpfl CRISPR system are introduced for stable integration into the genome of a plant cell. In these embodiments, the design of the transformation vector or the expression

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PCT/US2016/038181 system can be adjusted depending on for when, where and under what conditions the guide RNA and/or the Cpfl gene are expressed.

[00979] In particular embodiments, it is envisaged to introduce the components of the Cpfl CRISPR system stably into the genomic DNA of a plant cell. Additionally or alternatively, it is envisaged to introduce the components of the Cpf l CRISPR system for stable integration into the DNA of a. plant organelle such as, but not limited to a plastid, e mitochondrion or a chloroplast. [00980] The expression system for stable integration into the genome of a plant cell may contain one or more of the following elements: a promoter element that can be used to express the RNA and/or Cpfl enzyme in a plant cell; a 5' untranslated region to enhance expression ; an intron element to further enhance expression in certain cells, such as monocot cells; a multiplecloning site to provide convenient restriction sites for inserting the guide RNA and/or the Cpfl gene sequences and other desired elements; and a 3' untranslated region to provide for efficient termination of the expressed transcript, [00981] The elements of the expression system may be on one or more expression constructs which are either circular such as a plasmid or transformation vector, or non-circular such as linear double stranded DNA.

[00982] In a particular embodiment, a Cfpl CRISPR expression system comprises at least:

(a) a nucleotide sequence encoding a guide RNA (gRNA) that hybridizes with a target sequence in a plant, and wherein the guide RNA comprises a guide sequence and a direct repeat sequence, and (b) a nucleotide sequence encoding a Cpfl protein, wherein components (a) or (b) are located on the same or on different constructs, and whereby the different nucleotide sequences can be under control of the same or a different regulatory element operable in a plant cell.

[00983] DNA construct(s) containing the components of the Cpfl CRISPR system, and, where applicable, template sequence may be introduced into the genome of a plant, plant part, or plant cell by a variety of conventional techniques. The process generally comprises the steps of selecting a suitable host cell or host tissue, introducing the construct(s) into the host cell or host tissue, and regenerating plant cells or plants therefrom, [00984] In particular embodiments, the DNA construct may be introduced into the plant cell using techniques such as but not limited to electroporation, microinjection, aerosol beam

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PCT/US2016/038181 injection of plant cell protoplasts, or the DNA constructs can be introduced directly io plant tissue using biolistic methods, such as DNA particle bombardment (see also Fu et al., Transgenic Res. 2000 Feb;9(l):ll-9). The basis of particle bombardment is the acceleration of particles coated with gene/s of interest toward cells, resulting in the penetration of the protoplasm by the particles and typically stable integration into the genome, (see e.g. Klein et al, Nature (1987), Klein et ah, Bio/Technology (1992), Casas et ah, Proc. Nail. Acad. Sci. USA (1993). ).

[00985] In particular embodiments, the DNA constructs containing components of the Cpfl CRISPR system may be introduced into the plant by /4gro6ac/m«»i-mediated transformation. The DNA constructs may be combined with suitable T-DNA flanking regions and introduced into a conventional Agrobacterium tumefaciens host vector. The foreign DNA can be incorporated into the genome of plants by infecting the plants or by incubating plant protoplasts with Agrobacterium bacteria, containing one or more Ti (tumor-inducing) plasmids, (see e.g. Fraley et ah, (1985), Rogers et al., (1987) and U.S. Pat. No. 5,563,055).

[00986] In order to ensure appropriate expression in a plant cell, the components of the Cpfl CRISPR system described herein are typically placed under control of a plant promoter, i.e. a promoter operable in plant cells. The use of different types of promoters is envisaged.

[00987] A constitutive plant promoter is a promoter that is able to express the open reading frame (ORF) that it controls in all or nearly all of the plant tissues during all or nearly all developmental stages of the plant (referred to as constitutive expression”). One non-limiting example of a constitutive promoter is the cauliflower mosaic virus 35S promoter. Regulated promoter refers to promoters that direct gene expression not constitutively, but in a temporallyand/or spatially-regulated manner, and includes tissue-specific, tissue-preferred and inducible promoters. Different promoters may direct the expression of a gene in different tissues or cell types, or at different stages of development, or in response to different environmental conditions. In particular embodiments, one or more of the Cpfl CRISPR components are expressed under the control of a constitutive promoter, such as the cauliflower mosaic virus 35S promoter issuepreferred. promoters can be utilized to target enhanced expression in certain cell types within a particular plant tissue, for instance vascular cells in leaves or roots or in specific cells of the seed. Examples of particular promoters for use in the Cpfl CRISPR system-are found in Kawamata et ab, (1997) Plant Cell Physiol 38:792-803; Yamamoto et ab, (1997) Plant J 12:255-65; Hire et ab

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PCT/US2016/038181 (1992) Plant Mol Biol 20:207-18,Kuster et al, (1995) Plant Mol Biol 29:759-72, and Capana et al., (1994) Plant Mol Biol 25:681 -91.

[00988] Examples of promoters that are inducible and that allow for spatiotemporal control of gene editing or gene expression may use a form of energy. The form of energy may include but is not limited to sound energy, electromagnetic radiation, chemical energy and/or thermal energy. Examples of inducible systems include tetracycline inducible promoters (Tet-On or TetOff), small molecule two-hybrid transcription activations systems (FKBP, ABA, etc), or light inducible systems (Phytochrome, LOV domains, or cryptochrome)., such as a Light Inducible Transcriptional Effector (LITE) that direct changes in transcriptional activity in a sequencespecific manner. The components of a light inducible system may include a Cpfl CRISPR enzyme, a light-responsive cytochrome heterodimer (e.g. from Arabidopsis thaliana), and a transcriptional activation/repression domain. Further examples of inducible DNA binding proteins and methods for their use are provided in LS 61/736465 and US 61/721,283, which is hereby incorporated by reference in its entirety.

[00989] In particular embodiments, transient or inducible expression can be achieved by using, for example, chemical-regulated promotors, i.e. whereby the application of an exogenous chemical induces gene expression. Modulating of gene expression can also be obtained by a chemical-repressible promoter, where application of the chemical represses gene expression. Chemical-inducible promoters include, but are not limited to, the maize ln2-2 promoter, activated by benzene sulfonamide herbicide safeners (De Veyider ei al., (1997) Plant Cell Physiol 38:568-77), the maize GST promoter (GST-11-27, WO93/01294), activated by hydrophobic electrophilic compounds used as pre-emergent herbicides, and the tobacco PR-1 a promoter (Qno et al., (2004) Biosci Biotechnol Biochem 68:803-7) activated by salicylic acid. Promoters which are regulated by antibiotics, such as tetracycline-inducible and tetracyclinerepressible promoters (Gatz et al., (1991 ) Mol Gen Genet 227:229-37; U.S. Patent Nos. 5,814,618 and 5,789,156) can also be used herein.

Translocation to and/or expression in specific plant organelles [00990] The expression system may comprise elements for translocation to and/or expression in a specific plant organelle.

Chloroplast targeting

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PCT/US2016/038181 [00991] In particular embodiments, it is envisaged that the Cpfl CRISPR system is used to specifically modify chloroplast genes or to ensure expression in the chloroplast. For this purpose use is made of chloroplast transformation methods or compartimentalization of the Cpfl CRISPR components to the chloroplast. For instance, the introduction of genetic modifications in the plastid genome can reduce biosafety issues such as gene flow through pollen.

[00992] Methods of chloroplast transformation are known in the art. and include Particle bombardment, PEG treatment, and microinjection. Additionally, methods involving the translocation of transformation cassettes from the nuclear genome to the pastid can be used as described in WO2010061186.

[00993] Alternatively, it is envisaged to target one or more of the Cpfl CRISPR components to the plant chloroplast. This is achieved by incorporating in the expression construct a sequence encoding a chloroplast transit peptide (CTP) or plastid transit peptide, operably linked to the 5’ region of the sequence encoding the Cpfl protein. The CTP is removed in a processing step during translocation into the chloroplast. Chloroplast targeting of expressed proteins is well known to the skilled artisan (see for instance Protein Transport into Chloroplasts, 2010, Annual Review of Plant Biology, Vol. 61: 157-180) . In such embodiments it is also desired to target the guide RNA to the plant chloroplast. Methods and constructs which can be used for translocating guide RNA into the chloroplast by means of a chloroplast localization sequence are described, for instance, in US 20040142476, incorporated herein by reference. Such variations of constructs can be incorporated into the expression systems of the invention to efficiently translocate the Cpfl-guide RNA.

Introduction of polynucleotides encoding the CRISPP-Cpfl system in Algal cells.

[00994] Transgenic algae (or other plants such as rape) may be particularly useful in the production of vegetable oils or biofuels such as alcohols (especially methanol and ethanol) or other products. These may be engineered to express or overexpress high levels of oil or alcohols for use in the oil or biofuel industries.

[00995] US 8945839 describes a method for engineering Micro-Algae (Chlamydomonas reinhardtii cells) species) using Cas9. Using similar tools, the methods of the Cpfl CRISPR system described herein can be applied on Chlamydomonas species and other algae. In particular embodiments, Cpfl and guide RNA are introduced in algae expressed using a vector that expresses Cpfl under the control of a constitutive promoter such as Hsp70A-R.bc S2 or Beta2 295

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PCT/US2016/038181 tubulin. Guide RNA is optionally delivered using a vector containing T7 promoter. Alternatively, Cas9 mRNA and in vitro transcribed guide RNA can be delivered to algal cells. Electroporation protocols are available to the skilled person such as the standard recommended protocol from the GeneArt Chlamydomonas Engineering kit.

[00996] In particular embodiments, the endonuclease used herein is a Split Cpfl enzyme. Split Cpfl enzymes are preferentially used in Algae for targeted genome modification as has been described for Cas9 in WO 2015086795. Use of the Cpfl split system is particularly suitable for an inducible method of genome targeting and avoids the potential toxic effect of the Cpfl overexpression within the algae cell. In particular embodiments, Said Cpfl split domains (RuvC and HNH domains) can be simultaneously or sequentially introduced into the cell such that said split Cpfl domain(s) process the target nucleic acid sequence in the algae cell. The reduced size of the split Cpfl compared to the wild type Cpfl allows other methods of delivery of the CRISPR system to the cells, such as the use of Cell Penetrating Peptides as described herein. This method is of particular interest for generating genetically modified algae.

Introduction of polynucleotides encoding Cpfl components in yeast cells [00997] In particular embodiments, the invention relates to the use of the Cpfl CRISPR system for genome editing of yeast cells. Methods for transforming yeast cells which can be used to introduce polynucleotides encoding the Cpfl CRISPR system components are well known to the artisan and are reviewed by Kawai et al., 2010, Bioeng Bugs. 2010 Nov-Dec; 1(6): 395403). Non-limiting examples include transformation of yeast cells by lithium acetate treatment (which may further include carrier DNA and PEG treatment), bombardment or by electroporation.

Transient expression of Cpfl CRISP system components in plants and plant cell [00998] In particular embodiments, it is envisaged that the guide RNA and/or Cpfl gene are transiently expressed in the plant cell. In these embodiments, the Cpfl CRISPR system can ensure modification of a target gene only when both the guide RNA and the Cpfl protein is present in a cell, such that genomic modification can further be controlled. As the expression of the Cpfl enzyme is transient, plants regenerated from such plant cells typically contain no foreign DNA, In particular embodiments the Cpfl enzyme is stably expressed by the plant cell and the guide sequence is transiently expressed.

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PCT/US2016/038181 [00999] In particular embodiments, the Cpfl CRISPR system components can be introduced in the plant cells using a plant viral vector (Scholthof et al. 1996, Annu Rev Phytopathol. 1996;34:299-323). In further particular embodiments, said viral vector is a vector from a DNA virus. For example, geminivirus (e.g., cabbage leaf curl virus, bean yellow dwarf virus, wheat dwarf virus, tomato leaf curl virus, maize streak vims, tobacco leaf curl vims, or tomato golden mosaic virus) or nanovirus (e.g.. Faba bean necrotic yellow virus). In other particular embodiments, said viral vector is a vector from an RNA virus. For example, tobravirus (e.g., tobacco rattle vims, tobacco mosaic virus), potex virus (e.g., potato vims X), or hordeivirus (e g., barley stripe mosaic virus). The replicating genomes of plant viruses are non-integrative vectors. [001000] In particular embodiments, the vector used for transient expression of Cpfl CRISPR constructs is for instance a. pEAQ vector, which is tailored for Agrobacterium-mediated transient expression (Sainsbury F. et al., Plant Biotechnol J. 2009 Sep;7(7):682-93) in the protoplast. Precise targeting of genomic locations was demonstrated using a modified Cabbage Leaf Curl vims (CaLCuV) vector to express gRNAs in stable transgenic plants expressing a CRISPR enzyme (Scientific Reports 5, Article number: 14926 (2015), doi : .10. i038/srepl 4926).

[001001] In particular embodiments, double-stranded DNA fragments encoding the guide RNA and/or the Cpfl gene can be transiently introduced into the plant cell. In such embodiments, the introduced double-stranded DN A fragments are provided in sufficient quantity to modify the cell but do not persist after a contemplated period of time has passed or after one or more cell divisions. Methods for direct DNA transfer in plants are known by the skilled artisan (see for instance Davey et al. Plant Mol Biol. 1989 Sep; 13(3):273-85.) [001002] In other embodiments, an RNA polynucleotide encoding the Cpflprotein is introduced into the plant cell, which is then translated and processed by the host cell generating the protein in sufficient quantity to modify the cell (in the presence of at least one guide RNA) but which does not persist after a contemplated period of time has passed or after one or more cell divisions. Methods for introducing mRNA to plant protoplasts for transient expression are known by the skilled artisan (see for instance in Gallie, Plant Cell Reports (1993), 13; 119-122). [001003] Combinations of the different methods described above are also envisaged.

Delivery of Cpfl CRISPR components to the plant cell [001004] In particular embodiments, it is of interest to deliver one or more components of the Cpfl CRISPR system directly to the plant cell. This is of interest, inter alia, for the generation of

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PCT/US2016/038181 non-transgenic plants (see below). In particular embodiments, one or more of the Cpfl components is prepared outside the plant or plant cell and delivered to the cell. For instance in particular embodiments, the Cpfl protein is prepared in vitro prior to introduction to the plant cell. Cpfl protein can be prepared by various methods known by one of skill in the art and include recombinant production. After expression, the Cpfl protein is isolated, refolded if needed, purified and optionally treated to remove any purification tags, such as a His-tag. Once crude, partially purified, or more completely purified Cpfl protein is obtained, the protein may be introduced to the plant cell.

[001005] In particular embodiments, the Cpfl protein is mixed with guide RNA targeting the gene of interest to form a pre-assembled ribonucleoprotein.

[001006] The individual components or pre-assembled ribonucleoprotein can be introduced into the plant cell via electroporation, by bombardment with Cpfl-associated gene product coated particles, by chemical transfection or by some other means of transport across a cell membrane. For instance, transfection of a plant protoplast with a pre-assembled CRISPR ribonucleoprotein has been demonstrated to ensure targeted modification of the plant genome (as described by Woo et al. Nature Biotechnology, 2015; DOI; 10.1038Znbt.3389).

[001007] In particular embodiments, the Cpfl CRISPR system components are introduced into the plant cells using nanoparticles. The components, either as protein or nucleic acid or in a combination thereof, can be uploaded onto or packaged in nanoparticles and applied to the plants (such as for instance described in WO 2008042156 and US 20130185823). In particular, embodiments of the invention comprise nanoparticles uploaded with or packed with DNA molecule(s) encoding the Cpfl protein, DNA molecules encoding the guide RNA and/or isolated guide RNA as described in WO2015089419.

[001008] Further means of introducing one or more components of the Cpfl CRISPR system to the plant cell is by using cell penetrating peptides (CPP). Accordingly, in particular, embodiments the invention comprises compositions comprising a cell penetrating peptide linked to the Cpfl protein. In particular embodiments of the present invention, the Cpfl protein and/or guide RNA is coupled to one or more CPPs to effectively transport them inside plant protoplasts; see also Ramakrishna (20140Genome Res. 2014 Jun;24(6); 1020-7 for Cas9 in human cells). In other embodiments, the Cpfl gene and/or guide RNA are encoded by one or more circular or non-circular DNA molecule(s) which are coupled to one or more CPPs for plant protoplast

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PCT/US2016/038181 delivery. The plant protoplasts are then regenerated to plant cells and further to plants. CPPs are generally described as short peptides of fewer than 35 amino acids either derived from proteins or from chimeric sequences which are capable of transporting biomolecules across cell membrane in a receptor independent manner. CPP can be cationic peptides, peptides having hydrophobic sequences, amphipatic peptides, peptides having proline-rich and anti-microbial sequence, and chimeric or bipartite peptides (Pooga and Langel 2005). CPPs are able to penetrate biological membranes and as such trigger the movement of various biomolecules across cell membranes into the cytoplasm and to improve their intracellular routing, and hence facilitate interaction of the biolomolecule with the target. Examples of CPP include amongst others: Tat, a nuclear transcriptional activator protein required for viral replication by HIV typel, penetratin, Kaposi fibroblast growth factor (FGF) signal peptide sequence, integrin β3 signal peptide sequence; polyarginine peptide Args sequence, Guanine rich-molecular transporters, sweet arrow peptide, etc...

[001009] in particular embodiments, the methods described herein are used to modify endogenous genes or to modify their expression without the permanent introduction into the genome of the plant of any foreign gene, including those encoding CRISPR components, so as to avoid the presence of foreign DN A in the genome of the plant. This can be of interest as the regulatory requirements for non-transgenic plants are less rigorous.

[001010] In particular embodiments, this is ensured by transient expression of the Cpfl CRISPR components . In particular embodiments one or more of the CRISPR components are expressed on one or more viral vectors which produce sufficient Cpfl protein and guide RNA to consistently steadily ensure modification of a gene of interest according to a method described herein.

[001011] In particular embodiments, transient expression of Cpfl CRISPR constructs is ensured in plant protoplasts and thus not integrated into the genome. The limited window of expression can be sufficient to allow' the Cpfl CRISPR system to ensure modification of a target gene as described herein.

[001012] In particular embodiments, the different components of the Cpfl CRISPR system are introduced in the plant cell, protoplast or plant tissue either separately or in mixture, with the aid

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PCT/US2016/038181 of pariculate delivering molecules such as nanoparticles or CPP molecules as described herein above.

[001013] The expression of the Cpf l CRISPR components can induce targeted modification of the genome, either by direct activity of the Cpfl nuclease and optionally introduction of template DNA or by modification of genes targeted using the Cpfl CRISPR system as described herein. The different strategies described herein above allow Cpfl-mediated targeted genome editing without requiring the introduction of the Cpfl CRISPR components into the plant genome. Components which are transiently introduced into the plant cell are typically removed upon crossing.

Dcjecu-jg m<:dlilea·sons 07 ;he phn4 gemane·· ^eleesahle marker?:

[001014] in particular embodiments, where the method involves modification of an endogeneous target gene of the plant genome, any suitable method can be used to determine, after the plant, plant part or plant cell is infected or transfected with the Cpfl CRISPR system, whether gene targeting or targeted mutagenesis has occurred at the target site. Where the method involves introduction of a transgene, a transformed plant cell, callus, tissue or plant may be identified and isolated by selecting or screening the engineered plant material for the presence of the transgene or for traits encoded by the transgene. Physical and biochemical methods may be used to identify plant or plant cell transformants containing inserted gene constructs or an endogenous DNA modification. These methods include but are not limited to: 1) Southern analysis or PCR amplification for detecting and determining the structure of the recombinant DNA insert or modified endogenous genes; 2) Northern blot, Si RNase protection, primerextension or reverse transcriptase-PCR amplification for detecting and examining RNA transcripts of the gene constructs; 3) enzymatic assays for detecting enzyme or ribozyme activity, where such gene products are encoded by the gene construct or expression is affected by the genetic modification; 4) protein gel electrophoresis, Western blot techniques, immunoprecipitation, or enzyme-linked immunoassays, where the gene construct or endogenous gene products are proteins. Additional techniques, such as in situ hybridization, enzyme staining, and immunostaining, also may be used to detect the presence or expression of the recombinant construct or detect a modification of endogenous gene in specific plant organs and tissues. The methods for doing all these assays are well known to those skilled in the art.

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PCT/US2016/038181 [001015] Additionally (or alternatively), the expression system encoding the Cpfl CRISPR components is typically designed to comprise one or more selectable or detectable markers that provide a means to isolate or efficiently select cells that contain and/or have been modified by the Cpfl CRISPR system at an early stage and on a large scale.

In the case of Agrobacterium-mediated transformation, the marker cassette may be adjacent to or between flanking T-DNA borders and contained within a binary vector. In another embodiment, the marker cassette may be outside of the T-DNA. A selectable marker cassette may also be within or adjacent to the same T-DNA borders as the expression cassette or may be somewhere else within a second T-DNA on the binary vector (e.g., a 2 T-DNA system).

[001016] For particle bombardment or with protoplast transformation, the expression system can comprise one or more isolated linear fragments or may be part of a larger construct that might contain bacterial replication elements, bacterial selectable markers or other detectable elements. The expression cassette(s) comprising the polynucleotides encoding the guide and/or Cpfl may be physically linked to a marker cassette or may be mixed with a second nucleic acid molecule encoding a marker cassette. The marker cassette is comprised of necessary elements to express a detectable or selectable marker that allows for efficient selection of transformed cells. [001017] The selection procedure for the cells based on the selectable marker will depend on the nature of the marker gene. In particular embodiments, use is made of a selectable marker, i.e. a marker which allows a direct selection of the cells based on the expression of the marker. A selectable marker can confer positive or negative selection and is conditional or non-conditional on the presence of external substrates (Miki et al. 2004, 107(3): 193-232). Most commonly, antibiotic or herbicide resistance genes are used as a marker, whereby selection is be performed by growing the engineered plant material on media containing an inhibitory’ amount of the antibiotic or herbicide to which the marker gene confers resistance. Examples of such genes are genes that confer resistance to antibiotics, such as hygromycin (hpt) and kanamycin (nptll), and genes that confer resistance to herbicides, such as phosphinothricin (bar) and chlorosulfuron [001018] Transformed plants and plant cells may also be identified by screening for the activities of a visible marker, typically an enzyme capable of processing a colored substrate (e.g., the β-glucuronidase, luciferase, B or Cl genes). Such selection and screening methodologies are well known to those skilled in the art.

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Plant cultures and regeneration [001019] In particular embodiments, plant cells which have a modified genome and that are produced or obtained by any of the methods described herein, can be cultured to regenerate a whole plant which possesses the transformed or modified genotype and thus the desired phenotype. Conventional regeneration techniques are well known to those skilled in the art. Particular examples of such regeneration techniques rely on manipulation of certain phytohormones in a tissue culture growth medium, and typically relying on a biocide and/or herbicide marker which lias been introduced together with the desired nucleotide sequences. In further particular embodiments, plant regeneration is obtained from cultured protoplasts, plant callus, explants, organs, pollens, embryos or parts thereof ( see e.g. Evans et al. (1983), Handbook of Plant Cell Culture, Klee et al (1987) Ann. Rev. of Plant Phys.).

[001020] In particular embodiments, transformed or improved plants as described herein can be self-pollinated to provide seed for homozygous improved plants of the invention (homozygous for the DNA modification) or crossed with non-transgenic plants or different improved plants to provide seed for heterozygous plants. Where a recombinant DNA was introduced into the plant cell, the resulting plant of such a crossing is a plant which is heterozygous for the recombinant DNA molecule. Both such homozygous and heterozygous plants obtained by crossing from the improved plants and comprising the genetic modification (which can be a recombinant DNA) are referred to herein as progeny”. Progeny plants are plants descended from the original transgenic plant and containing die genome modification or recombinant DNA molecule introduced by the methods provided herein. Alternatively, genetically modified plants can be obtained by one of the methods described supra using the Cfpl enzyme whereby no foreign DNA is incorporated into the genome. Progeny of such plants, obtained by further breeding may also contain the genetic modification. Breedings are performed by any breeding methods that are commonly used for different crops (e.g., Allard, Principles of Plant Breeding, John Wiley & Sons, NY, U. of CA, Davis, CA, 50-98 (.1960).

Generation of plants with enhanced agronomic traits [001021] The Cpfl based CRISPR systems provided herein can be used to introduce targeted double-strand or single-strand breaks and/or io introduce gene activator and or repressor systems and without being limitative, can be used for gene targeting, gene replacement, targeted mutagenesis, targeted deletions or insertions, targeted inversions and/or targeted translocations.

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By co-expression of multiple targeting RNAs directed to achieve multiple modifications in a single cell, multiplexed genome modification can be ensured. This technology can be used to high-precision engineering of plants with improved characteristics, including enhanced nutritional quality, increased resistance to diseases and resistance to biotic and abiotic stress, and increased production of commercially valuable plant products or heterologous compounds. [001022] In particular embodiments, the Cpfl CRISPR system as described herein is ued to introduce targeted double-strand breaks (DSB) in an endogenous DNA sequence. The DSB activates cellular DNA repair pathways, which can be harnessed io achieve desired DNA sequence modifications near the break site. This is of interest where the inactivation of endogenous genes can confer or contribute to a desired trait. In particular embodiments, homologous recombination with a template sequence is promoted at the site of the DSB, in order to introduce a gene of interest.

[001023] In particular embodiments, the Cpfl CRISPR system may be used as a generic nucleic acid binding protein with fusion to or being operably linked to a functional domain for activation and/or repression of endogenous plant genes. Exemplary functional domains may include but are not limited to translational initiator, translational activator, translational repressor, nucleases, in particular ribonucleases, a spliceosome, beads, a tight inducible/controllable domain or a chemically inducible/controllable domain. Typically in these embodiments, the Cpfl protein comprises at least one mutation, such that it has no more than 5% of the activity of the Cpfl protein not having the at least one mutation; the guide RNA comprises a guide sequence capable of hybridizing to a target sequence.

[001024] The methods described herein generally result in the generation of “improved plants’ in that they have one or more desirable traits compared to the wildtype plant. In particular embodiments, the plants, plant cells or plant parts obtained are transgenic plants, comprising an exogenous DNA sequence incorporated into the genome of all or part of the cells of the plant. In particular embodiments, non-transgenic genetically modified plants, plant parts or cells are obtained, in that no exogenous DNA sequence is incorporated into the genome of any of the plant cells of the plant. In such embodiments, the improved plants are non-transgenic. Where only the modification of an endogenous gene is ensured and no foreign genes are introduced or maintained in the plant genome, the resulting genetically modified crops contain no foreign

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PCT/US2016/038181 genes and can thus basically be considered non-transgenic. The different applications of the Cpfl CRISPR system for plant genome editing are described more in detail below:

a) introduction of one or more foreign genes to confer an agricultural trait of interest [001025] The invention provides methods of genome editing or modifying sequences associated with or at a target locus of interest wherein the method comprises introducing a Cpfl effector protein complex into a plant cell, whereby the Cpfl effector protein complex effectively functions to integrate a DNA insert, e.g. encoding a foreign gene of interest, into the genome of the plant cell. In preferred embodiments the integration of the DNA insert is facilitated by HR with an exogenously introduced DNA template or repair template. Typically, the exogenously introduced DNA template or repair template is delivered together with the Cpfl effector protein complex or one component or a polynucleotide vector for expression of a component of the complex.

The Cpfl CRISPR systems provided herein allow for targeted gene delivery. It has become increasingly clear that the efficiency of expressing a gene of interest is to a great extent determined by the location of integration into the genome. The present methods allow for targeted integration of the foreign gene into a desired location in the genome. The location can he selected based on information of previously generated events or can be selected by methods disclosed elsewhere herein.

[001026] In particular embodiments, the methods provided herein include (a) introducing into the cell a Cpfl CRISPR complex comprising a guide RNA, comprising a direct repeat and a guide sequence, wherein the guide sequence hybrdizes to a target sequence that is endogenous to the plant cell; (b) introducing into the plant cell a Cpfl effector molecule which complexes with the guide RNA when the guide sequence hybridizes to the target sequence and induces a double strand break at or near the sequence to which the guide sequence is targeted; and (c) introducing into the cell a nucleotide sequence encoding an HDR repair template which encodes the gene of interest and which is introduced into the location of the DS break as a result of HDR. In particular embodiments, the step of introducing can include delivering to the plant cell one or more polynculeotides encoding Cpfl effector protein, the guide RNA and the repair template. In particular embodiments, the polynucleotides are delivered into the cell by a DNA virus (e.g,, a geminivirus) or an RNA virus (e.g., a tobravirus). In particular embodiments, the introducing steps include delivering to the plant cell a T-DNA containing one or more polynucleotide

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PCT/US2016/038181 sequences encoding the Cpfl effector protein, the guide RNA and the repair template, where the delivering is via Agrobacterium. The nucleic acid sequence encoding the Cpfl effector protein can be operably linked to a promoter, such as a constitutive promoter (e.g., a cauliflower mosaic virus 35S promoter), or a cell specific or inducible promoter. In particular embodiments, the polynucleotide is introduced by microprojectile bombardment. In particular embodiments, the method further includes screening the plant cell after the introducing steps to determine whether the repair template i.e. the gene of interest has been introduced. In particular embodiments, the methods include the step of regenerating a plant from the plant ceil. In further embodiments, the methods include cross breeding the plant to obtain a genetically desired plant lineage. Examples of foreign genes encoding a trait of interest are listed below.

b) editing of endogenous genes to confer an agricultural trait of interest [001027] The invention provides methods of genome editing or modifying sequences associated with or at a target locus of interest wherein the method comprises introducing a Cpfl effector protein complex into a plant cell, whereby the Cpfl complex modifies the expression of an endogenous gene of the plant. This can be achieved in different ways, In particular embodiments, the elimination of expression of an endogenous gene is desirable and the Cpfl CRISPR complex is used to target and cleave an endogenous gene so as to modify gene expression. In these embodiments, the methods provided herein include (a) introducing into the plant cell a Cpfl CRISPR complex comprising a guide RNA, comprising a direct repeat and a guide sequence, wherein the guide sequence hybrdizes to a target sequence within a gene of interest in the genome of the plant cell; and (b) introducing into the cell a Cpfl effector protein, which upon binding to the guide RNA comprises a guide sequence that is hybridized to the target sequence, ensures a double strand break at or near the sequence to which the guide sequence is targeted, In particular embodiments, the step of introducing can include delivering to the plant cell one or more polynucleotides encoding Cpfl effector protein and the guide RNA.

[001028] In particular embodiments, the polynucleotides are delivered into the cell by a DNA virus (e.g,, a geminivirus) or an RNA virus (e.g., a tobravirus). In particular embodiments, the introducing steps include delivering to the plant cell a T-DNA containing one or more polynucleotide sequences encoding the Cpfl effector protein and the guide RNA, where the delivering is via Agrobacterium. The polynucleotide sequence encoding the components of the Cpfl CRISPR system can be operably linked to a promoter, such as a constitutive promoter

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PCT/US2016/038181 (e.g., a cauliflower mosaic virus 35S promoter), or a cell specific or inducible promoter. In particular embodiments, the polynucleotide is introduced by microprojectile bombardment. In particular embodiments, the method further includes screening the plant cell after the introducing steps to determine whether the expression of the gene of interest has been modified. In particular embodiments, the methods include the step of regenerating a plant from the plant cell. In further embodiments, the methods include cross breeding the plant to obtain a genetically desired plant lineage.

[001029] In particular embodiments of the methods described above, disease resistant crops are obtained by targeted mutation of disease susceptibility genes or genes encoding negative regulators (e.g. Mio gene) of plant defense genes. In a particular embodiment, herbicide-tolerant crops are generated by targeted substitution of specific nucleotides in plant genes such as those encoding acetolactate synthase (ALS) and protoporphyrinogen oxidase (PPO). In particular embodiments drought and salt tolerant crops by targeted mutation of genes encoding negative regulators of abiotic stress tolerance, low amylose grains by targeted mutation of Waxy gene, rice or other grains with reduced rancidity by targeted mutation of major lipase genes in aleurone layer, etc. In particular embodiments. A more extensive list of endogenous genes encoding a traits of interest are listed below.

c) modulating of endogenous genes by the Cpfl CRISPR system to confer an agricultural trait of interest [001030] Also provided herein are methods for modulating (i.e. activating or repressing) endogenous gene expression using the Cpfl protein provided herein. Such methods make use of distinct RNA sequence(s) which are targeted to the plant genome by the Cpfl complex. More particularly the distinct RNA sequence(s) bind to two or more adaptor proteins (e.g. aptamers) whereby each adaptor protein is associated with one or more functional domains and wherein at least one of the one or more functional domains associated with the adaptor protein have one or more activities comprising methylase activity, demethylase activity, transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, DNA integration activity RNA cleavage activity, DNA cleavage activity or nucleic acid binding activity, The functional domains are used to modulate expression of an endogenous plant gene so as to obtain the desired trait. Typically, in these embodiments, the

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Cpfl effector protein has one or more mutations such that it has no more than 5% of the nuclease activity of the Cpfl effector protein not having the at least one mutation.

[001031] In particular embodiments, the methods provided herein include the steps of (a) introducing into the cell a Cpfl CRISPR complex comprising a guide RNA, comprising a direct repeat and a guide sequence, wherein the guide sequence hybrdizes to a target sequence that is endogenous to the plant cell; (b) introducing into the plant cell a Cpfl effector molecule which complexes with the guide RNA when the guide sequence hybridizes to the target sequence; and wherein either the guide RNA is modified to comprise a distinct RNA sequence (aptamer) binding to a functional domain and/or the Cpfl effector protein is modified in that it is linked to a functional domain. In particular embodiments, the step of introducing can include delivering to the plant cell one or more polynucleotides encoding the (modified) Cpfl effector protein and the (modified) guide RNA. The details the components of the Cpfl CRISPR system for use in these methods are described elsewhere herein.

[001032] In particular embodiments, the polynucleotides are delivered into the cell by a DNA virus (e.g., a geminivirus) or an RNA virus (e.g., a tobravirus). In particular embodiments, the introducing steps include delivering to the plant cell a T-DNA containing one or more polynucleotide sequences encoding the Cpfl effector protein and the guide RNA, where the delivering is via Agrobacterium. The nucleic acid sequence encoding the one or more components of the Cpfl CRISPR system can be operably linked to a promoter, such as a constitutive promoter (e.g., a cauliflower mosaic vims 35S promoter), or a cell specific or inducible promoter. In particular embodiments, the polynucleotide is introduced by microprojectile bombardment. In particular embodiments, the method further includes screening the plant cell after the introducing steps to determine whether the expression of the gene of interest has been modified. In particular embodiments, the methods include the step of regenerating a plant from the plant cell. In further embodiments, the methods include cross breeding the plant to obtain a genetically desired plant lineage. A more extensive list of endogenous genes encoding a traits of interest are listed below.

Use of Cpfl to modify polyploid plants [001033] Many plants are polyploid, which means they carry duplicate copies of their genomes—sometimes as many as six, as in wheat. The methods according to the present invention, which make use of the Cpfl CRISPR effector protein can be “multiplexed” to affect

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PCT/US2016/038181 all copies of a gene, or to target dozens of genes at once. For Instance, In particular embodiments, the methods of the present invention are used to simultaneously ensure a loss of function mutation in different genes responsible for suppressing defences against a disease. In particular embodiments, the methods of the present invention are used to simultaneously suppress the expression of the TaMLO-Al, TaMLO-Bl and TaMLO-Dl nucleic acid sequence in a wheat plant cell and regenerating a wheat plant therefrom, in order to ensure that the wheat plant is resistant to powdery mildew (see also WO2015109752).

Examplary genes conferring agronomic traits [001034] As described herein above, in particular embodiments, the invention encompasses the use of the Cpfl CRISPR. system as described herein for the insertion of a DNA of interest, including one or more plant expressible gene(s). In further particular embodiments, the invention encompasses methods and tools using the Cpfl system as described herein for partial or complete deletion of one or more plant expressed gene(s). In other further particular embodiments, the invention encompasses methods and tools using the Cpfl system as described herein to ensure modification of one or more plant-expressed genes by mutation, substitution, insertion of one of more nucleotides. In other particular embodiments, the invention encompasses the use of Cpfl CRISPR system as described herein to ensure modification of expression of one or more plant-expressed genes by specific modification of one or more of the regulatory elements directing expression of said genes.

[001035] In particular embodiments, the invention encompasses methods which involve the introduction of exogenous genes and/or the targeting of endogenous genes and their regulator}' elements, such as listed below:

[001036] 1. Genes that confer resistance to pests or diseases:

• Plant disease resistance genes. A plant can be transformed with cloned resistance genes to engineer plants that are resistant to specific pathogen strains. See, e.g., Jones et al., Science 266:789 (1994) (cloning of the tomato Cf- 9 gene for resistance to Cladosporium fulvunf); Martin et al.. Science 262:1432 (1993) (tomato Pto gene for resistance to Pseudomonas syringae pv. tomato encodes a protein kinase), Mindrinos et al.. Cell 78:1089 (1994) (Arabidopsmay be RSP2 gene for resistance to Pseudomonas syringae).

• Genes conferring resistance to a pest, such as soybean cyst nematode. See e.g., PCT .Application WO 96/30517; PCT .Application WO 93/19181.

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PCT/US2016/038181 • Bacillus thuringi easts proteins see, e.g., Geiser et al., Gene 48:109 (1986).

» Lectins, see, for example, Van Damme et al.. Plant Molec. Biol. 24:25 (1994.

• Vitamin-binding protein, such as avidin, see PCT application US93/06487, teaching the use of avidin and avidin homologues as larvicides against insect pests.

• Enzyme inhibitors such as protease or proteinase inhibitors or amylase inhibitors. See, e.g., Abe et al., I Biol. Chem. 262:16793 (1987), Huub et al., Plant Molec. Biol. 21:985 (1993)), Sumitani et al., Biosci. Biotech. Biochern. 57:1243 (1993) and U.S. Pat. No. 5,494,813.

• Insect-specific hormones or pheromones such as ecdysteroid or juvenile hormone, a variant thereof, a mimetic based thereon, or an antagonist or agonist thereof. See, for example Hammock et al., Nature 344:458 (1990).

® Insect-specific peptides or neuropeptides which, upon expression, disrupts the physiology of the affected pest. For example Regan, J. Biol. Chem. 269:9 (1994) and Pratt et al., Biochern. Biophys. Res, Comm. 163:1243 (1989). See also U.S, Pat. No. 5,266,317, • Insect-specific venom produced in nature by a snake, a wasp, or any other organism. For example, see Pang et ah, Gene 116: 165 (1992).

• Enzymes responsible for a hyperaccumulation of a monoterpene, a sesquiterpene, a steroid, hydroxamic acid, a phenylpropanoid derivative or another nonprotein molecule with insecticidal activity.

• Enzymes involved in the modification, including the post-translational modification, of a biologically active molecule; for example, a glycolytic enzyme, a proteolytic enzyme, a lipolytic enzyme, a nuclease, a cyclase, a transaminase, an esterase, a hydrolase, a phosphatase, a kinase, a phosphorylase, a polymerase, an elastase, a chitinase and a glucanase, whether natural or synthetic. See PCT application WO93/02197, Kramer et al.. Insect Biochern. Molec. Biol. 23:691 (1993) and Kawalleck et ah. Plant Molec. Biol. 21 :673 (1993).

» Molecules that stimulates signal transduction. For example, see Botella et ah, Plant Molec. Biol. 24:757 (1994), and. Griess et ah, Plant Physiol. 104:1467 (1994).

» Viral-invasive proteins or a complex toxin derived therefrom.See Beachy et ah, Ann. rev. Phytopathoh 28:451 (1990).

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PCT/US2016/038181 • Developmental-an/esfive proteins produced in nature by a pathogen or a parasite. See Lamb et al., Bio/Technology 10:1436 (1992) and Toubart et al., Plant J. 2:367 (1992), • A developmental-arrestive protein, produced in nature by a plant. For example, Logeraarm et al., Bio/Technology 10:305 (1992).

• In plants, pathogens are often host-specific. For example, some Fusarium species will causes tomato wilt but attacks only tomato, and other Fusarium species attack only wheat. Plants have existing and induced defenses to resist most pathogens. Mutations and recombination events across plant generations lead to genetic variability that gives rise to susceptibility, especially as pathogens reproduce with more frequency than plants. In plants there can be non-host resistance, e.g., the host and pathogen are incompatible or there can be partial resistance against all races of a pathogen, typically controlled by many genes and/or also complete resistance to some races of a pathogen but not to other races. Such resistance is typically controlled by a few- genes. Using methods and components of the CRISP-cpfl system, a new tool now exists to induce specific mutations in anticipation hereon. Accordingly, one can analyze the genome of sources of resistance genes, and in plants having desired characteristics or traits, use the method and components of the Cpfl CRISPR system to induce the rise of resistance genes. The present systems can do so with more precision than previous mutagenic agents and hence accelerate and improve plant breeding programs.

[001037] 2. Genes involved in plant diseases, such as those listed in WO 2013046247:

• Rice diseases: Magnaporthe grisea, Cochliobolus miyabeanus, Rhizoctonia solani,

Gibberella fujikuroi; Wheat diseases: Erysiphe graminis, Fusarium graminearum, F. avenaceum, F. culmorum, Microdochium nivale, Puceinia striiformis, P. graminis, P. recondita, Micronectriella nivale, Typhula sp., Ustilago tritici, Tilletia caries, Pseudocercosporell a herpotrichoides, Mycosphaerella graminicol a, Stagonospora nodorum, Pyrenophora tritici-repentis;Barley diseases: Erysiphe graminis, Fusarium graminearum, F. avenaceum, F. culmorum, Microdochium nivale, Puceinia striiformis, P. graminis, P. hordei, Ustilago nuda, Rhynchosporium secalis, Pyrenophora teres, Cochliobolus sativus, Pyrenophora graminea, Rhizoctonia solani;Maize diseases: Ustilago maydis, Cochliobolus heterostrophus, Gloeocercospora sorghi, Puceinia polysora, Cercospora zeae-mavdis, Rhizoctonia solani;

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PCT/US2016/038181 • Citrus diseases: Diaporthe citri, Elsinoe fawcetti, Penieillium digitaium, P. italicum, Phytophthora parasitica, Phytophthora citrophthora;Apple diseases: Monilinia mali, Valsa ceratosperma, Podosphaera leucotricha, Alteraaria altemata apple pathotype, Venturia inaequalis, Coiletotrichum acutatum, Phytophtora cactorum;

• Pear diseases: Venturia nashicola, V. pinna, Alteraaria altemata Japanese pear pathotype, Gymnosporangium haraeanum, Phytophtora cactorum;

» Peach diseases: Monilinia fructi cola, Cladosporium carpophilurn, Phomopsis sp., ® Grape diseases: Elsinoe ampelina, Glomerella cingulata, Uninuia necator, Phakopsora ampelopsidis, Guignardia bidweliii, Plasmopara viticola;

® Persimmon diseases: Gloesporium kaki, Cercospora kaki, Mycosphaerela nawae;

• Gourd diseases: Coiletotrichum lagenarium, Sphaerotheca fuliginea, Mycosphaerella meionis, Fusarium oxysporum, Pseudoperonospora cubensis, Phytophthora sp., Pythium sp.;

® Tomato diseases: Alteraaria solani, Cladosporium fulvum, Phytophthora infestans;

• Eggplant diseases: Phomopsis vexans, Erysiphe cichoracearum;

Brassicaceous vegetable diseases: .Alteraaria japonica, Cercosporella brassicae, Plasmodiophora brassicae, Peronospora parasitica;

• Welsh onion diseases: Puccinia allii, Peronospora destructor, • Soybean diseases: Cercospora kikuchii, Elsinoe glycines, Diaporthe phased orum var. sojae, Septoria glycines, Cercospora sojina, Phakopsora pachyrhizi, Phytophthora sojae, Rhizoctonia solani, Corynespora casiicola, Sclerotinia sclerotiorum;

• Kidney bean diseases: Colletrichum lindemthianum;

• Peanut diseases: Cercospora personata, Cercospora arachidicola, Sclerotiurn rolfsii;

» Pea diseases pea: Erysiphe pi si;

» Potato diseases: Alteraaria solani, Phytophthora infestans, Phytophthora erythroseptica, Spongospora subterranean, f. sp. Subterranean;

» Strawberry diseases: Sphaerotheca humuli, Glomerella cingulata;

® Tea diseases: Exobasidium reticulatum, Elsinoe leucospila, Pestalotiopsis sp., Col 1 etotri ch um theae~sin en si s;

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PCT/US2016/038181 • Tobacco diseases: Altemaria longipes, Erysiphe eichoracearum, CoUetotrichum iabacum, Peronospora tabacina, Phytophthora nicotianae;

• Rapeseed diseases: Sclerotinia sclerotiorum, Rhizocionia solani;

» Cotton diseases: Rhizocionia solani;

» Beet diseases: Cercospora beticola, Thanatephorus cucumeris, Thanatephorus cucumeris, Aphanomyces cochiioides;

• Rose diseases: Diplocarpon rosae, Sphaerotheca pannosa, Peronospora sparsa;

• Diseases of chrysanthemum and asteraceae: Bremia lactuca, Septoria chrysanthemiindici, Puccinia horiana;

® Diseases of various plants: Pythiuni aphanidermatum, Pythiuni debarianurn, Pythium graminicola, Pythium irregulars, Pythium uUimum, Botrytis cinerea, Sclerotinia sclerotiorum;

» Radish diseases: Altemaria brassicicola;

® Zoysia diseases: Sclerotinia homeocarpa, Rhizocionia solani;

• Banana diseases: Mycosphaereila fijiensis, Mycosphaerel la musicola;

• Sunflower diseases: Plasmopara halstedii;

• Seed diseases or diseases in the initial stage of growth of various plants caused by Aspergillus spp., Penicillium spp., Fusarium spp., Gibberella spp., Tricoderma spp., Thielaviopsis spp., Rhizopus spp., Mucor spp., Corticiura spp., Rhoma spp., Rhizocionia spp., Diplodia spp., or the like;

• Virus diseases of various plants mediated by Polymixa spp., Olpidiura spp., or the like. [001038] 3. Examples of genes that confer resistance to herbicides:

• Resistance to herbicides that inhibit the growing point or meristem, such as an imidazolinone or a sulfonylurea, for example, by Lee et ah, EMBO E 7:1241 (1988), and Miki etak, Theor. Appl. Genet. 80:449 (1990), respectively.

® Glyphosate tolerance (resistance conferred by, e.g., mutant 5-enolpyruvylshikimate-3phosphate synthase (EPSPs) genes, aroA genes and glyphosate acetyl transferase (GAT) genes, respectively), or resistance Io other phosphono compounds such as by gkrfosinate (phosphinothricin acetyl transferase (PAT) genes from Streptomyces species, including Streptomyces hygroscopicus and Streptomyces viridichromogenes), and to pyridinoxy or o L

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PCT/US2016/038181 phenoxy proprionic acids and cyclohexenes by ACCase inhibitor-encoding genes. See, for example, U.S. Pat. No. 4,940,835 and U.S. Pat. 6,248,876 , U.S. Pat. No. 4,769,061 , EP No. 0 333 033 and U.S. Pat No. 4,975,374. See also EP No. 0242246, DeGreef et al., Bio/Technology 7:61 (1989), Marshall et al., Theor. App], Genet. 83:435 (1992), WO 2005012515 to Castle et. al. and WO 2005107437.

• Resistance to herbicides that inhibit photosynthesis, such as a tri azine (psbA and gs+ genes) or a benzonitrile (nitrilase gene), and. glutathione S-transferase in Przibila et al., Plant Cell 3:169 (.1991), U.S. Pat. No. 4,8.10,648, and Hayes et at, Biochera. J. 285: 173 (1992).

« Genes encoding Enzymes detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition, e.g. n U.S. patent application Ser. No. 11/760,602.

Or a detoxifying enzyme is an enzyme encoding a phosphinothricin acetyl transferase (such as the bar or pat protein from Streptomyces species). Phosphinothricin aeetyltransferases are for example described in U.S. Pat. Nos. 5,561,236; 5,648,477; 5,646,024; 5,273,894, 5,637,489; 5,276,268; 5,739,082, 5,908,810 and 7,112,665.

• Hydroxyphenylpyruvatedioxygenases (HPPD) inhibitors, ie naturally occuring HPPD resistant enzymes, or genes encoding a mutated or chimeric HPPD enzyme as described in WO 96/38567, WO 99/24585, and WO 99/24586, WO 2009/144079, WO 2002/046387, or U.S. Pat. No. 6,768,044.

[001039] 4. Examples of genes involved in Abiotic stress tolerance:

• Transgene capable of reducing the expression and/or the activity of poiy(ADP-ribose) polymerase (PARP) gene in the plant cells or plants as described in WO 00/04173 or, WO/2006/045633.

• Transgenes capable of reducing the expression and/or the activity of the PARG encoding genes of the plants or plants ceils, as described e.g. in WO 2004/090140.

* Transgenes coding for a plant-functional enzyme of the nicotineamide adenine dinucleotide salvage synthesis pathway including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide adenyl transferase, nicotinamide adenine dinucleotide synthetase or nicotine amide phosphorybosyltransferase as described e.g. in EP 04077624.7, WO 2006/133827, PCT/EP07/002,433, EP 1999263, or WO 2007/107326.

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PCT/US2016/038181 • Enzymes involved in carbohydrate biosynthesis include those described in e.g. EP

0571427, WO 95/04826, EP 0719338, WO 96/15248, WO 96/19581, WO 96/27674, WO 97/11188, WO 97/26362, WO 97/32985, WO 97/42328, WO 97/44472, WO 97/45545, WO 98/27212, WO 98/40503, WO99/58688, WO 99/58690, WO 99/58654, WO 00/08184, WO 00/08185, WO 00/08175, WO 00/28052, WO 00/77229, WO 01/12782, WO 01/12826, WO 02/101059, WO 03/071860, WO 2004/056999, WO 2005/030942, WO 2005/030941, WO 2005/095632, WO 2005/095617, WO 2005/095619, WO

2005/095618, WO 2005/123927, WO 2006/018319, WO 2006/103107, WO 2006/108702, WO 2007/009823, WO 00/22140, WO 2006/063862, WO 2006/072603, WO 02/034923, EP 06090134.5, EP 06090228.5, EP 06090227.7, EP 07090007.1, EP 07090009.7, WO 01/14569, WO 02/79410, WO 03/33540, WO 2004/078983, WO 0.1/19975, WO 95/26407, WO 96/34968, WO 98/20145, WO 99/1.2950, WO 99/66050, WO 99/53072, U.S. Pat. No. 6,734,341, WO 00/11192, WO 98/22604, WO 98/32326, WO 01/98509, WO 01/98509, WO 2005/002359, U.S. Pat. No. 5,824,790, U.S. Pat. No. 6,013,861, WO 94/04693, WO 94/09144, WO 94/11520, WO 95/35026 or WO 97/20936 or enzymes involved in the production of polyfructose, especially of the inulin and levantype, as disclosed in EP 0663956, WO 96/01904, WO 96/21023, WO 98/39460, and WO 99/24593, the production of alpha-1,4-glueans as disclosed in WO 95/31553, US 2002031826, U.S. Pat. No. 6,284,479, U.S. Pat. No. 5,712,107, WO 97/47806, WO

97/47807, WO 97/47808 and WO 00/14249, the production of alpha-1,6 branched alpha1, 4-glucans, as disclosed in WO 00/73422, the production of alternan, as disclosed in e.g. WO 00/47727, WO 00/73422, EP 06077301.7, U.S. Pat. No. 5,908,975 and EP 0728213, the production of hyaiuronan, as for example disclosed in WO 2.006/032538, WO 2007/039314, WO 2007/039315, WO 2007/039316, ,1P 2006304779, and WO 2005/012529.

* Genes that improve drought resistance. For example, WO 2013122472 discloses that the absence or reduced level of functional Ubiquitin Protein Ligase protein (UPL) protein, more specifically, UPL3, leads to a decreased need for water or improved resistance to drought of said plant. Other examples of transgenic plants with increased drought tolerance are disclosed in, for example, US 2009/0144850, US 2007/0266453, and WO 2002/083911. US2009/0144850 describes a plant displaying a drought tolerance

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PCT/US2016/038181 phenotype due to altered expression of a DR02 nucleic acid. US 2007/0266453 describes a plant displaying a drought tolerance phenotype due to altered expression of a DR03 nucleic acid and WO 2002/08391 1 describes a plant having an increased tolerance to drought stress due to a reduced activity of an ABC transporter which is expressed in guard cells. Another example is the work by Kasuga and co-authors (1999), who describe that overexpression of cDNA encoding DREBI A in transgenic plants activated the expression of many stress tolerance genes under normal growing conditions and resulted in improved tolerance to drought, salt loading, and freezing. However, the expression of DREB1A also resulted in severe growth retardation under normal growing conditions (Kasuga (1999) Nat Biotechnol 17(3) 287-291).

[001040] In further particular embodiments, crop plants can be Improved by influencing specific plant traits. For example, by developing pesticide-resistant plants, improving disease resistance in plants, improving plant, insect and nematode resistance. Improving plant resistance against parasitic weeds, improving plant drought tolerance, improving plant nutritional value, improving plant stress tolerance, avoiding self-pollination, plant forage digestibility biomass, grain yield etc, A few specific non-limiting examples are provided hereinbelow.

[001041] In addition to targeted mutation of single genes, CpfICRISPR complexes can be designed to allow targeted mutation of multiple genes, deletion of chromosomal fragment, sitespecific integration of transgene, site-directed mutagenesis in vivo, and precise gene replacement or allele swapping in plants. Therefore, the methods described herein have broad applications in gene discovery and. validation, mutational and. cisgenic breeding, and hybrid breeding. These applications facilitate the production of a new generation of genetically modified crops with various improved agronomic traits such as herbicide resistance, disease resistance, abiotic stress tolerance, high yield, and superior quality.

[001042] Hybrid plants typically have advantageous agronomic traits compared to inbred plants. However, for self-pollinating plants, the generation of hybrids can be challenging. In different plant types, genes have been identified which are important for plant fertility, more particularly male fertility. For instance, in maize, at least, two genes have been identified which are important in fertility (Amitabh Mohanty International Conference on New' Plant Breeding Molecular Technologies Technology Development And Regulation, Oct 9-10, 2014, Jaipur,

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India; Svitashev et al. Plant Physiol· 2015 Oct; 169(2):931-45; Djukanovic et al· Plant J. 2013 Dec;76(5):888-99). The methods provided herein can be used to target genes required for male fertility so as to generate male sterile plants which can easily be crossed, to generate hybrids. In particular embodiments, the Cpfl CRISPR system provided herein is used for targeted mutagenesis of the cytochrome P450-like gene (MS26) or the meganuclease gene (MS45) thereby conferring male sterility to the maize plant. Maize plants which are as such genetically altered can be used in hybrid breeding programs.

[001043] In particular embodiments, the methods provided herein are used to prolong the fertility stage of a plant such as of a rice plant. For instance, a rice fertility stage gene such as Ehd3 can be targeted in order to generate a mutation in the gene and plantiets can be selected for a prolonged regeneration plant fertility stage (as described in CN 104004782)

TNej)fOpfHo_generate^enericv^jatioOia^ron^>frnter^ [001044] The availability of wild germpiasm and genetic variations in crop plants is the key to crop improvement programs, but. the available diversity in germpiasms from crop plants is limited. The present invention envisages methods for generating a diversity of genetic variations in a germpiasm of interest. In this application of the Cpfl CRISPR system a library of guide RNAs targeting different locations in the plant genome is provided and is introduced into plant cells together with the Cpfl effector protein. In this way a collection of genome-scale point mutations and gene knock-outs can he generated. In particular embodiments, the methods comprise generating a plant part or plant from the cells so obtained and. screening the cells for a trait of interest. The target genes can include both coding and non-coding regions. In particular embodiments, the trait is stress tolerance and the method is a method for the generation of stresstolerant crop varieties [001045] Ripening is a normal phase in the maturation process of fruits and vegetables. Only a few days after it starts it renders a fruit or vegetable inedible. This process brings significant losses to both farmers and consumers. In particular embodiments, the methods of the present Invention are used to reduce ethylene production. This is ensured by ensuring one or more of the following: a. Suppression of ACC synthase gene expression. ACC (1-aminocyclopropane-1carboxylic acid) synthase is the enzyme responsible for the conversion of S-adenosylraethionine

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PCT/US2016/038181 (SAM) to ACC, the second to the last step In ethylene biosynthesis. Enzyme expression is hindered when an antisense (“mirror-image”) or truncated copy of the synthase gene is inserted into the plant’s genome; b. Insertion of the ACC deaminase gene. The gene coding for the enzyme is obtained from Pseudomonas chlororaphis, a. common nonpathogeuie soil bacterium. It converts ACC to a different compound thereby reducing the amount of ACC available for ethylene production, c. Insertion of the SAM hydrolase gene. This approach is similar to ACC deaminase wherein ethylene production is hindered when the amount of its precursor metabolite is reduced; in this ease SAM is converted to homoserine. The gene coding for the enzyme is obtained from E. coli T3 bacteriophage and d. Suppression of ACC oxidase gene expression. ACC oxidase is the enzyme which catalyzes the oxidation of ACC to ethylene, the last step in the ethylene biosynthetic pathway. Using the methods described herein, down regulation of the ACC oxidase gene results in the suppression of ethylene production, thereby delaying fruit ripening. In particular embodiments, additionally or alternatively to the modifications described above, the methods described herein are used to modify ethylene receptors, so as to interfere with ethylene signals obtained by the fruit. In particular embodiments, expression of the ETR.1 gene, encoding an ethylene binding protein is modified, more particularly suppressed. In particular embodiments, additionally or alternatively to the modifications described above, the methods described herein are used to modify expression of the gene encoding Polygalacturonase (PG), which is the enzyme responsible for the breakdown of pectin, the substance that maintains the integrity of plant ceil walls. Pectin breakdown occurs at the start, of the ripening process resulting in the softening of the fruit. Accordingly, in particular embodiments, the methods described herein are used to introduce a mutation in the PG gene or to suppress activation of the PG gene in order to reduce the amount of PG enzyme produced thereby delaying pectin degradation.

[001046] Thus in particular embodiments, the methods comprise the use of the Cpfl CRISPR system to ensure one or more modifications of the genome of a plant cell such as described above, and regenerating a. plant therefrom. In particular embodiments, the plant is a tomato plant. Increasing storage life of plants [001047] In particular embodiments, the methods of the present invention are used to modify genes involved in the production of compounds which affect storage life of the plant or plant part. More particularly, the modification is in a gene that prevents the accumulation of reducing

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PCT/US2016/038181 sugars in potato tubers. Upon high-temperature processing, these reducing sugars react with free amino acids, resulting in brown, bitter-tasting products and elevated levels of acrylamide, which is a potential carcinogen. In particular embodiments, the methods provided herein are used to reduce or inhibit expression of the vacuolar invertase gene (VInv), which encodes a protein that breaks down sucrose to glucose and fructose (Clasen et al. DOI: 10.1111/pbi. 12370).

The useof the .Cpfl .CRISPR, .system to .enspre a .value .added trait [001048] in particular embodiments the Cpfl CRISPR system is used to produce nutritionally improved agricultural crops. In particular embodiments, the methods provided herein are adapted to generate “functional foods”, i.e. a modified food or food ingredient that may provide a health benefit beyond the traditional nutrients it contains and or “nuiraceutical”, i.e. substances that may he considered a food or part, of a food and provides health benefits, including the prevention and treatment of disease. In particular embodiments, the nutraceutical is useful in the prevention and/or treatment of one or more of cancer, diabetes, cardiovascular disease, and hypertension. [001049] Examples of nutritionally improved crops include (New'ell-McGIoughlin, Plant Physiology, July 2008, Vol. 147, pp. 939-953):

- modified protein quality, content and/or amino acid composition, such as have been described for Bahiagrass (Luciani et al. 2005, Florida Genetics Conference Poster), Canola (Roesler et ah, 1997, Plant Physiol 113 75-81), Maize (Cromwell et al, 1967,

1969 J Anim Sci 26 1325-1331, O’Quin et al. 2000 J Anim Sci 78 2144-2149, Yang et al. 2002, Transgenic Res 11 11-20, Young et al. 2004, Plant J 38 910-922), Potato (Yu J and Ao, 1997 Acta Bot Sin 39 329-334; Chakraborty et al. 2000, Proc Natl Acad Sci USA 97 3724-3729; Li et al. 2001) Chin Sci Bull 46 482-484, Rice (Katsube et al. 1999, Plant Physiol 120 1063-1074), Soybean (Dinkins et al. 2001, Rapp 2002, In Vitro Cell Dev Biol Plant 37 742-747), Sweet Potato (Egnin and Prakash 1997, In Vitro Cell Dev Biol 33 52A),

- essential amino acid content, such as has been described for Canola (Falco et al. 1995, Bio/Technology 13 577-582), Lupin (White et al. 2001, J Sci Food Agric 81 147-154), Maize (Lai and Messing, 2002, Agbios 2008 GM crop database (March 11, 2008)),

Potato (Zeh et al. 2001, Plant Physiol 127 792-802), Sorghum (Zhao et al. 2003, Kluwer Academic Publishers, Dordrecht, The Netherlands, pp 413-416), Soybean (Falco et al. 1995 Bio/Technology 13 577-582; Galili etal. 2002 Crit Rev Plant Sci 21 167-204).

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Oils and Fatty acids such as for Canola (Dehesh et al. (1996) Plant J 9 167-172 [PubMed]; Del Vecchio (1996) INFORM International News on Fats, Oils and Related Materials 7 230-243; Roesler et al. (1997) Plant Physiol 113 75—81 [PMC free article] [PubMed]; I roman and Ursin (2002, 2003) Abstracts of Papers of the American Chemical Society 223 U35; James et al. (2003) Am J Clin Nutr 77 1140-1145 [PubMed]; Agbios (2008, above), coton (Chapman et al. (2001). J Am Oil Chem Soc 78 941-947; Liu et al. (2002) J Am Coll Nutr 21 205S-211S [PubMed]; O'Neill (2007) Australian Life Scientist. http://www.biotechnews.com.au/index.php/id;866694817;fp;4;fpid;2 (June 17, 2008), Linseed (Abbadi et al., 2004, Plant Cell 16: 2734-2748), Maize (Young et al., 2004, Plant J 38 910-922), oil palm (Jalani et al. 1997, J Am Oil Chem Soc 74 1451— 1455; Parveez, 2003, AgBiotechNet 113 1-8), Rice (Anai et al,, 2003, Plant Cell Rep 21 988-992), Soybean (Reddy and Thomas, 1996, Nat Biotechnol 14 639-642; Kinney and Kwolton, 1998, Blackie Academic and Professional, London, pp 193-213), Sunflower (Arcadia, Biosciences 2008)

Carbohydrates, such as Fructans described for Chicory (Smeekens (1997) Trends Plant Sci 2 286-287, Sprenger et al. (1997) FEES Lett 400 355-358, Sevenier et al. (1998) Nat Biotechnol 16 843-846), Maize (Caimi et al. (1996) Plant Physiol 110 355-363), Potato (Hellwege et al. ,1997 Plant J 12 1057-1065), Sugar Beet (Smeekens et al. 1997, above), Inulin, such as described for Potato (Hellewege et al. 2000, Proc Natl Acad Sci USA 97 8699-8704), Starch, such as described for Rice (Schwall et al. (2000) Nat Biotechnol 18 551-554, Chiang et al. (2005) Mol Breed 15 125-143),

Vitamins and carotenoids, such as described for Canola (Shintani and DellaPenna (1998) Science 282 2098-2100), Maize (Rocheford et al. (2002) . J Am Coll Nutr 21 191S198S, Cahoon et al. (2003) Nat Biotechnol 21 1082-1087, Chen et al. (2003) Proc Natl Acad Sci USA 100 3525-3530), Mustardseed (Shewmaker et al. (1999) Plant J 20 401412, Potato (Ducreux et al., 2005, J Exp Bot 56 81-89), Rice (Ye et al. (2000) Science 287 303-305, Strawberry (Agius et al. (2003), Nat Biotechnol 21 177-181), Tomato (Rosati et al. (2000) Plant J 24 413-419, Fraser et al. (2001) J Sci Food Agric 81 822827, Mehta et al. (2002) Nat Biotechnol 20 613-618, Diaz de la Garza et al. (2004) Proc Natl Acad Sci USA 101 13720-13725, Enfissi et al. (2005) Plant Biotechnol J 3 17-27, DellaPenna (2007) Proc Natl Acad Sci USA 104 3675-3676.

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- Functional secondary metabolites, such as described for Apple (stilbenes, Szankowski et al. (2003) Plant Cell Rep 22: 141-149), Alfalfa (resveratrol, Hipskind and Paiva (2000) Mol Plant Microbe Interact 13 551--562), Kiwi (resveratrol, Kobayashi et al. (2000) Plant Cell Rep 19 904-910), Maize and Soybean (flavonoids, Yu et al. (2000) Plant Physiol 124 781--794), Potato (anthocyanin and alkaloid glycoside, Lukaszewicz et al. (2004) J Agric Food Chem 52 1526-1533), Rice (flavonoids & resveratrol, Stark-Lorenzen et al. (1997) Plant Cell Rep 16 668-673, Shin et al. (2006) Plant Biotechnol J 4 303-315), Tomato (+resveratrol, chlorogenic acid, flavonoids, stilbene; Rosati et al. (2000) above, Muir et al. (2001) Nature 19 470-474, Niggeweg et ak (2004) Nat Biotechnol 22 746-754, Giovinazzo et al. (2005) Plant Biotechnol J 3 57-69), wheat (caffeic and ferulic acids, resveratrol; United Press International (2002)); and

- Mineral availabilities such as described for Alfalfa (phytase, Austin-Phillips et al, (1999) http://www.molecularfarming.com/nonmedical.html), Lettuse (iron, Goto et al. (2000) Theor Appl Genet 100 658-664), Rice (iron, Lucca et al. (2002) J Am Coll Nutr 21 184S-190S), Maize, Soybean and wheate (phytase, Drakakaki et al. (2005) Plant Mol Biol 59 869-880, Denbow et al. (1998) Poult Sci 77 878-881, Brinch-Pedersen et al. (2000) Mol Breed 6 195-206).

[001050] In particular embodiments, the value-added trait is related to the envisaged health benefits of the compounds present in the plant. For instance, in particular embodiments, the value-added crop is obtained by applying the methods of the invention to ensure the modification of or induce/increase the synthesis of one or more of the following compounds:

- Carotenoids, such as α-Carotene present in carrots which Neutralizes free radicals that may cause damage to cells or β-Carotene present in various fruits and vegetables which neutralizes free radicals

- Lutein present in green vegetables which contributes to maintenance of healthy vision

- Lycopene present in tomato and tomato products, which is believed to reduce the risk of prostate cancer

- Zeaxanthin, present in citrus and maize, which contributes to mainteance of healthy vision

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Dietary fiber such as insoluble fiber present in wheat bran which may reduce the risk of breast and/or colon cancer and β-Glucan present in oat, soluble fiber present in Psylium and whole cereal grains which may reduce the risk of cardiovascular disease (CVD)

Fatty acids, such as ω-3 fatty acids which may reduce the risk of CAT) and improve mental and visual functions, Conjugated Linoleic acid, which may improve body composition, may decrease risk of certain cancers and GLA which may reduce inflammation risk of cancer and CVD, may improve body composition

Flavonoids such as Hydroxycinnamates, present in wheat which have Antioxidant-like activities, may reduce risk of degenerative diseases, flavonols, catechins and tannins present in fruits and vegetables which neutralize free radicals and may reduce risk of cancer

Glucosinolat.es, indoles, isothiocyanates, such as Sulforaphane, present in Cruciferous vegetables (broccoli, kale), horseradish, which neutralize free radicals, may reduce risk of cancer

Phenolics, such as stilbenes present in grape which May reduce risk of degenerative diseases, heart disease, and cancer, may have longevity effect and caffeic acid and ferulic acid present in vegetables and citrus which have Antioxidant-like activities, may reduce risk of degenerative diseases, heart disease, and eye disease, and epicatechin present in cacao which has Antioxidant-like activities, may reduce risk of degenerative diseases and heart di sease

Plant stanols/sterols present in maize, soy, wheat and wooden oils which May reduce risk of coronary heart disease by lowering blood cholesterol levels

Fructans, inulins, fructo-oligosaccharides present in Jerusalem artichoke, shallot, onion powder which may improve gastrointestinal health Saponins present in soybean, which may lower LDL cholesterol Soybean protein present in soybean which may reduce risk of heart disease Phytoestrogens such as isofiavones present in soybean which May reduce menopause symptoms, such as hot flashes, may reduce osteoporosis and CAT) and lignans present in flax, rye and vegetables, which May protect against heart disease and some cancers, may lower LDL cholesterol, total cholesterol.

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- Sulfides and thiols such as diallyl sulphide present in onion, garlic, olive, leek and scallon and Ally] methyl trisulfide, di thiol thrones present in cruciferous vegetables which may lower LDL cholesterol, helps to maintain healthy immune system

- Tannins, such as proanthocyanidins, present in cranberry, cocoa, which may improve urinary' tract health, may reduce risk of CVD and high blood pressure

- Etc.

[001051] In addition, the methods of the present invention also envisage modifying protein/starch functionality, shelf life, taste/aesthetics, fiber quality, and allergen, antinutrient, and toxin reduction traits.

[001052] Accordingly, the invention encompasses methods for producing plants with nutritional added value, said methods comprising introducing into a plant cell a gene encoding an enzyme involved in the production of a component of added nutritional value using the Cpfl CRISPR system as described herein and regenerating a plant from said plant cell, said plant characterized in an increase expression of said component of added nutritional value. In particular embodiments, the Cpfl CRISPR system is used to modify the endogenous synthesis of these compounds indirectly, e.g. by modifying one or more transcription factors that controls the metabolism of this compound. Methods for introducing a gene of interest into a plant cell and/or modifying an endogenous gene using the Cpfl CRISPR system are described herein above. [001053] Some specific examples of modifications in plants that have been modified to confer value-added traits are: plants with modified fatty acid metabolism, for example, by transforming a plant with an antisense gene of stearyl-ACP desaturase to increase stearic acid content of the plant. See Knultzon et al., Proc. Natl. Acad. Sci. U.S.A. 89:2624 (1992). Another example involves decreasing phytate content, for example by cloning and then reintroducing DNA associated with the single allele which may be responsible for maize mutants characterized by low levels of phytic acid. See Raboy et al, Maydica 35:383 (1990).

[001054] Similarly, expression of the maize (Zea mays) Tfs Cl and R, which regulate the production of flavonoids in maize aleurone layers under the control of a strong promoter, resulted in a high accumulation rate of anthocyanins in Arabidopsis (Arabidopsis thaliana), presumably by activating the entire pathway (Bruce et al., 2000, Plant Cell 12:65--80). DellaPenna (Welsch et al., 2007 Annu Rev Plant Biol 57: 711--738) found that Tf RAP2.2 and its interacting partner SINAT2 increased carotenogenesis in Arabidopsis leaves. Expressing the Tf

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Dofl induced the up-regulation of genes encoding enzymes for carbon skeleton production, a marked increase of amino acid content, and a reduction of the Glc level in transgenic Arabidopsis (Yanagisawa, 2004 Plant Cell Physiol 45: 386-391), and the DOF Tf AtDofl.l (OBP2) up-regulated all steps in the glucosinoiate biosynthetic pathway in Arabidopsis (Skirycz et al., 2006 Plant J 47: 10-24).

Reducing allergen in plants [001055] In particular embodiments the methods provided herein are used to generate plants with a reduced level of allergens, making them safer for the consumer. In particular embodiments, the methods comprise modifying expression of one or more genes responsible for the production of plant allergens. For instance, in particular embodiments, the methods comprise down-regulating expression of a Lol p5 gene in a plant cell, such as a ryegrass plant cell and regenerating a plant therefrom so as to reduce allergenicity of the pollen of said plant (Bhalla et al. 1999, Proc, Natl. Acad. Sci. USA Vol. 96: 11676-11680).

[001056] Peanut allergies and allergies to legumes generally are a real and serious health concern. The Cpfl effector protein system of the present invention can be used to identify and then edit or silence genes encoding allergenic proteins of such legumes. Without limitation as to such genes and proteins, Nicolaou et al. identifies allergenic proteins in peanuts, soybeans, lentils, peas, lupin, green beans, and mung beans. See, Nicolaou et al., Current Opinion in Allergy and Clinical Immunology 2011; 11 (3):222).

Screening methods for endogenous genes of interest [001057] The methods provided herein further allow the identification of genes of value encoding enzymes involved in the production of a component of added nutritional value or generally genes affecting agronomic traits of interest, across species, phyla, and plant kingdom. By selectively targeting e.g. genes encoding enzymes of metabolic pathways in plants using the Cpfl CRISPR. system as described herein, the genes responsible for certain nutritional aspects of a plant can be identified. Similarly, by selectively targeting genes which may affect a desirable agronomic trait, the relevant genes can be identified. Accordingly, the present invention encompasses screening methods for genes encoding enzymes involved in the production of compounds with a particular nutritional value and/or agronomic traits.

Further applications of the Cpfl CRISPR system in plants and yeasts

Use of Cpfl CRISPR system in biofuel production

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PCT/US2016/038181 [001058] The term “biofuel” as used herein is an alternative fuel made from plant and plantderived resources. Renewable biofuels can be extracted from organic matter whose energy has been obtained through a process of carbon fixation or are made through the use or conversion of biomass. This biomass can be used directly for biofuels or can be converted to convenient energy containing substances by thermal conversion, chemical conversion, and biochemical conversion. This biomass conversion can result in fuel in solid, liquid, or gas form. There are two types of biofuels: bioethanol and biodiesel. Bioethanol is mainly produced by the sugar fermentation process of cellulose (starch), which is mostly derived from maize and sugar cane. Biodiesel on the other hand is mainly produced from oil crops such as rapeseed, palm, and soybean. Biofuels are used mainly for transportation.

Enhancing plant properties for biofuel production [001059] In particular embodiments, the methods using the Cpfl CRISPR system as described herein are used to alter the properties of the cell wall in order to facilitate access by key hydrolysing agents for a more efficient release of sugars for fermentation. In particular embodiments, the biosynthesis of cellulose and/or lignin are modified. Cellulose is the major component of the cell wall. The biosynthesis of cellulose and lignin are co-regulated. By reducing the proportion of lignin in a plant the proportion of cellulose can be increased. In particular embodiments, the methods described herein are used to downregulate lignin biosynthesis in the plant so as to increase fermentable carbohydrates. More particularly, the methods described herein are used to downregulate at least a first lignin biosynthesis gene selected from the group consisting of 4-coumarate 3-hydroxylase (C3H), phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxyiase (C4H), hydroxycinnamoyl transferase (HCT), caffeic acid O-methyltransferase (COMT), caffeoyl CoA 3-O-methyltransferase (CCoAOMT), ferulate 5- hydroxylase (F5H), cinnamyl alcohol dehydrogenase (CAD), cinnamoyl CoAreductase (CCR), 4- coumarate-CoA ligase (4CL), monolignol-lignin-specific glycosyltransferase, and aldehyde dehydrogenase (ALDH) as disclosed in WO 2008064289 A2. [001060] In particular embodiments, the methods described herein are used to produce plant mass that produces lower levels of acetic acid during fermentation (see also WO 2010096488). More particularly, the methods disclosed herein are used to generate mutations in homologs to CaslL to reduce polysaccharide acetylation.

Modifying yeast for Biofuel production

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PCT/US2016/038181 [001061] In particular embodiments, the Cpfl enzyme provided herein is used for bioethanol production by recombinant micro-organisms. For instance, Cpfl can be used to engineer microorganisms, such as yeast, to generate biofuel or biopolymers from fermentable sugars and optionally to be able to degrade plant-derived lignocellulose derived from agricultural waste as a source of fermentable sugars. More particularly, the invention provides methods whereby the Cpfl CRISPR complex is used to introduce foreign genes required for biofuel production into micro-organisms and/or to modify endogenous genes why may interfere with the biofuel synthesis. More particularly the methods involve introducing into a micro-organism such as a yeast one or more nucleotide sequence encoding enzymes involved in the conversion of pyruvate to ethanol or another product of interest. In particular embodiments the methods ensure the introduction of one or more enzymes which allows the micro-organism to degrade cellulose, such as a cellulase. In yet further embodiments, the Cpfl CRISPR complex is used to modify endogenous metabolic pathways which compete with the biofuel production pathway, [001062] Accordingly, in more particular embodiments, the methods described herein are used to modify a micro-organism as follows:

[001063] to introduce at least one heterologous nucleic acid or increase expression of at least one endogenous nucleic acid encoding a plant cell wall degrading enzyme, such that said micro-organism is capable of expressing said nucleic acid and of producing and secreting said plant cell wall degrading enzyme;

[001064] to introduce at least one heterologous nucleic acid or increase expression of at least one endogenous nucleic acid encoding an enzyme that converts pyruvate to acetaldehyde optionally combined with at least one heterologous nucleic acid encoding an enzyme that converts acetaldehyde to ethanol such that said host cell is capable of expressing said nucleic acid; and/or [001065] to modify at least one nucleic acid encoding for an enzyme in a metabolic pathway in said host cell, wherein said pathway produces a metabolite other than acetaldehyde from pyruvate or ethanol from acetaldehyde, and wherein said modification results in a reduced production of said metabolite, or to introduce at least one nucleic acid encoding for an inhibitor of said enzyme.

Modifying Algae and plants for production of vegetable oils or biofuels

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PCT/US2016/038181 [001066] Transgenic algae or other plants such as rape may be particularly useful in the production of vegetable oils or biofuels such as alcohols (especially methanol and ethanol), for instance. These may be engineered to express or overexpress high levels of oil or alcohols for use in the oil or biofuel industries.

[001067] According to particular embodiments of the invention, the Cpfl CRISPR system is used to generate lipid-rich diatoms which are useful in biofuel production.

[001068] In particular embodiments it is envisaged to specifically modify genes that are involved in the modification of the quantity of lipids and/or the quality of the lipids produced by the algal cell. Examples of genes encoding enzymes involved in the pathways of fatty acid synthesis can encode proteins having for instance acetyl-CoA carboxylase, fatty acid synthase, 3ketoacyl_acyl- carrier protein synthase III, glycerol-3-phospate deshydrogena.se (G3PDH), Enoyl-acyl carrier protein reductase (Enoyl-ACP-reductase), glycerol-3-phosphate acyltransfera.se, lysophosphatidic acyl transferase or dl acyl glycerol acyltransferase, phospholipid: diacyl glycerol acyltransferase, phoshatidate phosphatase, fatty acid thioesterase such as palmitoyi protein thioesterase, or malic enzyme activities. In further embodiments it is envisaged to generate diatoms that have increased lipid accumulation. This can be achieved by targeting genes that decrease lipid catabolisation. Of particular interest for use in the methods of the present invention are genes involved in the activation of both triacylglycerol and free fatty acids, as well as genes directly involved in β-oxidation of fatty acids, such as acyl-CoA synthetase, 3-ketoacyl-CoA thiolase, acyl-CoA oxidase activity and phosphoglucomutase. The Cpfl CRISPR system and methods described herein can be used to specifically activate such genes in diatoms as to increase their lipid content, [001069] Organisms such as microalgae are widely used for synthetic biology. Stovicek et al. (Metab. Eng. Comm., 2015; 2:13 describes genome editing of industrial yeast, for example, Saccharomyces cerevisae, to efficiently produce robust strains for industrial production. Stovicek used a CRISPR-Cas9 system codon-optimized for yeast to simultaneously disrupt both alleles of an endogenous gene and knock in a heterologous gene. Cas9 and gRNA were expressed from genomic or episomal 2p-based vector locations. The authors also showed that gene disruption efficiency could he improved by optimization of the levels of Cas9 and gRNA expression. Hlavova et al. (Biotechnol. Adv. 2015) discusses development of species or strains of microalgae using techniques such as CRISPR to target nuclear and chloroplast genes for insertional

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PCT/US2016/038181 mutagenesis and screening. The methods of Stovicek and Hlavova may be applied to the Cpfl effector protein system of the present invention.

[001070] US 8945839 describes a method for engineering Micro-Algae (Chlamydomonas reinhardtii cells) species) using Cas9 , Using similar tools, the methods of the Cpfl CRISPR system described herein can be applied on Chlamydomonas species and other algae. In particular embodiments, Cpfl and guide RNA are introduced in algae expressed using a vector that expresses Cpfl under the control of a constitutive promoter such as Hsp7QA-Rbc S2 or Beta2 tubulin. Guide RNA will be delivered using a vector containing T7 promoter. Alternatively, Cpfl mRNA and in vitro transcribed guide RNA can be delivered to algal cells. Electroporation protocol follows standard recommended protocol from the Gene Art Chlamydomonas Engineering kit.

The use of Cpfl in the generation of micro-organisms capable of fatty acid production [001071 ] In particular embodiments, the methods of the invention are used for the generation of genetically engineered micro-organisms capable of the production of fatty esters, such as fatty acid methyl esters (FAME) and fatty acid ethyl esters (FAEE), [001072] Typically, host cells can be engineered to produce fatty esters from a carbon source, such as an alcohol, present in the medium, by expression or overexpression of a gene encoding a thioesterase, a gene encoding an acyl-CoA synthase, and a gene encoding an ester synthase. Accordingly, the methods provided herein are used to modify a micro-organisms so as to overexpress or introduce a thioesterase gene, a gene encloding an acyl-CoA synthase, and a gene encoding an ester synthase. In particular embodiments, the thioesterase gene is selected from tesA, 'tesA, tesB,fatB, fatB2,fatB3,fat.Al, or fatA. In particular embodiments, the gene encoding an acyl-CoA synthase is selected from fadDJadK, BH3103, pfl-4354, EAV15023, fadDl, fadD2, RPC 4074,fadDD35, fadDD22, faa39, or an identified gene encoding an enzyme having the same properties. In particular embodiments, the gene encoding an ester synthase is a gene encoding a synthase/acyl-CoA:diacylglycerl acyl transferase from Simmondsia ehinensis, Acinetobacter sp. ADP , Alcanivorax borkumensis, Pseudomonas aeruginosa, Fundibacter jadensis, Arabidopsis thaliana, or Alkaligenes eutrophus, or a variant thereof. Additionally or alternatively, the methods provided herein are used to decrease expression in said micro-organism of of at least one of a gene encoding an acyl-CoA dehydrogenase, a gene encoding an outer membrane protein receptor, and a gene encoding a

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PCT/US2016/038181 transcriptional regulator of fatty acid biosynthesis. In particular embodiments one or more of these genes is inactivated, such as by introduction of a mutation. In particular embodiments, the gene encoding an acyl-CoA dehydrogenase is fadE. In particular embodiments, the gene encoding a transcriptional regulator of fatty acid biosynthesis encodes a DNA transcription repressor, for example, fabR.

[001073] Additionally or alternatively, said micro-organism is modified to reduce expression of at least one of a gene encoding a pyruvate formate lyase, a gene encoding a lactate dehydrogenase, or both. In particular embodiments, the gene encoding a pyruvate formate lyase is pflB. In particular embodiments, the gene encoding a lactate dehydrogenase is IdhA. In particular embodiments one or more of these genes is inactivated, such as by introduction of a mutation therein.

[001074] In particular embodiments, the micro-organism is selected from the genus Escherichia, Bacillus, Lactohacillus, Rhodococctis, Synechococcus, Synechoystis, Pseudomonas, Aspergillus, Trichoderma, Neurospora, Fusarium, Humicola, Rhizomucor, Kluyveromyces, Pichia, Mucor, Myceliophtora, Penicillium, Phanerochaete, Pleurotus, Trameies, Chrysosporium, Saccharomyces, Stenotrophamonas, Schizosaccharomyces, Yarrow ia, or Streptomyces.

The use of Cpfl in the generation of micro-organisms capable of organic acid production [001075] The methods provided herein are further used to engineer micro-organisms capable of organic acid production, more particularly from pentose or hexose sugars. In particular embodiments, the methods comprise introducing into a micro-organism an exogenous LDH gene. In particular embodiments, the organic acid production in said micro-organisms is additionally or alternatively increased by inactivating endogenous genes encoding proteins involved in an endogenous metabolic pathway which produces a metabolite other than the organic acid of interest and/or wherein the endogenous metabolic pathway consumes the organic acid. In particular embodiments, the modification ensures that the production of the metabolite other than the organic acid of interest is reduced. According to particular embodiments, the methods are used to introduce at least one engineered gene deletion and/or inactivation of an endogenous pathway in which the organic acid is consumed or a gene encoding a product involved in an endogenous pathway which produces a metabolite other than the organic acid of interest. In particular embodiments, the at least one engineered gene deletion or inactivation is in

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PCT/US2016/038181 one or more gene encoding an enzyme selected from the group consisting of pyruvate decarboxylase (pdc), fumarate reductase, alcohol dehydrogenase (adh), acetaldehyde dehydrogenase, phosphoenolpyruvate carboxylase (ppc), D-lactate dehydrogenase (d-ldh), Llactate dehydrogenase (1-ldh), lactate 2-monooxygenase.

In further embodiments the at least one engineered gene deletion and/or inactivation is in an endogenous gene encoding pyruvate decarboxylase (pdc).

[001076] In further embodiments, the micro-organism is engineered to produce lactic acid and the at least one engineered gene deletion and/or inactivation is in an endogenous gene encoding lactate dehydrogenase. Additionally or alternatively, the micro-organism comprises at least one engineered gene deletion or inactivation of an endogenous gene encoding a cytochromedependent lactate dehydrogenase, such as a cytochrome B2-dependent L-lactate dehydrogenase. The use of Cpfl in the generation of improved xylose or cellobiose utilizing yeasts strains [001077] In particular embodiments, the Cpfl CRISPR system may be applied to select for improved xylose or cellobiose utilizing yeast strains. Error-prone PCR can be used to amplify one (or more) genes involved in the xylose utilization or cellobiose utilization, pathways. Examples of genes involved in xylose utilization pathways and cellobiose utilization pathways may include, without limitation, those described in Ha, S.J., et al. (2011) Proc. Natl. Acad. Sci. USA 108(2):504-9 and Galazka, EM., et al. (2010) Science 330(6000):84-6. Resulting libraries of double-stranded DNA molecules, each comprising a random mutation in such a selected gene could be co-transfonned with the components of the Cpfl CRISPR system into a yeast strain (for instance S288C) and strains can be selected with enhanced xylose or cellobiose utilization capacity, as described in WO2015138855.

[001078] Tadas Jakociunas et al. described the successful application of a multiplex CRISPR/Cas9 system for genome engineering of up to 5 different genomic loci in one transformation step in baker's yeast Saccharomyces cerevisiae (Metabolic Engineering Volume 28, March 2015, Pages 213-222) resulting in strains with high mevalonate production, a key intermediate for the industrially important isoprenoid biosynthesis pathway. In particular embodiments, the Cpfl CRISPR system may be applied in a multiplex genome engineering method as described herein for identifying additional high producing yeast strains for use in i soprenoi d synthesi s.

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SieuseofCpD.gnthe.generation„qfjacti.c acid„producinayeasts strains [001079] In another embodiment, successful application of a multiplex Cpfl CRISPR system is encompassed. In analogy with Vratislav Stovicek et al. (Metabolic Engineering Communications, Volume 2, December 2015, Pages 13--22), improved lactic acid-producing strains can be designed and obtained in a single transformation event. In a particular embodiment, the Cpfl CRISPR system is used for simultaneously inserting the heterologous lactate dehydrogenase gene and disruption of two endogenous genes PDC1 and PDC5 genes. Further applications of the Cpf l CRISPR system in plants [001080] In particular embodiments, the CRISPR system, and preferably the Cpfl CRISPR system described herein, can be used for visualization of genetic element dynamics. For example, CRISPR imaging can visualize either repetitive or non-repetitive genomic sequences, report telomere length change and telomere movements and monitor the dynamics of gene loci throughout the cell cycle (Chen et al., Ceil, 2013). These methods may also be applied to plants. [001081] Other applications of the CRISPR system, and preferably the Cpfl CRISPR system described herein, is the targeted gene disruption positive-selection screening in vitro and in vivo (Malina etaL, Genes and Development, 2013). These methods may also be applied to plants. [001082] In particular embodiments, fusion of inactive Cpfl endonucleases with histonemodifying enzymes can introduce custom changes in the complex epigenome (Rusk et al., Nature Methods, 2014). These methods may also be applied to plants.

[001083] In particular embodiments, the CRISPR system, and preferably the Cpfl CRISPR system described herein, can be used to purify a specific portion of the chromatin and identify the associated proteins, thus elucidating their regulatory roles in transcription (Waldrip et aL, Epigenetics, 2014). These methods may also be applied to plants.

[001084] In particular embodiments, present invention can be used as a therapy for virus removal in plant systems as it is able to cleave both viral DNA and RNA. Previous studies in human systems have demonstrated the success of utilizing CRISPR in targeting the single strand RNA virus, hepatitis C (A. Price, et al,, Proc. Natl. Acad. Sci, 2015) as well as the double stranded DNA virus, hepatitis B (V. Ramanan, et al., Sci. Rep, 2015). These methods may also be adapted for using the Cpfl CRISPR system in plants.

[001085] In particular embodiments, present invention could be used to alter genome complexicity. In further particular embodiment, the CRISPR system, and preferably the Cpfl >0

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CRISPR system described herein, can be used to disrupt or alter chromosome number and generate haploid plants, which only contain chromosomes from one parent. Such plants can he induced to undergo chromosome duplication and converted into diploid plants containing only homozygous alleles (Karimi-Ashtiyani et al., PNAS, 2015, Anton et al,, Nucleus, 2014), These methods may also be applied to plants.

[001086] In particular embodiments, the Cpfl CRISPR system described herein, can be used for self-cleavage. In these embodiments, the promotor of the Cpfl enzyme and gRNA can be a constitutive promotor and a second gRNA is introduced in the same transformation cassette, but controlled by an inducible promoter. This second gRNA can be designated to induce site-specific cleavage in the Cpfl gene in order to create a non-functional Cpfl. In a further particular embodiment, the second gRNA induces cleavage on both ends of the transformation cassette, resulting in the removal of the cassette from the host genome. This system offers a controlled duration of cellular exposure to the Cas enzyme and further minimizes off-target editing. Furthermore, cleavage of both ends of a CRISPR/Cas cassette can be used to generate transgenefree TO plants with bi-allelic mutations (as described for Cas9 e.g. Moore et al., Nucleic Acids Research, 2014; Schaeffer et al., Plant Science, 2015). The methods of Moore et al. may he applied to the Cpfl. CRISPR systems described herein. Sugano et al. (Plant Cell Physiol. 2014 Mar;55(3):475-81. doi: 10.1093/pcp/pcu014. Epub 2014 Jan 18) reports the application of CRISPR-Cas9 to targeted mutagenesis in the liverwort Marchantia polymorpha L., which has emerged as a model species for studying land plant evolution. The U6 promoter of M. polymorpha was identified and cloned to express the gRNA. The target sequence of the gRNA was designed to disrupt the gene encoding auxin response factor 1 (ARF1) in M, polymorpha. Using Agrobacterium-mediated transformation, Sugano et al. isolated stable mutants in the gametophyte generation of M. polymorpha. CRISPR-Cas9~based site-directed mutagenesis in vivo was achieved using either the Cauliflower mosaic virus 35S or M. polymorpha EFla promoter to express Cas9. Isolated mutant individuals showing an auxin-resistant phenotype were not chimeric. Moreover, stable mutants were produced by asexual reproduction of T1 plants. Multiple arfl alleles were easily established using CRIPSR-Cas9-based targeted mutagenesis. The methods of Sugano et al. may be applied to the Cpfl effector protein system of the present invention.

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PCT/US2016/038181 [001087] Kabadi et al· (Nucleic Acids Res. 2014 Oct 29;42(19):el47. doi; 10.1093/nar/gku749. Epub 2014 Aug 13) developed a single lentiviral system to express a Cas9 variant, a reporter gene and up to four sgRNAs from independent RNA polymerase III promoters that are incorporated into the vector by a convenient Golden Gate cloning method. Each sgRNA was efficiently expressed and can mediate multiplex gene editing and sustained transcriptional activation in immortalized and primary human cells. The methods of Kabadi et al, may he applied to the Cpfl effector protein system of the present invention.

[001088] Ling et al. (BMC Plant Biology 2014, 14:327) developed a CRISPR-Cas9 binary⁷ vector set based on the pGreen or pCAMBIA backbone, as well as a gRNA This toolkit requires no restriction enzymes besides Bsal to generate final constructs harboring maize-codon optimized Cas9 and one or more gRNAs with high efficiency in as little as one cloning step. The toolkit was validated using maize protoplasts, transgenic maize lines, and transgenic Arabidopsis lines and was shown to exhibit high efficiency and specificity. More importantly, using this toolkit, targeted mutations of three Arabidopsis genes were detected in transgenic seedlings of the Tl generation. Moreover, the multiple-gene mutations could be inherited by the next generation, (guide RNA)module vector set, as a toolkit for multiplex genome editing in plants. The toolbox of Lin et al. may be applied to the Cpfl effector protein system of the present invention.

[001089] Protocols for targeted plant genome editing via CRISPR-Cpfi are also available based on those disclosed for the CRISPR-Cas9 system in volume 1284 of the series Methods in Molecular Biology pp 239-255 10 February 2015. A detailed procedure to design, construct, and evaluate dual gRNAs for plant codon optimized Cas9 (pcoCas9) mediated genome editing using Arabidopsis thaliana and Nicotiana benthamiana protoplasts s model cellular systems are described. Strategies to apply the CRISPR-Cas9 system to generating targeted genome modifications in whole plants are also discussed. The protocols described in the chapter may be applied to the Cpfl effector protein system of the present invention.

[001090] Petersen (“Towards precisely glycol engineered plants,” Plant Biotech Denmark Annual meeting 2015, Copenhagen, Denmark) developed a method of using CRISPR/Cas9 to engineer genome changes in Arabidopsis, for example to glyco engineer Arabidopsis for production of proteins and products having desired posttranslational modifications. Hebelstrup et al. (Front Plant Sci. 2015 Apr 23; 6:247) outlines in pianta starch bioengineering, providing

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PCT/US2016/038181 crops that express starch modifying enzymes and directly produce products that normally are made by industrial chemical and/or physical treatments of starches. The methods of Petersen and Hebelstrup may be applied to the Cpfl effector protein system of the present invention.

[001091] Ma et al. (Mol Plant, 2015 Aug 3;8(8): 1274-84. doi: 10.1016/j.molp,2015.04.007) reports robust CRISPR-Cas9 vector system, utilizing a plant codon optimized Cas9 gene, for convenient and high-efficiency multiplex genome editing in monocot and dicot plants. Ma et al. designed PCR-based procedures to rapidly generate multiple sgRNA expression cassettes, which can be assembled into the binary⁷ CRISPR-Cas9 vectors in one round of cloning by Golden Gate ligation or Gibson Assembly. With this system, Ma et al. edited 46 target sites in rice with an average 85.4% rate of mutation, mostly in biallelic and homozygous status. Ma et al. provide examples of loss-of-function gene mutations in TO rice and ΊΊ Arabidopsis plants by simultaneous targeting of multiple (up to eight) members of a gene family, multiple genes in a biosynthetic pathway, or multiple sites in a single gene. The methods of M a et al. may be applied to the Cpfl effector protein system of the present invention.

[001092] Lowder et al. (Plant Physiol. 2015 Aug 21. pii: pp.00636.2015) also developed a. CRISPR-Cas9 toolbox enables multiplex genome editing and transcriptional regulation of expressed, silenced or non-coding genes in plants. This toolbox provides researchers with a protocol and reagents to quickly and efficiently assemble functional CRISPR-Cas9 T-DNA constructs for monocots and dicots using Golden Gate and Gateway cloning methods. It comes with a full suite of capabilities, including multiplexed gene editing and transcriptional activation or repression of plant endogenous genes. T-DNA based transformation technology is fundamental to modern plant biotechnology, genetics, molecular biology and physiology. As such, Applicants developed a method for the assembly of Cas9 (WT, nickase or dCas9) and gRNA(s) into a T-DNA destination-vector of interest. The assembly method is based on both Golden Gate assembly and MultiSite Gateway recombination. Three modules are required for assembly. The first module is a Cas9 entry vector, which contains promoterless Cas9 or its derivative genes flanked by attLl and attR5 sites. The second module is a gRNA entry vector which contains entry gRNA expression cassettes flanked by attL5 and attL2 sites. The third module includes attRI-attR2-containing destination T-DNA vectors that provide promoters of choice for Cas9 expression. The toolbox of Lowder et al. may be applied to the Cpfl effector protein system of the present i nvention.

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PCT/US2016/038181 [001093] In an advantageous embodiment, the plant may be a tree. The present invention may also utilize the herein disclosed CRISPR Cas system for herbaceous systems (see, e.g., Belhaj et al., Plant Methods 9: 39 and Harrison et al., Genes & Development 28: 1859-1872). In a particularly advantageous embodiment, the CRISPR Cas system of the present invention may target single nucleotide polymorphisms (SNPs) in trees (see, e.g., Zhou et al., New Phytologist, Volume 208, Issue 2, pages 298-301, October 2015), In the Zhou et al. study, the authors applied a CRISPR Cas system in the woody perennial Populus using the 4-coumarate:CoA ligase (4CL) gene family as a case study and achieved 100% mutational efficiency for two 4CL genes targeted, with even⁷ transformant examined carrying biallelic modifications. In the Zhou et al., study, the CRISPR-Cas9 system was highly sensitive to single nucleotide polymorphisms (SNPs), as cleavage for a third 4CL gene was abolished due to SNPs in the target sequence. These methods may be applied to the Cpfl effector protein system of the present invention. [001094] The methods of Zhou et al. (New Phytologist, Volume 208, Issue 2, pages 298-301, October 2015) may be applied to the present invention as follows. Two 4CL genes, 4CL1 and 4CL2, associated with lignin and flavonoid biosynthesis, respectively are targeted for CRISPRCas9 editing. The Populus tremula ^x alba clone 717-1B4 routinely used for transformation is divergent from the genome-sequenced Populus trichocarpa. Therefore, the 4CL1 and 4CL2 gRNAs designed from the reference genome are interrogated with in-house 717 RNA-Seq data to ensure the absence of SNPs which could limit Cas efficiency. A third gRNA designed for 4CL5, a genome duplicate of 4CL1, is also included. The corresponding 717 sequence harbors one SNP in each allele near/within the PAM, both of which are expected to abolish targeting by the 4CL5-gRNA. All three gRNA target sites are located within the first exon. For 717 transformation, the gRNA is expressed from the Medicago U6.6 promoter, along with a human codon-optimized Cas under control of the CaMV 35S promoter in a binary vector. Transformation wdth the Cas-only vector can serve as a control. Randomly selected 4CL1 and 4CL2 lines are subjected to amplicon-sequencing. The data is then processed and biallelic mutations are confirmed in all cases. These methods may be applied to the Cpfl effector protein system of the present invention.

[001095] In plants, pathogens are often host-specific. For example, Fusarium oxysporum f. sp. lycopersici causes tomato wilt but attacks only tomato, and F. oxysporum f dianthii Puccinia graminis f. sp. tritici attacks only wheat. Plants have existing and induced defenses to resist

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PCT/US2016/038181 most pathogens. Mutations and recombination events across plant generations lead to genetic variability that gives rise to susceptibility, especially as pathogens reproduce with more frequency than plants. In plants there can be non-host resistance, e.g., the host and pathogen are incompatible. There can also be Horizontal Resistance, e.g., partial resistance against all races of a pathogen, typically controlled by many genes and Vertical Resistance, e.g., complete resistance to some races of a pathogen hut not to other races, typically controlled by a few genes. In a Gene-for-Gene level, plants and pathogens evolve together, and the genetic changes in one balance changes in other. Accordingly, using Natural Variability, breeders combine most useful genes for Yield, Quality, Uniformity, Hardiness, Resistance. The sources of resistance genes include native or foreign Varieties, Heirloom Varieties, Wild Plant Relatives, and Induced Mutations, e.g., treating plant material with mutagenic agents. Using the present invention, plant breeders are provided with a new tool to induce mutations. Accordingly, one skilled in the art can analyze the genome of sources of resistance genes, and in Varieties having desired characteristics or traits employ the present invention to induce the rise of resistance genes, with more precision than previous mutagenic agents and hence accelerate and improve plant breeding programs.

Improved plants and yeast cells [001096] The present invention also provides plants and yeast cells obtainable and obtained by the methods provided herein. The improved plants obtained by the methods described herein may be useful in food or feed production through expression of genes which, for instance ensure tolerance to plant pests, herbicides, drought, low or high temperatures, excessive water, etc. [001097] The improved plants obtained by the methods described herein, especially crops and algae may be useful in food or feed production through expression of, for instance, higher protein, carbohydrate, nutrient or vitamin levels than would normally be seen in the wildtype. In this regard, improved plants, especially pulses and tubers are preferred.

[001098] Improved algae or other plants such as rape may be particularly useful in the production of vegetable oils or biofuels such as alcohols (especially methanol and ethanol), for instance. These may be engineered to express or overexpress high levels of oil or alcohols for use in the oil or biofuel industries.

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PCT/US2016/038181 [001099] The invention also provides for improved parts of a plant. Plant parts include, but are not limited to, leaves, stems, roots, tubers, seeds, endosperm, ovule, and pollen. Plant parts as envisaged herein may be viable, nonviabie, regeneratable, and/or non- regeneratable.

[001100] It is also encompassed herein to provide plant ceils and plants generated according to the methods of the invention. Gametes, seeds, embryos, either zygotic or somatic, progeny or hybrids of plants comprising the genetic modification, which are produced by traditional breeding methods, are also included within the scope of the present invention. Such plants may contain a heterologous or foreign DNA sequence inserted at or instead of a target sequence. Alternatively, such plants may contain only an alteration (mutation, deletion, insertion, substitution) in one or more nucleotides. As such, such plants will only be different from their progenitor plants by the presence of the particular modification.

[001101] Thus, the invention provides a plant, animal or cell, produced by the present methods, or a progeny thereof. The progeny may be a ci one of the produced plant or animal, or may result from sexual reproduction by crossing with other individuals of the same species to introgress further desirable traits into their offspring. The cell may be In vivo or ex vivo in the eases of multicellular organisms, particularly animals or plants.

Cpfl Effector Protein Complexes Can Be Used In Non-Human Organisms /'Animals [001102] In an aspect, the invention provides a non-human eukaryotic organism; preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments. In other aspects, the invention provides a eukaryotic organism, preferably a multicellular eukaryotic organism, comprising a eukaryotic host cell according to any of the described embodiments. The organism in some embodiments of these aspects may be an animal; for example a mammal. Also, the organism may be an arthropod such as an insect. The organism also may be a plant. Further, the organism may be a fungus.

[001103] The present invention may also be extended to other agricultural applications such as, for example, farm and production animals. For example, pigs have many features that make them attractive as biomedical models, especially in regenerative medicine. In particular, pigs with severe combined immunodeficiency (SCID) may provide useful models for regenerative medicine, xenotransplantation (discussed also elsewhere herein), and tumor development and will aid in developing therapies for human SCID patients. Lee et al., (Proc Natl Acad Sci U S A. 2014 May 20,111(20):7260-5) utilized a reporter-guided transcription activator-like effector

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PCT/US2016/038181 nuclease (TALEN) system to generated targeted modifications of recombination activating gene (RAG) 2 in somatic cells at high efficiency, including some that affected both alleles. The Cpfl effector protein may be applied to a similar system.

[001104] The methods of Lee et al., (Proc Natl Acad Sci U S A. 2014 May 20,111 (20):7260-5) may be applied to the present invention analogously as follows. Mutated pigs are produced by targeted modification of RAG2 in fetal fibroblast cells followed by SCNT and embryo transfer. Constructs coding for CRISPR Cas and a reporter are electroporated into fetal-derived fibroblast cells. After 48 h, transfected cells expressing the green fluorescent protein are sorted into individual wells of a 96-well plate at an estimated dilution of a single cell per well. Targeted modification of RAG2 are screened by amplifying a genomic DNA fragment flanking any CRISPR Cas cutting sites followed by sequencing the PCR products. After screening and ensuring lack of off-site mutations, cells carrying targeted modification of RAG2 are used for SCNT. The polar body, along with a portion of the adjacent cytoplasm of oocyte, presumably containing the metaphase II plate, are removed, and a donor cell are placed in the perivitelline. The reconstructed embryos are then electrically porated to fuse the donor cell with the oocyte and then chemically activated. The activated embryos are incubated in Porcine Zygote Medium 3 (PZM3) with 0.5 μΜ Scriptaid (S7817; Sigma-Aldrich) for 14—16 h. Embryos are then washed to remove the Scriptaid and cultured in PZM3 until they were transferred into the oviducts of surrogate pigs.

[001105] The present invention is also applicable to modifying SNPs of other animals, such as cows. Tan et al. (Proc Natl Acad Sci U S A. 2013 Oct 8; 110(41): 16526—16531) expanded the livestock gene editing toolbox to include transcription activator-like (TAL) effector nuclease (TALEN)- and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9stimulated homology-directed repair (HDR) using plasmid, rAAV, and oligonucleotide templates. Gene specific gRNA sequences were cloned into the Church lab gRNA vector (Addgene ID: 41824) according to their methods (Mali P, et al. (2013) RNA-Guided Human Genome Engineering via Cas9. Science 339(6121):823-826). The Cas9 nuclease was provided either by co-transfection of the hCas9 plasmid (Addgene ID: 41815) or mRNA synthesized from RCIScript-hCas9. This RCIScript-hCas9 was constructed by sub-cloning the Xbal-Agel fragment from the hCas9 plasmid (encompassing the hCas9 cDNA) into the RCIScript plasmid.

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PCT/US2016/038181 [001106] Heo et al. (Stem Cells Dev. 2015 Feb l;24(3):393-402. doi: 10.1089/scd.2014.0278. Epub 2014 Nov 3) reported highly efficient gene targeting in the bovine genome using bovine pluripotent cells and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 nuclease. First, Heo et al, generate induced pluripotent stem cells (iPSCs) from bovine somatic fibroblasts by the ectopic expression of yamanaka factors and θ8Κ3β and MEK inhibitor (2i) treatment, Heo et al. observed that these bovine iPSCs are highly similar to naive pluripotent stem cells with regard to gene expression and developmental potential in teratomas. Moreover, CRISPR-Cas9 nuclease, which was specific for the bovine NANOG locus, showed highly efficient editing of the bovine genome in bovine iPSCs and embryos.

[001107] Igenity® provides a profile analysis of animals, such as cows, to perform and transmit traits of economic traits of economic importance, such as carcass composition, carcass quality, maternal and reproductive traits and average daily gain. The analysis of a comprehensive Igenity® profile begins with the discovery of DNA markers (most often single nucleotide polymorphisms or SNPs). All the markers behind the Igenity® profile were discovered by independent scientists at research institutions, including universities, research organizations, and government entities such as USDA. Markers are then analyzed at Igenity® in validation populations. Igenity® uses multiple resource populations that represent various production environments and biological types, often working with industry partners from the seedstock, cow-calf, feedlot and/or packing segments of the beef industry to collect phenotypes that are not commonly available. Cattle genome databases are widely available, see, e.g., the NAGRP Cattle Genome Coordination Program (http://w^rww.aninialgenome.org,^/cattle/maps/db.html). Thus, the present invention maybe applied to target bovine SNPs. One of skill in the art may utilize the above protocols for targeting SNPs and apply them to bovine SNPs as described, for example, by Tan et al. or Heo et al.

[001108] Qingjian Zou et al. (Journal of Molecular Cell Biology Advance Access published October 12, 2015) demonstrated increased muscle mass in dogs by targeting targeting the first exon of the dog Myostatin (MSTN) gene (a negative regulator of skeletal muscle mass). First, the efficiency of the sgRNA was validated, using cotransfection of the the sgRNA targeting MSTN with a Cas9 vector into canine embryonic fibroblasts (CEFs). Thereafter, MSTN KO dogs were generated by micro-injecting embryos with normal morphology with a mixture of Cas9 mRNA and MSTN sgRNA and auto-transplantation of the zygotes into the oviduct of the

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PCT/US2016/038181 same female dog. The knock-out puppies displayed an obvious muscular phenotype on thighs compared with its wild-type littermate sister. This can also be performed using the Cpfl CRISPR systems provided herein.

Livestock - Pigs [001109] Viral targets in livestock may include, in some embodiments, porcine CD163, for example on porcine macrophages. CD 163 is associated with infection (thought to be through viral cell entry) by PRRSv (Porcine Reproductive and Respiratory Syndrome virus, an arterivirus). Infection by PRRSv, especially of porcine alveolar macrophages (found in the lung), results in a previously incurable porcine syndrome (“Mystery swine disease” or “blue ear disease”) that causes suffering, including reproductive failure, weight loss and high mortality rates in domestic pigs. Opportunistic infections, such as enzootic pneumonia, meningitis and ear oedema, are often seen due to immune deficiency through loss of macrophage activity. It also has significant economic and environmental repercussions due to increased antibiotic use and financial loss (an estimated $660m per year).

[001110] As reported by Kristin M Whitworth and Dr Randall Prather et al. (Nature Biotech 3434 published online 07 December 2015) at the University of Missouri and in collaboration with Genus Pic, CD 163 was targeted using CRISPR-Cas9 and the offspring of edited pigs were resistant when exposed to PRRSv. One founder male and one founder female, both of whom had mutations in exon 7 of CD 163, were bred to produce offspring. The founder male possessed an Il-bp deletion in exon 7 on one allele, which results in a frameshift mutation and missense translation at amino acid 45 in domain 5 and a subsequent premature stop codon at amino acid 64, The other allele had a 2-bp addition in exon 7 and a 377-bp deletion in the preceding intron, which were predicted to result in the expression of the first 49 amino acids of domain 5, followed by a premature stop code at amino acid 85. The sow had a 7 bp addition in one allele that when translated was predicted to express the first 48 amino acids of domain 5, followed by a premature stop codon at amino acid 70. The sow’s other allele was unamplifiable. Selected offspring were predicted to be a null animal (CD163-/-), i.e. a CDI63 knock out.

[001 1 1 1] Accordingly, in some embodiments, porcine alveolar macrophages may be targeted by the CRISPR protein. In some embodiments, porcine CD163 may be targeted by the CRISPR protein. In some embodiments, porcine CD 163 may be knocked out through induction of a DSB or through insertions or deletions, for example targeting deletion or modification of exon 7, j j 9

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PCT/US2016/038181 including one or more of those described above, or in other regions of the gene, for example deletion or modification of exon 5.

[001112] An edited pig and its progeny are also envisaged, for example a CD163 knock out pig. This may be for livestock, breeding or modelling purposes (i.e. a porcine model). Semen comprising the gene knock out is also provided.

[001113] CD163 is a member of the scavenger receptor cysteine-rich (SRCR) superfamily. Based on in vitro studies SRCR domain 5 of the protein is the domain responsible for unpackaging and release of the viral genome. As such, other members of the SRCR superfaniily may also be targeted in order to assess resistance to other viruses. PRRSV is also a member of the mammalian arterivirus group, which also includes murine lactate dehydrogenase-elevating vims, simian hemorrhagic fever virus and equine arteritis virus. The arteriviruses share important pathogenesis properties, including macrophage tropism and the capacity to cause both severe disease and persistent infection. Accordingly, arteri viruses, and in particular murine lactate dehydrogenase-elevating virus, simian hemorrhagic fever virus and equine arteritis virus, may be targeted, for example through porcine CD163 or homologues thereof in other species, and murine, simian and equine models and knockout also provided.

[001114] Indeed, this approach may be extended to viruses or bacteria that cause other livestock diseases that may be transmitted to humans, such as Swine Influenza Virus (SIV) strains which include influenza C and the subtypes of influenza A known as H1N1, H1N2, H2N1, H3N1, H3N2, and H2N3, as well as pneumonia, meningitis and oedema mentioned above.

Therapeutic Targeting with RNA-guided Cpfl Effector Protein Complex [001115] As will be apparent, it is envisaged that the present system can be used to target any polynucleotide sequence of interest. The invention provides a non-naturally occurring or engineered composition, or one or more polynucleotides encoding components of said composition, or vector or delivery systems comprising one or more polynucleotides encoding components of said composition for use in a modifying a target cell in vivo, ex vivo or in vitro and, may be conducted in a manner alters the cell such that once modified the progeny or cell line of the CRISPR modified cell retains the altered phenotype. The modified cells and progeny may be part of a multi-cellular organism such as a plant or animal with ex vivo or in vivo application of CRISPR system to desired cell types. The CRISPR invention may be a

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PCT/US2016/038181 therapeutic method of treatment. The therapeutic method of treatment may comprise gene or genome editing, or gene therapy.

Treating pathogens., like bacterial, fungal and parasitic pathogens [001116] The present invention may also be applied to treat bacterial, fungal and parasitic pathogens. Most research efforts have focused on developing new antibiotics, which once developed, would nevertheless be subject to the same problems of drug resistance. The invention provides novel CRISPR-based alternatives which overcome those difficulties. Furthermore, unlike existing antibiotics, CRISPR-based treatments can be made pathogen specific, inducing bacterial cell death of a target pathogen while avoiding beneficial bacteria. [001117] Jiang et al. (“RNA-guided editing of bacterial genomes using CRISPR-Cas systems,” Nature Biotechnology vol, 31, p, 233-9, March 2013) used a CRISPR-Cas9 system to mutate or kill 5. pneumoniae and E. coli. The work, which introduced precise mutations into the genomes, relied on dual-RNA:Cas9-directed cleavage at the targeted genomic site to kill unmutated cells and circumvented the need for selectable markers or counter-selection systems. CRISPR systems have be used to reverse antibiotic resistance and eliminate the transfer of resistance between strains. Bickard et al. showed that Cas9, reprogrammed to target virulence genes, kills virulent, but not avirulent, S. aureus. Reprogramming the nuclease to target antibiotic resistance genes destroyed staphylococcal plasmids that harbor antibiotic resistance genesand immunized against the spread of plasmid-borne resistance genes, (see, Bikard et al., “Exploiting CRISPRCas nucleases to produce sequence-specific antimicrobials,” Nature Biotechnology vol. 32, 1146-1150, doi:i0.1038/nbt.3043, published online 05 October 2014.) Bikard showed that CRISPR-Cas9 antimicrobials function in vivo to kill S. aureus in a mouse skin colonization model. Similarly, Yosef et al used a CRISPR system to target genes encoding enzymes that confer resistance to β-Iactam antibiotics (see Yousef et al., “Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria,” Proc. Natl. Acad. Sci. USA, vol. 112, p. 7267-7272, doi: 10.1073/pnas.1500107112 published online May 18, 2015).

[001118] CRISPR systems can be used to edit genomes of parasites that are resistant to other genetic approaches. For example, a CRISPR-Cas9 system was shown to introduce doublestranded breaks into the in the Plasmodiumyoelii genome (see, Zhang et al,, “Efficient Editing of Malaria Parasite Genome Using the CRISPR/Cas9 System,” mBio. vol. 5, eOI414-14, Jul-Aug 2014). Ghorbal et al. (“Genome editing in the human malaria parasite Plasmodium

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PCT/US2016/038181 falciparumusing the CRISPR-Cas9 system,” Nature Biotechnology, vol. 32, p. 819-821, doi: 10.1038/nbt.2925, published online June 1, 2014) modified the sequences of two genes, orcl and kelchlS, which have putative roles in gene silencing and emerging resistance to artemisinin, respectively. Parasites that were altered at the appropriate sites were recovered with very high efficiency, despite there being no direct selection for the modification, indicating that neutral or even deleterious mutations can be generated using this system. CRISPR-Cas9 is also used to modify the genomes of other pathogenic parasites, including Toxoplasma gondii (see Shen et al., “Efficient gene disruption in diverse strains of Toxoplasma gondii using CRISPR/CAS9,” mBio vol. 5:e01114-14, 2014; and Sidik et al, “Efficient Genome Engineering of Toxoplasma gondii Using CRISPR/Cas9,” PLoS One vol. 9, el00450, doi: 10.1371/jounial.pone.0100450, published online June 27, 2014).

[001119] Vyas et al. (“A Candida albicans CRISPR system permits genetic engineering of essential genes and gene families,” Science Advances, vol, 1, el500248, DOI:

10.1126/sciadv. 1500248, April 3, 2015) employed a CRISPR system to overcome long-standing obstacles to genetic engineering in C. albicans and efficiently mutate in a single experiment both copies of several different genes. In an organism where several mechanisms contribute to drug resistance, Vyas produced homozygous double mutants that no longer displayed the hyperresistance to fluconazole or cycioheximide displayed by the parental clinical isolate Can90. Vyas also obtained homozygous loss-of-function mutations in essential genes of C. albicans by creating conditional alleles. Null alleles of DCR1, which is required for ribosomal RNA processing, are lethal at low temperature but viable at high temperature. Vyas used a repair template that introduced a nonsense mutation and Isolated dcrl/dcrl mutants that, failed to grow at 16°C.

[001.120] The CRISPR system of the present invention for use in P, falciparum by disrupting chromosomal loci. Ghorbal et al. (“Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system”, Nature Biotechnology, 32, 819-821. (2014), DOT 10.1038/nbt.2925, June 1, 2014) employed a CRISPR system to introduce specific gene knockouts and single-nucleotide substtitions in. the malaria genome. To adapt the CRISPR~Cas9 system to P. falciparum, Ghorbal et al. generated expression vectors for under the control of plasmodial regulatory elements in the pUFl-Cas9 epi some that also carries the drug-selectable marker ydbodh, which gives resistance to DSME & P. falciparum dihydroorotate dehydrogenase

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PCT/US2016/038181 (PfDHODH) inhibitor and for transcription of the sgRNA, used P. falciparum U6 small nuclear (sn)RNA regulator)-· elements placing the guide RNA and the donor DNA template for homologous recombination repair on the same plasmid, pL7. See also, Zhang C. et al. (“Efficient editing of malaria parasite genome using the CR1SPR/Cas9 system”, MBio, 2014 Jul 1, 5(4):E01414~I4, doi: 10.1128/MbIO.01414~14) and Wagner et al. (“Efficient CRISPR-Casfo mediated genome editing in Plasmodium falciparum, Nature Methods 11, 915-918 ( 2014), DOL 10.103 8/nmeth. 3 063).

[001121] Cas-mediated genome editing might be used to introduce protective mutations in somatic tissues to combat nongenetic or complex diseases. For example, NHEJ-mediated inactivation of the CCR5 receptor in lymphocytes (Lombardo et al,, Nat Biotechnol. 2007 Nov, 25(11): 1298-306) may be a viable strategy for circumventing HIV infection, whereas deletion of PCSK9 (Cohen et al., Nat Genet. 2005 Feb; 37(2):161-5) orangiopoietin (Musunuru et al., N Engl J Med. 2010 Dec 2; 363(23):2220-7) may provide therapeutic effects against statin-resistant hypercholesterolemia or hyperlipidemia. Although these targets may be also addressed using siRNA-mediated protein knockdown, a unique advantage of NHEJ-mediated gene inactivation is the ability to achieve permanent therapeutic benefit without the need for continuing treatment. As with all gene therapies, it will of course be important to establish that each proposed therapeutic use has a favorable benefit-risk ratio.

[001122] Hydrodynamic delivery of plasmid DNA encoding Cas9 nd guide RNA along with a repair template into the liver of an adult mouse model of tyrosinemia was shown to be able to correct the mutant Fah gene and rescue expression of the wild-type Fah protein in ~1 out of 250 cells (Nat Biotechnol. 2014 Jun; 32(6):551-3), In addition, clinical trials successfully used ZF nucleases to combat HIV infection by ex vivo knockout of the CCR5 receptor. In all patients, HIV DNA levels decreased, and in one out of four patients, HIV RNA became undetectable (Tebas et al., N Engl J Med. 2014 Mar 6; 370(10):901-10). Both of these results demonstrate the promise of programmable nucleases as a new therapeutic platform.

[001123] In another embodiment, self-inactivating lentiviral vectors with an siRNA targeting a common exon shared by HIV tat/rev, a nucleolar-localizing TAR decoy, and an anti-CCR5specific hammerhead ribozyme (see, e.g., DiGiusto et al. (2010) Sci Transl Med 2:36ra43) may be used/and or adapted to the CRISPR-Cas system of the present invention. A minimum of 2.5 κ

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10⁶ CD34+ cells per kilogram patient weight may be collected and prestimulated for 16 to 20 hours in X-VIVO 15 medium (Lonza) containing 2 pmol/L-glutamine, stem cell factor (100 ng/ml), Fit-3 ligand (Flt-3L) (100 ng/ml), and thrombopoietin (10 ng/ml) (CellGenix) at a density of 2 χ 10⁶ cells/ml. Prestimulated cells may be transduced with lentiviral at a multiplicity of infection of 5 for 16 to 24 hours in 75-cirri tissue culture flasks coated with fibronectin (25 mg/cm^z) (RetroNectin,Takara Bio Inc,).

[001124] With the knowledge in the art and the teachings in this disclosure the skilled person can correct HSCs as to immunodeficiency condition such as HIV / AIDS comprising contacting an HSC with a CRISPR-Cas9 system that targets and knocks out CCR5. An guide RNA (and advantageously a dual guide approach, e.g., a pair of different guide RNAs; for instance, guide RNAs targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs)) that targets and knocks out CCR5-and-Cpfl protein containing particle is contacted with HSCs. The so contacted cells can be administered; and optionally treated / expanded; cf. Cartier. See also Kiem, “Hematopoietic stem cell-based gene therapy for HIV disease,” Cell Stem Cell. Feb 3, 2012; 10(2): 137-147, incorporated herein by reference along with the documents it cites; Mandal et al, “Efficient Ablation of Genes in Human Hematopoietic Stem and Effector Cells using CRISPR/Cas9,” Cell Stem Cell, Volume 15, Issue 5, p643-652, 6 November 2014; incorporated herein by reference along with the documents it cites. Mention is also made of Ebina, “CRISPR/Cas9 system to suppress HIV-1 expression by editing HIV-1 integrated proviral DNA” SCIENTIFIC REPORTS | 3 :2510 1 DOI: 10.1038/srep02510, incorporated herein by reference along with the documents it cites, as another means for combatting HIV/AIDS using a CRISPR-Cpfl system, [001125] The rationale for genome editing for HIV treatment originates from the observation that individuals homozygous for loss of function mutations in CCR5, a cellular co-receptor for the virus, are highly resistant to infection and otherwise healthy, suggesting that mimicking this mutation with genome editing could be a safe and effective therapeutic strategy [Liu, R., et al. Cell 86, 367-377 (1996)], This idea was clinically validated when an HIV infected patient was given an allogeneic bone marrow transplant from a donor homozygous for a loss of function CCR5 mutation, resulting in undetectable levels of HIV and restoration of normal CD4 T-cell counts [Hutter, G., et al. The New England journal of medicine 360, 692-698 (2009)]. Although bone marrow' transplantation is not a realistic treatment strategy for most HIV patients, due to

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PCT/US2016/038181 cost and potential graft vs. host disease, HIV therapies that convert a patient’s own T-cells into CCR5 are desirable.

[001126] Early studies using ZFNs and NHEJ to knockout CCR5 in humanized mouse models of HIV showed that transplantation of CCR5 edited CD4 T cells improved viral load and CD4 Tcell counts [Perez, E.E., et al. Nature biotechnology 26, 808-816 (2008)]. Importantly, these models also showed that HIV infection resulted in selection for CCR5 null cells, suggesting that editing confers a fitness advantage and potentially allowing a small number of edited cells to create a therapeutic effect.

[001127] As a result of this and other promising preclinical studies, genome editing therapy that knocks out CCR5 in patient T cells has now been tested in humans [Holt, N., et al. Nature biotechnology 28, 839-847 (2010); Li, L., et al. Molecular therapy : the journal of the American Society of Gene Therapy 21, 1259-1269 (2013)]. In a recent phase I clinical trial, CD4+ T cells from patients with HIV were removed, edited with ZFNs designed to knockout the CCR5 gene, and autologously transplanted back into patients [Tebas, P., et al. The New England journal of medicine 370, 901-910 (2014)].

[001128] In another study (Mandal et al., Cell Stem Cell, Volume 15, Issue 5, p643-652, 6 November 2014), CRISPR-Cas9 has targeted two clinical relevant genes, B2M and CCR5, in human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types. HSPCs that had undergone genome editing with CRISPR-Cas9 retained multilineage potential. Predicted on- and off-target mutations were examined via target capture sequencing in HSPCs and low levels of off-target mutagenesis were observed at only one site. These results demonstrate that CRISPR-Cas9 can efficiently ablate genes in HSPCs with minimal off-target mutagenesis, which have broad applicability for hematopoietic cell-based therapy.

[001129] Wang et al. (PLoS One. 2014 Dec 26;9(12):el 15987. doi: 10,1371/journal.pone.0115987) silenced CCR5 via CRISPR associated protein 9 (Cas9) and single guided RNAs (guide RNAs) with lent!viral vectors expressing Cas9 and CCR5 guide RNAs, Wang et al. showed that a single round transduction of lentiviral vectors expressing Cas9 and CCR5 guide RNAs into HIV-1 susceptible human CD4+ cells yields high frequencies of CCR5 gene disruption. CCR5 gene-disrupted cells are not only resistant to R5-tropic HIV-1,

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PCT/US2016/038181 including transmitted/founder (T/F) HIV-1 isolates, but also have selective advantage over CCR5 gene-undisrupted cells during R5-tropic HIV-1 infection. Genome mutations at potential offtarget sites that are highly homologous to these CCR5 guide RNAs in stably transduced cells even at 84 days post transduction were not detected by a T7 endonuclease I assay.

[001130] Fine et al. (Sci Rep. 2015 Jul 1;5:10777. doi: I0.1038/srepl0777) identified a twocassette system expressing pieces of the S. pyogenes Cas9 (SpCas9) protein which splice together in cellula to form a functional protein capable of site-specific DNA cleavage. With specific CRISPR guide strands, Fine et al. demonstrated the efficacy of this system in cleaving the HBB and CCR5 genes in human HEK-293T cells as a single Cas9 and as a pair of Cas9 nickases. The trans-spliced SpCas9 (tsSpCas9) displayed -35% of the nuclease activity compared with the wild-type SpCas9 (wtSpCas9) at standard transfection doses, but had substantially decreased activity at lower dosing levels. The greatly reduced open reading frame length of the tsSpCas9 relative to wtSpCas9 potentially allows for more complex and longer genetic elements to be packaged into an AAV vector including tissue-specific promoters, multiplexed guide RNA expression, and effector domain fusions to SpCas9.

Li et al. (J Gen Virol. 2015 Aug;96(8):2381-93. doi: 10.1099/vir.0.000139. Epub 2015 Apr 8) demonstrated that CRISPR-Cas9 can efficiently mediate the editing of the CCR5 locus In cell lines, resulting in the knockout of CCR5 expression on the cell surface. Next-generation sequencing revealed that various mutations were introduced around the predicted cleavage site of CCR5, For each of the three most effective guide RNAs that were analyzed, no significant offtarget effects were detected at the 15 top-scoring potential sites. By constructing chimeric Ad5F35 adenoviruses carrying CRISPR-Cas9 components, Li et al, efficiently transduced primary CD4+ T-lymphocytes and disrupted CCR5 expression, and the positively transduced cells were conferred with HIV-1 resistance.

[001131] One of skill in the art may utilize the above studies of, for example, Holt, N., et al. Nature biotechnology 28, 839-847 (2010), Li, L., et al. Molecular therapy : the journal of the American Society of Gene Therapy 21, 1259-1269 (2013), Mandal et al.. Cell Stem Cell, Volume 15, Issue 5, p643-652, 6 November 2014, Wang et al. (PLoS One. 2014 Dec 26;9(12):el 15987. doi: 10.1371/journal.pone.Ol 15987), Fine et al. (Sci Rep. 2015 Jul 1,5:10777. doi: 10.1038/srep 10777) and Li et al. (J Gen Virol. 2015 Aug;96(8):2381-93. doi:

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10.1099/vir.Q.000139. Epub 2015 Apr 8) for targeting CCR5 with the CRISPR Cas system of the present invention.

Treating pathogens., like viral pathogens, such as HBV [001132] The present invention may also be applied to treat hepatitis B virus (HBV). However, the CRISPR Cas system must be adapted to avoid the shortcomings of RNAi, such as the risk of oversatring endogenous small RNA pathways, by for example, optimizing dose and sequence (see, e.g., Grimm et al., Nature vol. 441, 26 May 2006). For example, low doses, such as about 1-10 x 10¹⁴ particles per human are contemplated. In another embodiment, the CRISPR Cas system directed against HBV may be administered in liposomes, such as a stable nucleic-acidlipid particle (SNALP) (see, e.g., Morrissey et al., Nature Biotechnology, Vol. 23, No. 8, August 2005), Daily intravenous injections of about 1, 3 or 5 mg/kg/day of CRISPR Cas targeted to HBV RNA in a SNALP are contemplated. The daily treatment may be over about three days and then weekly for about five weeks. In another embodiment, the system of Chen et al. (Gene Therapy (2007) 14, 11—19) may be used/and or adapted for the CRISPR Cas system of the present invention. Chen et al. use a double-stranded adenoassociated virus 8-pseudotyped vector (dsAAV2/8) to deliver shRNA. A single administration of dsAAV2/8 vector (1 x 10¹² vector genomes per mouse), carrying HBV-specific shRNA, effectively suppressed the steady level of HBV protein, mRNA and replicative DNA in liver of HB V transgenic mice, leading to up to 2-3 logic decrease in HBV load in the circulation. Significant HBV suppression sustained for at least 120 days after vector administration. The therapeutic effect of shRNA was target sequence dependent and did not involve activation of interferon. For the present invention, a CRISPR Cas system directed to HBV may be cloned into an AAV vector, such as a dsAAV2/8 vector and administered to a human, for example, at a dosage of about 1 x 10¹⁵ vector genomes to about 1 x 10^iO vector genomes per human. In another embodiment, the method of Wooddell et al. (Molecular Therapy vol. 21 no. 5, 973-985 May 2013) may be used/and or adapted to the CRISPR Cas system of the present invention. Woodell et al. show that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, Wooddell et al. show that a single coinjection of NAG-MLP with potent chol-siRNAs

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PCT/US2016/038181 targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. Intraveinous coinjections, for example, of about 6 mg/kg of NAG-MLP and 6 mg/kg of HBV specific CRISPR Cas may be envisioned for the present invention. In the alternative, about 3 mgdig of NAG-MLP and 3 mg/kg of HBV specific CRISPR Cas may be delivered on day one, followed by administration of about about 2-3 mg/kg of NAGMLP and 2-3 mg/kg of HBV specific CRISPR Cas two weeks later.

[001133] Lin et al. (Mol Ther Nucleic Acids. 2014 Aug 19;3:el86. doi: 10.1038/mtna.2014.38) designed eight gRNAs against HBV of genotype A. With the HBV-specific gRNAs, the CRISPR-Cas9 system significantly reduced the production of HBV core and surface proteins in Huh-7 cells transfected with an HBV-expression vector. Among eight screened gRNAs, two effective ones were identified. One gRNA targeting the conserved HBV sequence acted against different genotypes. Using a hydrodynamics-HBV persistence mouse model, Lin et al. further demonstrated that this system could cleave the intrahepatic HBV genome-containing plasmid and facilitate its clearance in vivo, resulting in reduction of serum surface antigen levels. These data suggest that the CRISPR-Cas9 system could disrupt the HBV-expressing templates both in vitro and in vivo, indicating its potential in eradicating persistent HBV infection.

[001134] Dong et al. (Antiviral Res. 2015 Jun; 118:110-7. doi: 10.1016/j,antiviral.2015.03.015, Epub 2015 Apr 3) used the CRISPR-Cas9 system to target the HBV genome and efficiently inhibit HBV infection. Dong et al. synthesized four single-guide RNAs (guide RNAs) targeting the conserved regions of HBV. The expression of these guide RNAS with Cas9 reduced the viral production in Huh7 cells as well as in HBV-replication cell HepG2.2.15. Dong et al. further demonstrated that CRISPR-Cas9 direct cleavage and cleavage-mediated mutagenesis occurred in HBV cccDNA of transfected cells. In the mouse model carrying HBV cccDNA, injection of guide RNA-Cas9 plasmids via rapid tail vein resulted in the low level of cccDNA and HBV protein.

[001135] Liu et al. (J Gen Virol. 2015 Aug;96(8):2252-61. doi: 10.1099/vir.Q.000159. Epub 2015 Apr 22) designed eight guide RNAs (gRNAs) that targeted the conserved regions of different HBV genotypes, which could significantly inhibit HBV replication both in vitro and in vivo to investigate the possibility of using the CR1SPR-Cas9 system to disrupt the HBV DNA templates. The HBV-specific gRNA/Cpfl system could inhibit the replication of HBV of

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PCT/US2016/038181 different genotypes in cells, and the viral DNA was significantly reduced by a single gRNA/Cpfl system and cleared by a combination of different gRNA/Cpfl systems.

[001136] Wang et al. (World J Gastroenterol. 2015 Aug 28;21(32):9554-65. doi: 10.3748/wjg.v21.i32.9554) designed 15 gRNAs against HBV of genotypes A-D. Eleven combinations of two above gRNAs (dual-gRNAs) covering the regulator)' region of HBV were chosen. The efficiency of each gRNA and 11 dual-gRNAs on the suppression of HBV (genotypes A-D) replication was examined by the measurement of HBV surface antigen (HBsAg) or e antigen (HBeAg) in the culture supernatant. The destruction of HBV-expressing vector was examined in HuH7 cells co-transfected with dual-gRNAs and HBV-expressing vector using polymerase chain reaction (PCR) and sequencing method, and the destruction of cccDNA was examined in HepAD38 cells using KC1 precipitation, plasmid-safe ATP-dependent DNase (PSAD) digestion, rolling circle amplification and quantitative PCR combined method. The cytotoxicity of these gRNAs was assessed by a mitochondrial tetrazolium assay. All of gRNAs could significantly reduce HBsAg or HBeAg production in the culture supernatant, which was dependent on the region in which gRNA against. All of dual gRNAs could efficiently suppress HBsAg and/or HBeAg production for HBV of genotypes A-D, and the efficacy of dual gRNAs in suppressing HBsAg and/or HBeAg production was significantly increased when compared to the single gRNA used alone. Furthermore, by PCR direct sequencing we confirmed that these dual gRNAs could specifically destroy HBV expressing template by removing the fragment between the cleavage sites of the two used gRNAs. Most importantly, gRNA-5 and gRNA-12 combination not only could efficiently suppressing HBsAg and/or HBeAg production, but also destroy the cccDNA reservoirs in HepAD38 cells.

[001137] Karimova et al. (Sci Rep. 2015 Sep 3:5:13734. doi: 10.1038/srepl3734) identified cross-genotype conserved HBV sequences in the S and X region of the HBV genome that were targeted for specific and effective cleavage by a Cas9 nickase. This approach disrupted not only episomal cccDNA and chromosomally integrated HBV target sites in reporter cell lines, but also HBV replication in chronically and de novo infected hepatoma cell lines, [001138] One of skill in the art may utilize the above studies of, for example, Lin et al. (Mol Ther Nucleic Acids. 2014 Aug 19;3:el86. doi: 10.1038/mtna.2014.38), Dong et al. (.Antiviral Res. 2015 Jun;l 18:110-7. doi: 10.1016/).antiviral.2015.03.015. Epub 2015 Apr 3), Liu et al. (J Gen Virol. 2015 Aug;96(8):2252-61. doi: 10.1099/vir.0.000159. Epub 2015 Apr 22), Wang et al.

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PCT/US2016/038181 (World J Gastroenterol. 2015 Aug 28;21(32):9554-65. doi: 10.3748/wjg.v21.i32.9554) and Karimova et al. (Sci Rep. 2015 Sep 3;5:13734. doi: 10.1038/srepl3734) for targeting HBV with the CRISPR Cas system of the present invention.

[001139] Chronic hepatitis B virus (HBV) infection is prevalent, deadly, and seldom cured due to the persistence of viral episornal DNA (cccDNA) in infected cells. Ramanan et al. (Ramanan V, Shlomai A, Cox DB, Schwartz RE, Michailidis E, Bhatta A, Scott DA, Zhang F, Rice CM, Bhatia SN, .Sci Rep. 2015 Jun 2:5:10833. doi: 10.1038/srepl0833, published online 2nd June 2015.) showed that the CRISPR/Cas9 system can specifically target and cleave conserved regions in the HBV genome, resulting in robust suppression of viral gene expression and replication. Upon sustained expression of Cas9 and appropriately chosen guide RNAs, they demonstrated cleavage of cccDNA by Cas9 and a dramatic reduction in both cccDNA and other parameters of viral gene expression and replication. Thus, they showed that directly targeting viral episornal DNA is a novel therapeutic approach to control the virus and possibly cure patients. This is also described in WO2015Q89465 Al, in the name of The Broad Institute et al., the contents of which are hereby incorporated by reference [001140] As such targeting viral episornal DNA in HBV is preferred in some embodiments.

[001141] The present invention may aiso be applied to treat pathogens, e.g. bacterial, fungal and parasitic pathogens. Most research efforts have focused on developing new antibiotics, which once developed, would nevertheless be subject to the same problems of drug resistance. The invention provides novel CRISPR-based alternatives which overcome those difficulties. Furthermore, unlike existing antibiotics, CRISPR-based treatments can be made pathogen specific, inducing bacterial cell death of a target pathogen while avoiding beneficial bacteria.

[001142] The present invention may also be applied to treat hepatitis C virus (HCV). The methods of Roelvinki et al. (Molecular Therapy vol. 20 no. 9, 1737-1749 Sep 2012) may be applied to the CRISPR Cas system. For example, an AAV vector such as AAV8 may be a contemplated vector and for example a dosage of about 1.25 χ 1011 to 1.25 * 1013 vector genomes per kilogram body weight (vg/kg) may be contemplated.The present invention may also be applied to treat pathogens, e.g. bacterial, fungal and parasitic pathogens. Most research efforts have focused on developing new antibiotics, which once developed, would nevertheless be subject to the same problems of drug resistance. The invention provides novel CRISPR-based alternatives which overcome those difficulties. Furthermore, unlike existing antibiotics, CRISPR-based treatments can be made pathogen specific, inducing bacterial cell death of a target pathogen while avoiding beneficial bacteria.

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PCT/US2016/038181 [001143] Jiang et al. (“RNA-guided editing of bacterial genomes using CRISPR-Cas systems,” Nature Biotechnology vol. 31, p. 233-9, March 2013) used a CRISPR-Cas9 system to mutate or kill N. pneumoniae and E. coli. The work, which introduced precise mutations into the genomes, relied on dual-RNA: Cas9-directed cleavage at the targeted genomic site to kill unmutated cells and circumvented the need for selectable markers or counter-selection systems. CRISPR systems have be used to reverse antibiotic resistance and eliminate the transfer of resistance between strains. Bickard et al. showed that Cas9, reprogrammed to target virulence genes, kills virulent, but not avirulent, S. aureus. Reprogramming the nuclease to target antibiotic resistance genes destroyed staphylococcal plasmids that harbor antibiotic resistance genesand immunized against the spread of plasmid-borne resistance genes, (see, Bikard et al., “Exploiting CRISPRCas nucleases to produce sequence-specific antimicrobials,” Nature Biotechnology vol. 32, 1146-1150, doi:10.1038/nbt.3043, published online 05 October 2014.) Bikard showed that CRISPR-Cas9 antimicrobials function in vivo to kill S. aureus in a mouse skin colonization model. Similarly, Yosef et al used a CRISPR system to target genes encoding enzymes that confer resistance to β-lactam antibiotics (see Yousef et al., “Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria,” Proc. Natl. Acad. Sci. USA, vol. 112, p. 7267-7272, doi: 10.1073/pnas.1500107112 published online May 18, 2015).

[001144] CRISPR systems can he used to edit genomes of parasites that are resistant to other genetic approaches. For example, a CRISPR-Cas9 system was shown to introduce doublestranded breaks into the in the Plasmodiumyoelii genome (see, Zhang et ah, “Efficient Editing of Malaria Parasite Genome Using the CRISPR/Cas9 System,” mBio. vol. 5, ¢01414-14, Jul-Aug 2014). Ghorbal et al. (“Genome editing in the human malaria parasite Plasmodium falciparumusing the CRISPR-Cas9 system,” Nature Biotechnology, vol. 32, p. 819-821, doi: 10.1038/nbt.2925, published online June 1, 2014) modified the sequences of two genes, orcl and kelchl3, which have putative roles in gene silencing and emerging resistance to artemisinin, respectively. Parasites that were altered at the appropriate sites were recovered with very high efficiency, despite there being no direct selection for the modification, indicating that neutral or even deleterious mutations can be generated using this system. CRISPR-Cas9 is also used to modify the genomes of other pathogenic parasites, including Toxoplasma gondii (see Shen et al., “Efficient gene disruption in diverse strains of Toxoplasma gondii using CRISPR/CAS9,” mBio vol. 5:e01114-14, 2014; and Sidik et al., “Efficient Genome Engineering of Toxoplasma gondii

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Using CRISPR/Cas9,” PLoS One vol. 9, el00450, doi: 10.1371/joumal.pone.0100450, published online June 27, 2014).

[001145] Vyas et al. (“A Candida albicans CRISPR system permits genetic engineering of essential genes and gene families,” Science Advances, vol, 1, el500248, DOI:

10.1126/sciadv. 1500248, April 3, 2015) employed a CRISPR system to overcome long-standing obstacles to genetic engineering in C. albicans and efficiently mutate in a single experiment both copies of several different genes. In an organism where several mechanisms contribute to drug resistance, Vyas produced homozygous double mutants that no longer displayed the hyperresistance to fluconazole or cycloheximide displayed by the parental clinical isolate Can90. Vyas also obtained homozygous loss-of-function mutations in essential genes of (', albicans by creating conditional alleles. Null alleles of DCR1, which is required for ribosomal RNA processing, are lethal at low temperature but viable at high temperature. Vyas used a repair template that introduced a nonsense mutation and Isolated dcrl/dcrl mutants that failed to grow at 16°C.

[001146] The CRISPR-Cas systems of the present invention can be used to correct genetic mutations that were previously attempted with limited success using TALEN and ZFN and have been identified as potential targets for Cas9 systems, including as in published applications of Editas Medicine describing methods to use Cas9 systems to target loci to therapeutically address disesaes with gene therapy, including, WO 2015/048577 CRISPR-RELATED METHODS AND COMPOSITIONS of Gluckmann et al.; WO 2015/070083 CRISPR-RELATED METHODS

AND COMPOSITIONS WITH GOVERNING gRNAS of Glucksmann et al.; In some embodiments, the treatment, prophylaxis or diagnosis of Primary Open Angle Glaucoma (POAG) is provided. The target is preferably the MYOC gene. This is described in WO2015153780, the disclosure of which is hereby incorporated by reference.

[001147] Mention is made of WO2015/134812 CRISPR/CAS-RELATED METHODS AND

COMPOSITIONS FOR TREATING USHER SYNDROME AND RETINITIS PIGMENTOSA of Maeder et al. Through the teachings herein the invention comprehends methods and materials of these documents applied in conjunction with the teachings herein. In an aspect of ocular and auditory gene therapy, methods and compositions for treating Usher Syndrome and RetinisPigmentosa may be adapted to the CRISPR-Cas system of the present invention (see, e.g., WO

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2015/134812). In an embodiment, the WO 2015/134812 involves a treatment or delaying the onset or progression of Usher Syndrome type IIA (USH2A, USH11A) and retinitis pigmentosa 39 (RP39) by gene editing, e.g., using CRISPR-Cas9 mediated methods to correct the guanine deletion at position 2299 in the USH2A gene (e.g., replace the deleted guanine residue at position 2299 in the USH2A gene).A similar effect can be achieved with Cpfl. In a related aspect, a mutation is targeted by cleaving with either one or more nuclease, one or more nickase, or a combination thereof, e.g., to induce HDR with a donor template that corrects the point mutation (e.g., the single nucleotide, e.g., guanine, deletion). The alteration or correction of the mutant USH2A gene can be mediated by any mechanism. Exemplary mechanisms that can be associated with the alteration (e.g., correction) of the mutant HSH2A gene include, but are not limited to, non-homologous end joining, microhomology-mediated end joining (MMEJ), homology-directed repair (e.g., endogenous donor template mediated), SDSA (synthesis dependent strand annealing), single-strand annealing or single strand invasion. In an embodiment, the method used for treating Usher Syndrome and Retinis-Pigmentosa can include acquiring knowledge of the mutation carried by the subject, e.g., by sequencing the appropriate portion of the USH2A gene.

[001148] Mention is also made of WO 2015/138510 and through the teachings herein the invention (using a CRISPR-Cas9 system) comprehends providing a treatment or delaying the onset or progression of Leber’s Congenital Amaurosis 10 (LCA 10). LCA 10 is caused by a mutation in the CEP290 gene, e.g., a c,2991+1655, adenine to guanine mutation in the CEP290 gene which gives rise to a cryptic splice site in intron 26. This is a mutation at nucleotide 1655 of intron 26 of CEP290, e.g., an A to G mutation. CEP290 is also known as; CT87; MKS4; POC3; rdl6; BBS14; JBTS5; LCAJO; NPHP6; SLSN6; and 3HllAg (see, e.g., WO 2015/138510). In an aspect of gene therapy, the invention involves introducing one or more breaks near the site of the LCA target position (e.g., c.2991 + 1655; A to G) in at least one allele of the CEP290 gene. Altering the LCA10 target position refers to (1) break-induced introduction of an indel (also referred to herein as NHEJ-mediated introduction of an indel) in close proximity to or including a LCA10 target position (e.g., C.299I+1655A to G), or (2) break-induced deletion (also referred to herein as NHEJ-mediated deletion) of genomic sequence including the mutation at a LCA10 target position (e.g., C.2991+1655A to G). Both approaches give rise to the loss or destruction of

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PCT/US2016/038181 the cryptic splice site resulting from the mutation at the LCA 10 target position. Accordingly, the use of Cpfl in the treatment of LCA is specifically envisaged.

[001149] Researchers are contemplating whether gene therapies could be employed to treat a wide range of diseases. The CRISPR systems of the present invention based on Cpfl effector protein are envisioned for such therapeutic uses, including, but noted limited to further exexmplified targeted areas and with delivery methods as below. Some examples of conditions or diseases that might be usefully treated using the present system are included in the examples of genes and references included herein and are currently associated with those conditions are also provided there. The genes and conditions exemplified are not exhaustive.

Treating Diseases of the Circulatory System [001150] The present invention also contemplates delivering the CRISPR-Cas system, specifically the novel CRISPR effector protein systems described herein, to the blood or hematopoetic stem cells. The plasma exosomes of Wahlgren et al. (Nucleic Acids Research, 2012, Vol. 40, No. 17 el30) were previously described and may be utilized to deliver the CRISPR Cas system to the blood. The nucleic acid-targeting system of the present invention is also contemplated to treat hemoglobinopathies, such as thalassemias and sickle cell disease. See, e.g.. International Patent Publication No. WO 2013/126794 for potential targets that may be targeted by the CRISPR Cas system of the present invention.

[001151] Drakopoulou, “Review Article, The Ongoing Challenge of Hematopoietic Stem CellBased Gene Therapy for β-Thalassemia,” Stem Cells International, Volume 2011, Article II) 987980, 10 pages, doi: 10.4061/2011/987980, incorporated herein by reference along with the documents it cites, as if set out in full, discuss modifying HSCs using a lentivirus that delivers a gene for β-globin or γ-globin. In contrast to using lentivirus, with the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to β-Thalassemia using a CRISPR-Cas system that targets and corrects the mutation (e.g., with a suitable HDR template that delivers a coding sequence for β-globin or γ-globin, advantageously non-sickling β-globin or γ-globin); specifically, the guide RNA can target mutation that give rise to β-Thalassemia, and the HDR can provide coding for proper expression of β-globin or γ-globin. An guide RNA that targets the mutation-and-Cas protein containing particle is contacted with HSCs carrying the mutation. The particle also can contain a suitable HDR template to correct the mutation for proper expression of β-globin or γ-globin; or the HSC can be contacted with a second particle or

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PCT/US2016/038181 a vector that contains or delivers the HDR template. The so contacted cells can be administered; and optionally treated / expanded; cf. Cartier. In this regard mention is made of: Cavazzana, “Outcomes of Gene Therapy for β-Thalassemia Major via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral p^A'^187Q-Globin Vector.” tif2014.org/abstractFiles/Jean%20Antoine%20Ribeil__Abstract.pdf; Cavazzana-Calvo, “Transfusion independence and HMGA2 activation after gene therapy of human βthalassaemia”, Nature 467, 318--322 (16 September 2010) doi:10.1038/natureQ9328; Nienhuis, “Development of Gene Therapy for Thalassemia, Cold Spring Harbor Perpsectives in Medicine, doi: 10.1101/cshperspect.a011833 (2012), LentiGlobin BB305, a lentiviral vector containing an engineered β-globin gene (PA-T87Q); and Xie et al., “Seamless gene correction of βthalassaemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyback” Genome Research gr.173427.114 (2014) httpfowww.genome.org/cgi/doi/!0.1101/gr. 173427.114 (Cold Spring Harbor Laboratory Press); that is the subject of Cavazzana work involving human βthalassaemia and the subject of the Xie work, are all incorporated herein by reference, together with all documents cited therein or associated therewith. In the instant invention, the HDR template can provide for the HSC to express an engineered β-globin gene (e.g., PA-T87Q), or βglobin as in Xie.

[001152] Xu et al. (Sei Rep. 2015 Jul 9;5:12065. doi: 10.1038/srep 12065) have designed TALENs and CRISPR-Cas9 to directly target the intron2 mutation site IVS2-654 in the globin gene, Xu et al. observed different frequencies of double-strand breaks (DSBs) at IVS2-654 loci using TALENs and CRISPR-Cas9, and TALENs mediated a higher homologous gene targeting efficiency compared to CRISPR-Cas9 when combined with the piggyBac transposon donor. In addition, more obvious off-target events were observed for CRISPR-Cas9 compared to TALENs. Finally, TALENs-corrected iPSC clones were selected for erythroblast differentiation using the OP9 co-culture system and detected relatively higher transcription of HBB than the uncorrected cells.

[001153] Song et al, (Stem Cells Dev. 2015 May 1;24(9): 1053-65. doi: 10.1089/scd.2014.0347. Epub 2015 Feb 5) used CRISPR/ Cas9 to correct β-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no offtargeting effects. Then, Song et al. evaluated the differentiation efficiency of the gene-corrected β-Thal iPSCs. Song et al. found that during hematopoietic differentiation, gene-corrected β-Thal

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PCT/US2016/038181 iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected β-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Song et al.’s study suggested that hematopoietic differentiation efficiency of β-Thal iPSCs was greatly improved once corrected by the CRISPR-Cas9 system. Similar methods may be performed utilizing the CRISPR-Cas systems described herein, e.g. systems comprising Cpfl effector proteins.

[001154] Sickle cell anemia is an autosomal recessive genetic disease in which red blood cells become sickle-shaped. It is caused by a single base substitution in the β-globin gene, which is located on the short arm of chromosome 11. As a result, valine is produced instead of glutamic acid causing the production of sickle hemoglobin (HbS). This results in the formation of a distorted shape of the erythrocytes. Due to this abnormal shape, small blood vessels can be blocked, causing serious damage to the bone, spleen and skin tissues. This may lead to episodes of pain, frequent infections, hand-foot syndrome or even multiple organ failure. The distorted erythrocytes are also more susceptible to hemolysis, which leads to serious anemia.. As in the case of β-thalassaemia, sickle cell anemia can be corrected by modifying HSCs with the CRISPR-Cas system. The system allows the specific editing of the cell's genome by cutting its DNA and then letting it repair itself. The Cas protein is inserted and directed by a RNA guide to the mutated point and then it cuts the DNA at that point. Simultaneously, a healthy version of the sequence is inserted. This sequence is used by the cell’s own repair system to fix the induced cut. In this way, the CRISPR-Cas allows the correction of the mutation in the previously obtained stem cells. With the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to sickle cell anemia using a CRISPR-Cas system that targets and corrects the mutation (e.g., with a suitable HDR template that delivers a coding sequence for β-globin, advantageously non-sickling β-globin); specifically, the guide RNA can target mutation that give rise to sickle cell anemia, and the HDR can provide coding for proper expression of β-globin. An guide RN A that targets the mutation-and-Cas protein containing particle is contacted with HSCs carrying the mutation. The particle also can contain a suitable HDR template to correct the mutation for proper expression of β-globin; or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. The so contacted cells can be

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PCT/US2016/038181 administered; and optionally treated / expanded, cf. Cartier. The 11 DR template can provide for the HSC to express an engineered β-globin gene (e.g., PA-T87Q), or β-globin as in Xie.

[001155] Williams, “Broadening the Indications for Hematopoietic Stem Cell Genetic Therapies,” Cell Stem Cell 13:263-264 (2013), incorporated herein by reference along with the documents it cites, as if set out in full, report lentivirus-mediated gene transfer into HSC/P cells from patients with the lysosomal storage disease metachromatic leukodystrophy disease (MLD), a genetic disease caused by deficiency of arylsulfatase A (ARSA), resulting in nerve demyelination; and lentivirus-mediated gene transfer into HSCs of patients with Wiskott-Aldrich syndrome (W AS ) (patients with defective W AS protein, an effector of the small GTPase CDC42 that regulates cytoskeletal function in blood cell lineages and thus suffer from immune deficiency with recurrent infections, autoimmune symptoms, and thrombocytopenia with abnormally small and dysfunctional platelets leading to excessive bleeding and an increased risk of leukemia and lymphoma). In contrast to using lentivirus, with the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to MLD (deficiency of arylsulfatase A (ARSA)) using a CRISPR-Cas system that targets and corrects the mutation (deficiency of arylsulfatase A (ARSA)) (e.g., with a suitable HDR template that delivers a coding sequence for ARSA); specifically, the guide RNA can target mutation that gives rise to MLD (deficient ARSA), and the HDR can provide coding for proper expression of ARSA. An guide RNA that targets the mutation-and-Cas protein containing particle is contacted with HSCs carrying the mutation. The particle also can contain a suitable HDR template to correct the mutation for proper expression of ARSA; or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. The so contacted cells can be administered; and optionally treated / expanded; cf. Cartier. In contrast to using lentivirus, with the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to WAS using a CRISPR-Cas system that targets and corrects the mutation (deficiency of WAS protein) (e.g., with a suitable HDR template that delivers a coding sequence for WAS protein); specifically, the guide RNA can target mutation that gives rise to WAS (deficient WAS protein), and the HDR can provide coding for proper expression of WAS protein. An guide RNA that targets the mutation-and-Cpfl protein containing particle is contacted with HSCs carrying the mutation. The particle also can contain a suitable HDR template to correct the mutation for proper expression of WAS protein; or the HSC can be contacted with a second particle or a

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PCT/US2016/038181 vector that contains or delivers the HDR template. The so contacted cells can be administered, and optionally treated / expanded; cf. Cartier.

[001156] Watts, “Hematopoietic Stem Cell Expansion and Gene Therapy” Cytotherapy 13(10):1164-1171. doi: 10.3109/14653249.2011.620748 (2011), incorporated herein by reference along with the documents it cites, as if set out in full, discusses hematopoietic stem cell (HSC) gene therapy, e.g., virus-mediated HSC gene thereapy, as an highly attractive treatment option for many disorders including hematologic conditions, immunodeficiencies including HIV/AIDS, and other genetic disorders like lysosomal storage diseases, including SCID-ΧΙ, ADA-SCID, βthalassemia, X-linked CGD, Wiskott-Aldrich syndrome, Fanconi anemia, adrenoleukodystrophy (ALD), and metachromatic leukodystrophy (MLD).

[001157] US Patent Publication Nos. 20110225664, 20110091441, 20100229252,

20090271881 and 20090222937 assigned to Cellectis, relates to CREI variants , wherein at least one of the two I-Crel monomers has at least two substitutions, one in each of the two functional subdomains of the LAGLIDADG (SEQ ID NO: 26) core domain situated respectively from positions 26 to 40 and 44 to 77 of I-Crel, said variant being able to cleave a DNA target sequence from the human interleukin-2 receptor gamma chain (IL2RG) gene also named common cytokine receptor gamma chain gene or gamma C gene. The target sequences identified in US Patent Publication Nos. 20110225664, 20110091441, 20100229252, 20090271881 and 20090222937 may be utilized for the nucleic acid-targeting system of the present invention. [001158] Severe Combined Immune Deficiency (SCID) results from a defect in lymphocytes T maturation, always associated with a functional defect in lymphocytes B (Cavazzana-Calvo et al., Annu, Rev, Med., 2005, 56, 585-602; Fischer et al., Immunol. Rev., 2005, 203, 98-109). Overall incidence is estimated to 1 in 75 000 births. Patients with untreated SCID are subject to multiple opportunist micro-organism infections, and do generally not live beyond one year. SCID can be treated by allogenic hematopoietic stem cell transfer, from a familial donor. Histocompatibility with the donor can vary widely. In the case of Adenosine Deaminase (ADA) deficiency, one of the SCID forms, patients can be treated by injection of recombinant Adenosine Deaminase enzyme.

[001159] Since the ADA gene has been shown to be mutated in SCID patients (Giblett et al., Lancet, 1972, 2, 1067-1069), several other genes involved in SCID have been identified (Cavazzana-Calvo et al., Annu. Rev. Med., 2005, 56, 585-602; Fischer et ah, Immunol. Rev.,

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2005, 203, 98-109). There are four major causes for SCID: (i) the most frequent form of SCID, SCID-X1 (X-linked SCID or X-SCID), is caused by mutation in the IL2RG gene, resulting in the absence of mature T lymphocytes and NK cells. IL2RG encodes the gamma C protein (Noguchi, et al., Cell, 1993, 73, 147-157), a common component of at least five interleukin receptor complexes. These receptors activate several targets through the JAK3 kinase (Macchi et al., Nature, 1995, 377, 65-68), which inactivation results in the same syndrome as gamma C inactivation; (ii) mutation in the ADA gene results in a defect in purine metabolism that is lethal for lymphocyte precursors, which in turn results in the quasi absence of B, T and NK cells, (iii) V(D)J recombination is an essential step in the maturation of immunoglobulins and T lymphocytes receptors (TCRs). Mutations in Recombination Activating Gene 1 and 2 (RAG1 and RAG2) and Artemis, three genes involved in this process, result in the absence of mature T and B lymphocytes; and (iv) Mutations in other genes such as CD45, involved in T cell specific signaling have also been reported, although they represent a minority of cases (Cavazzana-Calvo et al., Annu. Rev. Med., 2005, 56, 585-602; Fischer et al., Immunol. Rev., 2005, 203, 98-109). Since when their genetic bases have been identified, the different SCID forms have become a paradigm for gene therapy approaches (Fischer et al., Immunol. Rev., 2005, 203, 98-109) for two major reasons. First, as in all blood diseases, an ex vivo treatment can be envisioned. Hematopoietic Stem Cells (HSCs) can be recovered from bone marrow, and keep their pluripotent properties for a few cell divisions. Therefore, they can be treated in vitro, and then reinjected into the patient, where they repopulate the bone marrow. Second, since the maturation of lymphocytes is impaired in SCID patients, corrected cells have a selective advantage. Therefore, a small number of corrected cells can restore a functional immune system. This hypothesis was validated several times by (i) the partial restoration of immune functions associated with the reversion of mutations in SCID patients (Hirschhorn et al., Nat. Genet., 1996, 13, 290-295; Stephan et al., N. Engl. J. Med., 1996, 335, 1563-1567; Bousso et al., Proc. Natl., Acad. Sci. USA, 2000, 97, 274-278, Wada et al., Proc. Natl. Acad. Sci. USA, 2001, 98, 86978702, Nishikomori et al.. Blood, 2004, 103, 4565-4572), (ii) the correction of SCID-X1 deficiencies in vitro in hematopoietic cells (Candotti et al., Blood, 1996, 87, 3097-3102; Cavazzana-Calvo et ah, Blood, 1996, Blood, 88, 3901-3909, Taylor et al,, Blood, 1996, 87, 3103-3107; Hacein-Bey et al., Blood, 1998, 92, 4090-4097), (iii) the correction of SCID-X1 (Soudais et al., Blood, 2000, 95, 3071-3077; Tsai et al., Blood, 2002, 100, 72-79), JAK-3

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PCT/US2016/038181 (Bunting et al., Nat. Med., 1998, 4, 58-64; Bunting et ai., Hum. Gene Ther., 2000, 11, 23532364) and RAG2 (Yates et al., Blood, 2002, 100, 3942-3949) deficiencies in vivo in animal models and (iv) by the result of gene therapy clinical trials (Cavazzana-Calvo et al., Science, 2000, 288, 669-672; Aiuti et al., Nat, Med,, 2002; 8, 423-425; Gaspar et al,, Lancet 2004, 364, 2181-2187).

[001160] US Patent Publication No. 20110182867 assigned to the Children’s Medical Center Corporation and the President and Fellows of Harvard College relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies. The targets disclosed in US Patent Publication No. 20110182867, such as BCL11A, may be targeted by the CRISPR Cas system of the present invention for modulating fetal hemoglobin expression. See also Bauer et al. (Science 11 October 2013: Vol. 342 no. 6155 pp. 253-257) and Xu et al. (Science 18 November 2011: Vol, 334 no. 6058 pp. 993-996) for additional BCL11A targets, [001161] With the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to a genetic hematologic disorder, e.g,, β-Thalassemia, Hemophilia, or a genetic lysosomal storage disease.

HSC—Delivery to and Editing of Hematopoetic Stem Cells; and Particular Conditions. [001162] The term “Hematopoetic Stem Cell” or “HSC” is meant to include broadly those cells considered to be an HSC, e.g., blood cells that give rise to all the other blood cells and are derived from mesoderm; located in the red bone marrow, which is contained in the core of most bones. HSCs of the invention include cells having a phenotype of hematopoeitic stem cells, identified by small size, lack of lineage (tin) markers, and markers that belong to the cluster of differentiation series, like: CD34, CD38, CD90, CD133, CD1Q5, CD45, and also c-kit, - the receptor for stem cell factor. Hematopoietic stem cells are negative for the markers that are used for detection of lineage commitment, and are, thus, called Lin-; and, during their purification by FACS, a number of up to 14 different mature blood-lineage markers, e.g., CD 13 & CD33 for myeloid, CD71 for erythroid, CD19 for B cells, CD61 for megakaryocytic, etc. for humans, and, B220 (murine CD45) for B cells, Mac-1 (CD1 lb/CD18) for monocytes, Gr-1 for Granulocytes, Terl 19 for erythroid cells, I17Ra, CD3, CD4, CDS, CDS for T cells, etc. Mouse HSC markers: CD341o/-, SCA-1+, Thyl.l+/lo, CD38+, C-kit+, lin-, and Human HSC markers: CD34+, CD59+, Thyl/CD90+, CD381o/-, C-kit/CDl 17+, and lin-. HSCs are identified by markers.

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Hence in embodiments discussed herein, the HSCs can be CD34+ cells. HSCs can also be hematopoietic stem cells that are CD34-/CD38-. Stem cells that may lack c-kit on the cell surface that are considered in the art as HSCs are within the ambit of the invention, as well as CD133+ cells likewise considered HSCs in the art.

[001163] The CRISPR-Cas (eg Cpfl) system may be engineered to target genetic locus or loci in HSCs. Cas (eg Cpfl) protein, advantageously codon-optimized for a eukaryotic cell and especially a mammalian cell, e.g.,a human cell, for instance, HSC, and sgRNA targeting a locus or loci in HSC, e.g., the gene EMX1, may be prepared. These may be delivered via particles. The particles may be formed by the Cas (eg Cpfl) protein and the gRNA being admixed. The gRNA and Cas (eg Cpfl) protein mixture may for example be admixed with a mixture comprising or consisting essentially of or consisting of surfactant, phospholipid, biodegradable polymer, lipoprotein and alcohol, whereby particles containing the gRNA and Cas (eg Cpfl) protein may be formed. The invention comprehends so making particles and particles from such a method as well as uses thereof.

[001164] More generally, particles may be formed using an efficient process. First, Cas (eg Cpfl) protein and gRNA targeting the gene EMX1 or the control gene LacZ may be mixed together at a suitable, e.g.,3:l to 1:3 or 2:1 to 1:2 or 1:1 molar ratio, at a suitable temperature, e.g., 15-30C, e.g., 20-25C, e.g., room temperature, for a suitable time, e.g., 15-45, such as 30 minutes, advantageously in sterile, nuclease free buffer, e.g., IX PBS. Separately, particle components such as or comprising: a surfactant, e.g., cationic lipid, e.g., 1,2-di oleoyl-3 trimethylammonium-propane (DOTAP); phospholipid, e.g., dimyristoylphosphatidylcholine (DMPC); biodegradable polymer, such as an ethylene-glycol polymer or PEG, and a lipoprotein, such as a low-density lipoprotein, e.g., cholesterol may be dissolved in an alcohol, advantageously a Cl-6 alkyl alcohol, such as methanol, ethanol, isopropanol, e.g., 100% ethanol. The two solutions may be mixed together to form particles containing the Cas (eg Cpfl)-gRNA complexes. In certain embodiments the particle can contain an HDR template. That can be a particle co-administered with gRNA+Cas (eg Cpfl) protein-contain! ng particle, or i.e,, in addition to contacting an HSC with an gRNA+Cas (eg Cpfl) protein-containing particle, the HSC is contacted with a particle containing an HDR template; or the HSC is contacted with a particle containing all of the gRNA, Cas (eg Cpfl) and the HDR template. The HDR template can be administered by a separate vector, whereby in a first instance the particle penetrates an

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HSC cell and the separate vector also penetrates the cell, wherein the HSC genome is modified by the gRNA+Cas (eg Cpfl) and the HDR template is also present, whereby a genomic loci is modified by the HDR; for instance, this may result in correcting a mutation.

[001165] After the particles form, HSCs in 96 well plates may be transfected with 15ug Cas (eg Cpfl) protein per well. Three days after transfection, HSCs may be harvested, and the number of insertions and deletions (indels) at the EMXI locus may be quantified.

[001166] This illustrates how HSCs can be modified using CRISPR-Cas (eg Cpfl) targeting a genomic locus or loci of interest in the HSC. The HSCs that are to be modified can be in vivo, i.e., in an organism, for example a human or a non-human eukaryote, e.g., animal, such as fish, e.g., zebra fish, mammal, e.g., primate, e.g., ape, chimpanzee, macaque, rodent, e.g., mouse, rabbit, rat, canine or dog, livestock (cow / bovine, sheep / ovine, goat or pig), fowl or poultry, e.g., chicken. The HSCs that are to be modified can be in vitro, i.e., outside of such an organism. And, modified HSCs can be used ex vivo, i.e,, one or more HSCs of such an organism can be obtained or isolated from the organism, optionally the HSC(s) can be expanded, the HSC(s) are modified by a composition comprising a CRISPR-Cas (eg Cpfl) that targets a genetic locus or loci in the HSC, e.g., by contacting the HSC(s) with the composition, for instance, wherein the composition comprises a particle containing the CRISPR enzyme and one or more gRNA that targets the genetic locus or loci in the HSC, such as a particle obtained or obtainable from admixing an gRNA and Cas (eg Cpfl) protein mixture with a mixture comprising or consisting essentially of or consisting of surfactant, phospholipid, biodegradable polymer, lipoprotein and alcohol (wherein one or more gRNA targets the genetic locus or loci in the HSC), optionally expanding the resultant modified HSCs and administering to the organism the resultant modified HSCs. In some instances the isolated or obtained HSCs can be from a first organism, such as an organism from a same species as a second organism, and the second organism can be the organism to which the the resultant modified HSCs are administered, e.g., the first organism can be a donor (such as a relative as in a parent or sibling) to the second organism. Modified HSCs can have genetic modifications to address or allexdate or reduce symptoms of a disease or condition state of an individual or subject or patient. Modified HSCs, e.g., in the instance of a first organism donor to a second organism, can have genetic modifications to have the HSCs have one or more proteins e.g. surface markers or proteins more like that of the second organism. Modified HSCs can have genetic modifications to simulate a a disease or condition state of an

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PCT/US2016/038181 individual or subject or patient and would be re-administered to a non-human organism so as to prepare an animal model. Expansion of HSCs is within the ambit of the skilled person from this disclosure and knowledge in the art, see e.g., Lee, “Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4.” Blood. 2013 May 16;121(20):4082-9. doi: 10.1182/blood-2012-09-455204. Epub 2013 Mar 21.

[001167] As indicated to improve activity, gRNA may be pre-complexed with the Cas (eg Cpfl) protein, before formulating the entire complex in a particle. Formulations may be made with a different molar ratio of different components known to promote delivery of nucleic acids into cells (e.g. l,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-ditetradecanoyl-snglycero-3-phosphocholine (DMPC), polyethylene glycol (PEG), and cholesterol) For example DOTAP : DMPC : PEG : Cholesterol Molar Ratios may be DOTAP 100, DMPC 0, PEG 0, Cholesterol 0; or DOTAP 90, DMPC 0, PEG 10, Cholesterol 0; or DOTAP 90, DMPC 0, PEG 5, Cholesterol 5. DOTAP 100, DMPC 0, PEG 0, Cholesterol 0. The invention accordingly comprehends admixing gRNA, Cas (eg Cpfl) protein and components that form a particle; as well as particles from such admixing.

[001168] In a preferred embodiment, particles containing the Cas (eg Cpfl)-gRNA complexes may be formed by mixing Cas (eg Cpfl) protein and one or more gRNAs together, preferably at a 1:1 molar ratio, enzyme: guide RNA. Separately, the different components known to promote delivery of nucleic acids (e.g. DOTAP, DMPC, PEG, and cholesterol) are dissolved, preferably in ethanol. The two solutions are mixed together to form particles containing the Cas (eg Cpfl )gRNA complexes. After the particles are formed, Cas (eg Cpfl)-gRNA complexes may be transfected into cells (e.g, HSCs). Bar coding may be applied. The particles, the Cas-9 and/or the gRNA may be barcoded.

[001169] The invention in an embodiment comprehends a method of preparing an gRNA-andCas (eg Cpfl) protein containing particle comprising admixing an gRNA and Cas (eg Cpfl) protein mixture with a mixture comprising or consisting essentially of or consisting of surfactant, phospholipid, biodegradable polymer, lipoprotein and alcohol. An embodiment comprehends an gRNA-and-Cas (eg Cpfl) protein containing particle from the method. The invention in an embodiment comprehends use of the particle in a method of modifying a genomic locus of interest, or an organism or a non-human organism by manipulation of a target sequence in a genomic locus of interest, comprising contacting a cell containing the genomic locus of interest

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PCT/US2016/038181 with the particle wherein the gRNA targets the genomic locus of interest; or a method of modifying a genomic locus of interest, or an organism or a non-human organism by manipulation of a target sequence in a genomic locus of interest, comprising contacting a cell containing the genomic locus of interest with the particle wherein the gRNA targets the genomic locus of interest. In these embodiments, the genomic locus of interest is advantageously a genomic locus in an HSC.

[001170] Considerations for Therapeutic Applications: A consideration in genome editing therapy is the choice of sequence-specific nuclease, such as a variant of a Cpfl nuclease. Each nuclease variant may possess its own unique set of strengths and weaknesses, many of which must be balanced in the context of treatment to maximize therapeutic benefit. Thus far, two therapeutic editing approaches with nucleases have shown significant promise: gene disruption and gene correction. Gene disruption involves stimulation of NHEJ to create targeted indels in genetic elements, often resulting in loss of function mutations that are beneficial to patients. In contrast, gene correction uses HDR to directly reverse a disease causing mutation, restoring function while preserving physiological regulation of the corrected element. HDR may also be used to insert a therapeutic transgene into a defined ‘safe harbor’ locus in the genome to recover missing gene function. For a specific editing therapy to be efficacious, a sufficiently high level of modification must be achieved in target cell populations to reverse disease symptoms. This therapeutic modification ‘threshold’ is determined by the fitness of edited cells following treatment and the amount of gene product necessary to reverse symptoms. With regard to fitness, editing creates three potential outcomes for treated cells relative to their unedited counterparts: increased, neutral, or decreased fitness. In the case of increased fitness, for example in the treatment of SCID-XI, modified hematopoietic progenitor cells selectively expand relative to their unedited counterparts. SCID-XI is a disease caused by mutations in the IL2RG gene, the function of which is required for proper development of the hematopoietic lymphocyte lineage [Leonard, W.J., et al. Immunological reviews 138, 61-86 (1994); Kaushansky, K. & Williams, W.J. Williams hematology, (McGraw-Hill Medical, New York, 2010)]. In clinical trials with patients who received viral gene therapy for SCID-XI, and a rare example of a spontaneous correction of SCID-XI mutation, corrected hematopoietic progenitor cells may be able to overcome this developmental block and expand relative to their diseased counterparts to mediate therapy [Bousso, P., et al. Proceedings of the National Academy of Sciences of the United States

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PCT/US2016/038181 of America 97, 274-278 (2000), Hacein-Bey-Abina, S., et al. The New England journal of medicine 346, 1185-1193 (2002); Gaspar, H.B., et al. Lancet 364, 2181-2187 (2004)]. In this case, where edited cells possess a selective advantage, even low numbers of edited cells can be amplified through expansion, providing a therapeutic benefit to the patient. In contrast, editing for other hematopoietic diseases, like chronic granulomatous disorder (CGD), would induce no change in fitness for edited hematopoietic progenitor cells, increasing the therapeutic modification threshold. CGD is caused by mutations in genes encoding phagocytic oxidase proteins, which are normally used by neutrophils to generate reactive oxygen species that kill pathogens [Mukherjee, S. & Thrasher, A.J. Gene 525, 174-181 (2013)]. As dysfunction of these genes does not influence hematopoietic progenitor cell fitness or development, but only the ability of a mature hematopoietic cell type to fight Infections, there would be likely no preferential expansion of edited cells in this disease. Indeed, no selective advantage for gene corrected cells in CGD has been observed in gene therapy trials, leading to difficulties with longterm cell engraftment [Malech, H.L., et al. Proceedings of the National Academy of Sciences of the United States of America 94, 12133-12138 (1997); Kang, H.J., et al. Molecular therapy : the journal of the American Society of Gene Therapy 19, 2092-2101 (2011)]. As such, significantly higher levels of editing would be required to treat diseases like CGD, where editing creates a neutral fitness advantage, relative to diseases where editing creates increased fitness for target cells. If editing imposes a fitness disadvantage, as would be the case for restoring function to a tumor suppressor gene in cancer cells, modified cells would be outcompeted by their diseased counterparts, causing the benefit of treatment to be low relative to editing rates. This latter class of diseases would be particularly difficult to treat with genome editing therapy, [001171] In addition to cell fitness, the amount of gene product necessary to treat disease also influences the minimal level of therapeutic genome editing that must be achieved to reverse symptoms. Haemophilia B is one disease where a small change in gene product levels can result in significant changes in clinical outcomes. This disease is caused by mutations in the gene encoding factor IX, a protein normally secreted by the liver into the blood, where it functions as a component of the clotting cascade. Clinical severity of haemophilia B is related to the amount of factor IX activity. Whereas severe disease is associated with less than 1% of normal activity, milder forms of the diseases are associated with greater than 1% of factor IX activity [Kaushansky, K. & Williams, W.J. Williams hematology, (McGraw-Hill Medical, New York,

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2010); Lofqvist, T,, et al. Journal of internal medicine 241, 395-400 (1997)]. This suggests that editing therapies that can restore factor IX expression to even a small percentage of liver cells could have a large impact on clinical outcomes. A study using ZFNs to correct a mouse model of haemophilia B shortly after birth demonstrated that 3-7% correction was sufficient to reverse disease symptoms, providing preclinical evidence for this hypothesis [Li, H., et al. Nature 475, 217-221 (2011)].

[001172] Disorders where a small change in gene product levels can influence clinical outcomes and diseases where there is a fitness advantage for edited cells, are ideal targets for genome editing therapy, as the therapeutic modification threshold is low enough to permit a high chance of success given the current technology. Targeting these diseases has now resulted in successes with editing therapy at the preclinical level and a phase I clinical trial. Improvements in DSB repair pathway manipulation and nuclease deliver}⁷ are needed to extend these promising results to diseases with a neutral fitness advantage for edited cells, or where larger amounts of gene product are needed for treatment. The Table below shows some examples of applications of genome editing to therapeutic models, and the references of the below⁷ Table and the documents cited in those references are hereby incorporated herein by reference as if set out in full.

Disease Type	Nuclease Platform Employed	Therapeutic Strategy	References
Hemophilia B	ZFN	HDR-mediated insertion of correct gene sequence	Li, H„ et al. Nature 475, 217-221 (2.011)
SCID	ZFN	HDR-mediated insertion of correct gene sequence	Genovese, P., etal. Nature 510, 235-240 (2014)
Hereditary tyrosinemia	CRISPR	HDR-m edi ated correction of mutation i n liver	Yin, H., et al. Nature biotechnology 32, 551-553 (2014)

[001173] Addressing each of the conditions of the foreging table, using the CRISPR-Cas (eg Cpfl) system to target by either HDR-mediated correction of mutation, or HDR-mediated insertion of correct gene sequence, advantageously via a deliver}’ system as herein, e.g., a particle delivery system, is within the ambit of the skilled person from this disclosure and the knowledge in the art. Thus, an embodiment comprehends contacting a Hemophilia B, SCID (e.g., SCID-X1, ADA-SCID) or Hereditary tyrosinemia mutation-carrying HSC with an gRNA366

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PCT/US2016/038181 and-Cas (eg Cpfl) protein containing particle targeting a genomic locus of interest as to Hemophilia B, SCID (e.g., SCID-X1, ADA-SCID) or Hereditary tyrosinemia (e.g., as in Li, Genovese or Yin). The particle also can contain a suitable HDR template to correct the mutation; or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. In this regard, it is mentioned that Haemophilia B is an X-linked recessive disorder caused by loss-of-function mutations in the gene encoding Factor IX, a crucial component of the clotting cascade. Recovering Factor IX activity to above 1% of its levels in severely affected individuals can transform the disease into a significantly milder form, as infusion of recombinant Factor LX into such patients prophylactically from a young age to achieve such levels largely ameliorates clinical complications. With the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to Haemophilia B using a CRISPR-Cas (eg Cpfl) system that targets and corrects the mutation (X-linked recessive disorder caused by lossof-function mutations in the gene encoding Factor IX) (e.g., with a suitable HDR template that delivers a coding sequence for Factor IX); specifically, the gRNA can target mutation that give rise to Haemophilia B, and the HDR can provide coding for proper expression of Factor IX. An gRNA that targets the mutation-and-Cas (eg Cpfl) protein containing particle is contacted with HSCs carrying the mutation. The particle also can contain a suitable HDR template to correct the mutation for proper expression of Factor IX; or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. The so contacted cells can be administered; and optionally treated / expanded; cf. Cartier, discussed herein, [001174] In Cartier, “MINI-SYMPOSIUM: Χ-Linked Adrenoleukodystrophypa,

Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in XLinked Adrenoleukodystrophy,” Brain Pathology 20 (2010) 857-862, incorporated herein by reference along with the documents it cites, as if set out in full, there is recognition that allogeneic hematopoietic stem cell transplantation (HSCT) was utilized to deliver normal lysosomal enzyme to the brain of a patient with Hurler’s disease, and a discussion of HSC gene therapy to treat ALD. In two patients, peripheral CD34+cells were collected after granulocytecolony stimulating factor (G-CSF) mobilization and transduced with an myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer binding site substituted (MND)-ALD lentiviral vector. CD34+ cells from the patients were transduced with the MNDALD vector during 16 h in the presence of cytokines at low concentrations. Transduced CD34+

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PCT/US2016/038181 cells were frozen after transduction to perform on 5% of cells various safety tests that included in particular three replication-competent lentivirus (RCL) assays. Transduction efficacy of CD34+ cells ranged from 35% to 50% with a mean number of lentiviral integrated copy between 0.65 and 0.70, After the thawing of transduced CD34+ cells, the patients were reinfused with more than 4.106 transduced CD34+ cells/kg following full myeloablation with busulfan and cyclophos-phamide. The patient’s HSCs were ablated to favor engraftment of the gene-corrected HSCs. Hematological recovery occurred between days 13 and 15 for the two patients. Nearly complete immunological recover)⁷ occurred at 12 months for the first patient, and at 9 months for the second patient. In contrast to using lentivirus, with the knowledge in the art and the teachings in this disclosure, the skilled person can correct HSCs as to ALD using a CRISPR-Cas (Cpfl) system that targets and corrects the mutation (e.g., with a suitable HDR template); specifically, the gRNA can target mutations in ABCD1, a gene located on the X chromosome that codes for ALD, a peroxisomal membrane transporter protein, and the HDR can provide coding for proper expression of the protein. An gRNA that targets the mutation-and-Cas (Cpfl) protein containing particle is contacted with HSCs, e.g., CD34+ cells carrying the mutation as in Cartier. The particle also can contain a suitable HDR template to correct the mutation for expression of the peroxisomal membrane transporter protein; or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. The so contacted cells optimally can be treated as in Cartier. The so contacted cells can be administered as in Cartier.

[001175] Mention is made of WO 2015/148860, through the teachings herein the invention comprehends methods and materials of these documents applied in conjunction with the teachings herein. In an aspect of blood-related disease gene therapy, methods and compositions for treating beta thalassemia may be adapted to the CRISPR-Cas system of the present invention (see, e.g., WO 2015/148860). In an embodiment, WO 2015/148860 involves the treatment or prevention of beta thalassemia, or its symptoms, e.g., by altering the gene for B-cell CLL/lymphoma 11A (BCLL1A). The BCL11A gene is also known as B-cell CLL/lymphoma 11 A, BCL11A -L, BCL11A -S, BCL11AXL, CTIP 1, HBFQTL5 and ZNF. BCL11A encodes a zinc-finger protein that is involved in the regulation of globin gene expression. By altering the BCL11A gene (e.g., one or both alleles of the BCL11A gene), the levels of gamma globin can he increased. Gamma globin can replace beta globin in the hemoglobin complex and effectively carry oxygen to tissues, thereby ameliorating beta thalassemia di sease phenotypes.

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PCT/US2016/038181 [001176] Mention is also made of WO 2015/148863 and through the teachings herein the invention comprehends methods and materials of these documents which may be adapted to the CRISPR-Cas system of the present invention. In an aspect of treating and preventing sickle cell disease, which is an inherited hematologic disease, WO 2015/148863 comprehends altering the BCL11A gene. By altering the BCL11A gene (e.g., one or both alleles of the BCL11A gene), the levels of gamma globin can be increased. Gamma globin can replace beta globin in the hemoglobin complex and effectively carry oxygen to tissues, thereby ameliorating sickle cell disease phenotypes.

[001177] In an aspect of the invention, methods and compositions which involve editing a target nucleic acid sequence, or modulating expression of a target nucleic acid sequence, and applications thereof in connection with cancer immunotherapy are comprehended by adapting the CRISPR-Cas system of the present invention. Reference is made to the application of gene therapy in WO 2015/161276 which involves methods and compositions which can be used to affect T-cell proliferation, survival and/or function by altering one or more T-cell expressed genes, e.g., one or more of FAS, BID, CTLA4, PDCD1, CBLB, PTPN6, TRAC and/or TRBC genes. In a related aspect, T-cell proliferation can be affected by altering one or more T -cell expressed genes, e.g., the CBLB and/or PTPN6 gene, FAS and/ or BID gene, CTLA4 and/or PDCDI and/or TRAC and/or TRBC gene.

[001178] Chimeric antigen receptor (CAR)19 T-cells exhibit anti-leukemic effects in patient malignancies. However, leukemia patients often do not have enough T-cells to collect, meaning that treatment must involve modified T cells from donors. Accordingly, there is interest in establishing a bank of donor T-cells, Qasim et al. (“First Clinical Application of Talen Engineered Universal CAR19 T Cells in B-ALL” ASH 57th Annual Meeting and Exposition, Dec. 5-8, 2015, Abstract 2046 (https://ash.confex.com/ash/2015/webprogram/Paper81653.html published online November 2015) discusses modifying CAR19 T cells to eliminate the risk of graft-versus-host disease through the disruption of T-cell receptor expression and CD52 targeting. Furthermore, CD52 cells were targeted such that they became insensitive to Alemtuzumab, and thus allowed Alemtuzumab to prevent host-mediated rejection of human leukocyte antigen (HLA) mismatched CAR19 T-cells. Investigators used third generation selfinactivating lentiviral vector encoding a 4g7 CAR19 (CD19 scFv-4-lBB-CD3() linked to RQR8, then electroporated cells with two pairs of TALEN mRNA for multiplex targeting for both the T369

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PCT/US2016/038181 cell receptor (TCR) alpha constant chain locus and the CD52 gene locus. Cells which were still expressing TCR following ex vivo expansion were depleted using CliniMacs α/β TCR depletion, yielding a T-cell product (UCART19) with <1% TCR expression, 85% of which expressed CAR19, and 64% becoming CD52 negative. The modified CAR19 T cells were administered to treat a patient’s relapsed acute lymphoblastic leukemia. The teachings provided herein provide effective methods for providing modified hematopoietic stem cells and progeny thereof, including but not limited to cells of the myeloid and lymphoid lineages of blood, including T cells, B cells, monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, and megakaryocytes or platelets, and natural killer cells and their precursors and progenitors. Such cells can be modified by knocking out, knocking in, or otherwise modulating targets, for example to remove or modulate CD52 as described above, and other targets, such as, without limitation, CXCR4, and PD-1. Thus compositions, cells, and method of the invention can be used to modulate immune responses and to treat, without limitation, malignancies, viral infections, and immune disorders, in conjunction with modification of administration of T cells or other cells to patients.

[001179] Mention is made of WO 2015/148670 and through the teachings herein the invention comprehends methods and materials of this document applied in conjunction with the teachings herein. In an aspect of gene therapy, methods and compositions for editing of a target sequence related to or in connection with Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) are comprehended. In a related aspect, the invention described herein comprehends prevention and treatment of HIV infection and AIDS, by introducing one or more mutations in the gene for C-C chemokine receptor type 5 (CCR5). The CCR5 gene is also known as CKR5, CCR-5, CD 195, CKR-5, CCCKR5, CMKBR5, IDDM22, and CC-CKR-5. In a further aspect, the invention described herein comprehends provide for prevention or reduction of HIV infection and/or prevention or reduction of the ability for HIV to enter host cells, e.g., in subjects who are already infected. Exemplary host cells for HIV include, but are not limited to, CD4 cells, T cells, gut associated lymphatic tissue (GALT), macrophages, dendritic cells, myeloid precursor cell, and microglia. Viral entry into the host cells requires interaction of the viral glycoproteins gp41 and gp120 with both the CD4 receptor and a coreceptor, e.g., CCR5. If a co-receptor, e.g., CCR5, is not present on the surface of the host cells, the virus cannot bind and enter the host cells. The progress of the disease is thus impeded. By

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PCT/US2016/038181 knocking out or knocking down CCR5 in the host cells, e.g., by introducing a protective mutation (such as a CCR5 delta 32 mutation), entry of the HIV vims into the host cells is prevented.

[001180] X-linked Chronic granulomatous disease (CGD) is a hereditary disorder of host defense due to absent or decreased activity of phagocyte NADPH oxidase. Using a CRISPR-Cas (Cpfl) system that targets and corrects the mutation (absent or decreased activity of phagocyte NADPH oxidase) (e.g., with a suitable HDR template that delivers a coding sequence for phagocyte NADPH oxidase); specifically, the gRNA can target mutation that gives rise to CGD (deficient phagocyte NADPH oxidase), and the HDR can provide coding for proper expression of phagocyte NADPH oxidase. An gRNA that targets the mutation-and-Cas (Cpfl) protein containing particle is contacted with HSCs carrying the mutation. The particle also can contain a suitable HDR template to correct the mutation for proper expression of phagocyte NADPH oxidase; or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. The so contacted cells can be administered; and optionally treated / expanded, cf. Cartier.

[001181] Fanconi anemia: Mutations in at least 15 genes (FANCA, FANCB, FANCC, FANCDI/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BACIΠ,/BRIPl, FANCL/PHF9/PQG, FANCM, FANCNZPALB2, FANCO/Rad51C, and FANCP/SLX4/BTBD12) can cause Fanconi anemia. Proteins produced from these genes are involved in a cell process known as the FA pathway. The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is blocked due to DNA damage. The FA pathway sends certain proteins to the area of damage, which trigger DNA repair so DNA replication can continue. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand cross-links (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked together, which stops the process of DNA replication. ICLs can be caused by a buildup of toxic substances produced in the body or by treatment with certain cancer therapy drugs. Eight proteins associated with Fanconi anemia group together to form a complex known as the FA core complex. The FA core complex activates two proteins, called FANCD2 and FANCI. The activation of these two proteins brings DNA repair proteins to the area of the ICE so the cross-link can be removed and DNA replication can continue, the FA core complex. More in particular, the FA core complex is

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PCT/US2016/038181 a nuclear multiprotein complex consisting of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM, functions as an E3 ubiquitin ligase and mediates the activation of the ID complex, which is a heterodimer composed of FANCD2 and FANCL Once monoubiquitinated, it interacts with classical tumor suppressors downstream of the FA pathway including FANCD1/BRCA2, FANCN/PALB2, FANCJ/BRIPI, and FANCO/Rad5IC and thereby contributes to DNA repair via homologous recombination (HR). Eighty to 90 percent of FA cases are due to mutations in one of three genes, FANCA, FANCC, and FANCG. These genes provide instructions for producing components of the FA core complex. Mutations in such genes associated with the FA core complex will cause the complex to be nonfunctional and disiupt the entire FA pathway. As a result, DNA damage is not repaired efficiently and ICLs build up over time. Geiselhart, “Review Article, Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies,” Anemia Volume 2012 (2012), Article ID 265790, http://dx.doi.org/10.1155/20I2/265790 discussed FA and an animal experiment involving intraf emoral injection of a ientivirus encoding the F ANCC gene resulting in correction of HSCs in vivo. Using a CRISPR-Cas (Cpfl) system that targets and one or more of the mutations associated with FA, for instance a CRISPR-Cas (Cpfl) system having gRNA(s) and HDR template(s) that respectively targets one or more of the mutations of FANCA, FANCC, or FANCG that give rise to FA and provide corrective expression of one or more of FANCA, FANCC or FANCG; e.g., the gRNA can target a mutation as to FANCC, and the HDR can provide coding for proper expression of FANCC. An gRNA that targets the mutation(s) (e.g., one or more involved in FA, such as mutation(s) as to any one or more of FANCA, FANCC or FANCG)-and-Cas (Cpfl) protein containing particle is contacted with HSCs carrying the mutation(s). The particle also can contain a suitable HDR template(s) to correct the mutation for proper expression of one or more of the proteins involved in FA, such as any one or more of FANCA, FANCC or FANCG, or the HSC can be contacted with a second particle or a vector that contains or delivers the HDR template. The so contacted cells can be administered; and optionally treated / expanded; cf. Cartier.

[001182] The particle in the herein discussion (e.g., as to containing gRNA(s) and Cas (Cpfl), optionally HDR template(s), or HDR template(s); for instance as to Hemophilia B, SCID, SCIDXI, ADA-SCID, Hereditary tyrosinemia, β-thalassemia, X-linked CGD, Wiskott-Aldrich

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PCT/US2016/038181 syndrome, Fanconi anemia, adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), HIV/AIDS, Immunodeficiency disorder, Hematologic condition, or genetic lysosomal storage disease) is advantageously obtained or obtainable from admixing an gRNA(s) and Cas (Cpfl) protein mixture (optionally containing HDR template(s) or such mixture only containing HDR template(s) when separate particles as to template(s) is desired) with a mixture comprising or consisting essentially of or consisting of surfactant, phospholipid, biodegradable polymer, lipoprotein and alcohol (wherein one or more gRNA targets the genetic locus or loci in the HSC).

[001183] Indeed, the invention is especially suited for treating hematopoietic genetic disorders with genome editing, and immunodeficiency disorders, such as genetic immunodeficiency disorders, especially through using the particle technology herein-discussed. Genetic immunodeficiencies are diseases where genome editing interventions of the instant invention can successful. The reasons include: Hematopoietic cells, of which immune cells are a subset, are therapeutically accessible. They can be removed from the body and transplanted autologously or allogenically. Further, certain genetic immunodeficiencies, e.g., severe combined immunodeficiency (SCID), create a proliferative disadvantage for immune cells. Correction of genetic lesions causing SCID by rare, spontaneous ‘reverse’ mutations indicates that correcting even one lymphocyte progenitor may be sufficient to recover immune function in patients.../...L/Users/t kowalski/AppData/Local/Microsoft/Windows/Temporary Internet

Files/Content,Outlook/GA8VY8LK/Treating SCID for Ellen.docx - ENREF1 See Bousso, P,, et al. Diversity, functionality, and stability of the T cell repertoire derived in vivo from a single human T cell precursor. Proceedings of the National Academy of Sciences of the United States of America 97, 274-278 (2000). The selective advantage for edited cells allows for even low levels of editing to result in a therapeutic effect. This effect of the instant invention can be seen in SCID, Wiskott-Aldrich Syndrome, and the other conditions mentioned herein, including other genetic hematopoietic disorders such as alpha- and beta- thalassemia, where hemoglobin deficiencies negatively affect the fitness of erythroid progenitors.

[001184] The activity of NHEJ and HDR DSB repair varies significantly by cell type and cell state. NHEJ is not highly regulated by the cell cycle and is efficient across cell types, allowing for high levels of gene disruption in accessible target cell populations. In contrast, HDR acts primarily during S/G2 phase, and is therefore restricted to cells that are actively dividing,

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PCT/US2016/038181 limiting treatments that require precise genome modifications to mitotic cells [Ciccia, A. & Elledge, S.J. Molecular cell 40, 179-204 (2010); Chapman, J.R., et al. Molecular cell 47, 497510 (2012)].

[001185] The efficiency of correction via HDR may be controlled by the epigenetic state or sequence of the targeted locus, or the specific repair template configuration (single vs. double stranded, long vs. short homology arms) used [Hacein-Bey-Abina, S,, et al. The New England journal of medicine 346, 1185-1193 (2002); Gaspar, H.B., et al. Lancet 364, 2181-2187 (2004); Beumer, K.J., et al. G3 (2013)]. The relative activity of NHEJ and HDR machineries in target ceils may also affect gene correction efficiency, as these pathways may compete to resolve DSBs [Beumer, K.J., et al. Proceedings of the National Academy of Sciences of the United States of America 105, 19821-19826 (2008)]. HDR also imposes a delivery challenge not seen with NHEJ strategies, as it requires the concurrent delivery of nucleases and repair templates. In practice, these constraints have so far led to low levels of HDR in therapeutically relevant cell types. Clinical translation has therefore largely focused on NHEJ strategies to treat disease, although proof-of-concept preclinical HDR treatments have now been described for mouse models of haemophilia B and hereditary tyrosinemia [Li, H., et al. Nature 475, 217-221 (2011); Yin, H., et al. Nature biotechnology 32, 551-553 (2014)].

[001186] Any given genome editing application may comprise combinations of proteins, small RNA molecules, and/or repair templates, making deliver)⁷ of these multiple parts substantially more challenging than small molecule therapeutics. Two main strategies for delivery of genome editing tools have been developed: ex vivo and in vivo. In ex vivo treatments, diseased cells are removed from the body, edited and then transplanted back into the patient. Ex vivo editing has the advantage of allowing the target cell population to be well defined and the specific dosage of therapeutic molecules delivered to cells to be specified. The latter consideration may be particularly important when off-target modifications are a concern, as titrating the amount of nuclease may decrease such mutations (Hsu et al., 2013). Another advantage of ex vivo approaches is the typically high editing rates that can be achieved, due to the development of efficient delivery systems for proteins and nucleic acids into cells in culture for research and gene therapy applications.

[001187] There may be drawbacks with ex vivo approaches that limit application to a small number of diseases. For instance, target cells must be capable of surviving manipulation outside

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PCT/US2016/038181 the body. For many tissues, like the brain, culturing cells outside the body is a major challenge, because cells either fail to survive, or lose properties necessary for their function in vivo. Thus, in view of this disclosure and the knowledge in the art, ex vivo therapy as to tissues with adult stem cell populations amenable to ex vivo culture and manipulation, such as the hematopoietic system, by the CRISPR-Cas (Cpfl) system are enabled. [Bunn, H.F. & Aster, J. Pathophysiology of blood disorders, (McGraw-Hill, New York, 2011)] [001188] In vivo genome editing involves direct delivery of editing systems to cell types in their native tissues. In vivo editing allows diseases in which the affected cell population is not amenable to ex vivo manipulation to be treated. Furthermore, delivering nucleases to cells in situ allows for the treatment of multiple tissue and cell types. These properties probably allow in vivo treatment to be applied to a wider range of diseases than ex vivo therapies, [001189] To date, in vivo editing has largely been achieved through the use of viral vectors with defined, tissue-specific tropism. Such vectors are currently iimited in terms of cargo carrying capacity and tropism, restricting this mode of therapy to organ systems where transduction with clinically useful vectors is efficient, such as the liver, muscle and eye [Kotterman, M,A. & Schaffer, D.V. Nature reviews. Genetics 15, 445-451 (2014); Nguyen, T.H. & Ferry, N. Gene therapy 11 Suppl 1, S76-84 (2004), Boye, S.E., et al. Molecular therapy : the journal of the American Society of Gene Therapy 21, 509-519 (2013)].

[001190] A potential barrier for in vivo delivery is the immune response that may be created in response to the large amounts of virus necessary for treatment, but this phenomenon is not unique to genome editing and is observed with other virus based gene therapies [Bessis, N., et al. Gene therapy 11 Suppi 1, SI0-17 (2004)]. It is also possible that peptides from editing nucleases themselves are presented on MHC Class I molecules to stimulate an immune response, although there is little evidence to support this happening at the preclinical level. Another major difficulty with this mode of therapy is controlling the distribution and consequently the dosage of genome editing nucleases in vivo, leading to off-target mutation profiles that may be difficult to predict. However, in view⁷ of this disclosure and the knowledge in the art, including the use of virus- and particle-based therapies being used in the treatment of cancers, in vivo modification of HSCs, for instance by delivery' by either particle or virus, is within the ambit of the the skilled person. [001191] Ex Vivo Editing Therapy: The long standing clinical expertise with the purification, culture and transplantation of hematopoietic cells has made diseases affecting the blood system

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PCT/US2016/038181 such as SCID, Fanconi anemia, Wiskott-Aldrich syndrome and sickle cell anemia the focus of ex vivo editing therapy. /Another reason to focus on hematopoietic cells is that, thanks to previous efforts to design gene therapy for blood disorders, delivery systems of relatively high efficiency already exist. With these advantages, this mode of therapy can be applied to diseases where edited cells possess a fitness advantage, so that a small number of engrafted, edited cells can expand and treat disease. One such disease is HIV, where infection results in a fitness disadvantage to CD4+ T cells.

[001192] Ex vivo editing therapy has been recently extended to include gene correction strategies. The barriers to HDR ex vivo were overcome in a recent paper from Genovese and colleagues, who achieved gene correction of a mutated IL2RG gene in hematopoietic stem cells (HSCs) obtained from a patient suffering from SCID-X1 [Genovese, P,, et al. Nature 510, 235240 (2014)]. Genovese et. al. accomplished gene correction in HSCs using a multimodal strategy. First, HSCs were transduced using integration-deficient lentivirus containing an HDR template encoding a therapeutic cDNA for IL2RG. Following transduction, cells were electroporated with mRNA encoding ZFNs targeting a mutational hotspot in 1L2RG to stimulate HDR based gene correction. To increase HDR rates, culture conditions were optimized with small molecules to encourage HSC division. With optimized culture conditions, nucleases and HDR templates, gene corrected HSCs from the SCID-X1 patient were obtained in culture at therapeutically relevant rates. HSCs from unaffected individuals that underwent the same gene correction procedure could sustain long-term hematopoiesis in mice, the gold standard for HSC function. HSCs are capable of giving rise to all hematopoietic cell types and can be autologously transplanted, making them an extremely valuable cell population for all hematopoietic genetic disorders [Weissman, I.L. & Shizuru, J.A. Biood 112, 3543-3553 (2008)]. Gene corrected HSCs could, in principle, be used to treat a wide range of genetic blood disorders making this study an exciting breakthrough for therapeutic genome editing.

[001193] In Vivo Editing Therapy: In vivo editing can be used advantageously from this disclosure and the knowledge in the art, For organ systems where delivery is efficient, there have already been a number of exciting preclinical therapeutic successes. The first example of successful in vivo editing therapy was demonstrated in a mouse model of haemophilia B [Li, H., et al. Nature 475, 217-221 (2011)]. As noted earlier, Haemophilia B is an X-linked recessive disorder caused by loss-of-function mutations in the gene encoding Factor IX, a crucial

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PCT/US2016/038181 component of the clotting cascade. Recovering Factor IX activity to above 1% of its levels in severely affected individuals can transform the disease into a significantly milder form, as infusion of recombinant Factor IX into such patients prophylactically from a young age to achieve such levels largely ameliorates clinical complications [Lofqvist, T., et al. Journal of internal medicine 241, 395-400 (1997)]. Thus, only low levels of HDR gene correction are necessary⁷ to change clinical outcomes for patients. In addition, Factor IX is synthesized and secreted by the liver, an organ that can be transduced efficiently by viral vectors encoding editing systems.

[001194] Using hepatotropic adeno-associated viral (AAV) serotypes encoding ZFNs and a corrective HDR template, up to 7% gene correction of a mutated, humanized Factor IX gene in the murine liver was achieved [Li, H., et al. Nature 475, 217-221 (2011)]. This resulted in improvement of clot formation kinetics, a measure of the function of the clotting cascade, demonstrating for the first time that in vivo editing therapy is not only feasible, but also efficacious. As discussed herein, the skilled person is positioned from the teachings herein and the knowledge in the art, e.g., Li to address Haemophilia B with a particle-containing HDR template and a CRISPR-Cas (Cpfl) system that targets the mutation of the X-linked recessive disorder to reverse the loss-of-function mutation.

[001195] Building on this study, other groups have recently used in vivo genome editing of the liver with CRISPR-Cas to successfully treat a mouse model of hereditary tyrosinemia and to create mutations that provide protection against cardiovascular disease. These two distinct applications demonstrate the versatility of this approach for disorders that involve hepatic dysfunction [Yin, H., et al. Nature biotechnology 32, 551-553 (2014), Ding, Q., et al. Circulation research 115, 488-492 (2014)]. Application of in vivo editing to other organ systems are necessary⁷ to prove that this strategy is widely applicable. Currently, efforts to optimize both viral and non-viral vectors are underway to expand the range of disorders that can be treated with this mode of therapy [Kotterman, M.A. & Schaffer, D.V. Nature reviews. Genetics 15, 445-451 (2014), Yin, H., et al. Nature review's. Genetics 15, 541-555 (2014)]. As discussed herein, the skilled person is positioned from the teachings herein and the knowledge in the art, e.g., Yin to address hereditary tyrosinemia with a particle-containing HDR. template and a CRISPR-Cas (Cpfl) system that targets the mutation.

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PCT/US2016/038181 [001196] Targeted deletion, therapeutic applications: Targeted deletion of genes may be preferred. Preferred are, therefore, genes involved in immunodeficiency disorder, hematologic condition, or genetic lysosomal storage disease, e.g., Hemophilia B, SCID, SCID-X1, ADASCID, Hereditary tyrosinemia, β-thalassemia, X-linked CGD, Wiskott-Aldrich syndrome, Fanconi anemia, adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), H1V/AIDS, other metabolic disorders, genes encoding mis-folded proteins involved in diseases, genes leading to loss-of-function involved in diseases; generally, mutations that can be targeted in an HSC, using any herein-dsicussed delivery system, with the particle system considered advantageous.

[001197] In the present invention, the immunogenicity of the CRISPR enzyme in particular may be reduced following the approach first set out in Tangri et al with respect to erythropoietin and subsequently developed. Accordingly, directed evolution or rational design may be used to reduce the immunogenicity of the CRISPR enzyme (for instance a Cpfl) in the host species (human or other species).

[001198] Genome editing: The CRISPR/Cas (Cpfl) systems of the present invention can be used to correct genetic mutations that were previously attempted with limited success using TALEN and ZFN and lentiviruses, including as herein discussed, see also WO2013163628. Treating Disease of the Brain, Central Nervous and Immune Systems [001199] The present invention also contemplates delivering the CRISPR-Cas system to the brain or neurons. For example, RNA interference (RNAi) offers therapeutic potential for this disorder by reducing the expression of HIT, the disease-causing gene of Huntington’s disease (see, e.g., McBride et al.. Molecular Therapy vol, 19 no. 12 Dec. 2011, pp. 2152-2162), therefore Applicant postulates that it may be used/and or adapted to the CRISPR-Cas system. The CRISPR-Cas system may be generated using an algorithm to reduce the off-targeting potential of antisense sequences. The CRISPR-Cas sequences may target either a sequence in exon 52 of mouse, rhesus or human huntingtin and expressed in a viral vector, such as AAV. Animals, including humans, may be injected with about three microinjections per hemisphere (six injections total): the first 1 mm rostral to the anterior commissure (12 μΐ) and the two remaining injections (12 μΐ and 10 μί, respectively) spaced 3 and 6 mm caudal to the first injection with Iel2 vg/ml of AAV at a rate of about 1 μΙ/minute, and the needle was left in place for an additional 5 minutes to allow the injectate to diffuse from the needle tip.

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PCT/US2016/038181 [001200] DiFiglia et al· (PNAS, October 23, 2007, vol. 104, no. 43, 17204-17209) observed that single administration into the adult striatum of an siRNA targeting Htt can silence mutant Htt, attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of HD. DiFiglia injected mice intrastriatally with 2 μϊ of Cy3-labeled cc-siRNA-Htt or unconjugated siRNA-Htt at 10 μΜ. A similar dosage of CRISPR Cas targeted to Htt may be contemplated for humans in the present invention, for example, about 5-10 ml of 10 μΜ CRISPR Cas targeted to Htt may be injected intrastriatally. [001201] In another example, Boudreau et al. (Molecular Therapy vol. 17 no. 6 june 2009) injects 5 μΐ of recombinant AAV serotype 2/1 vectors expressing htt-specific RNAi virus (at 4 x 10^lZ viral genomes/ml) into the straiatum. A similar dosage of CRISPR Cas targeted to Hit may be contemplated for humans in the present invention, for example, about 10-20 ml of 4 x 1()¹² viral genomes/ml) CRISPR Cas targeted to Htt may be injected intrastriatally.

[001202] In another example, a CRISPR Cas targetd to HTT may be administered continuously (see, e.g., Yu et al., Cell 150, 895-908, August 31, 2012). Yu et al. utilizes osmotic pumps delivering 0.25 ml/hr (Model 2004) to deliver 300 mg/day of ss-siRNA or phosphate-buffered saline (PBS) (Sigma Aldrich) for 28 days, and pumps designed to deliver 0.5 μϊ/hr (Model 2002) were used to deliver 75 mg/day of the positive control MOE ASO for 14 days. Pumps (Durect Corporation) were filled with ss-siRNA or MOE diluted in sterile PBS and then incubated at 37 C for 24 or 48 (Model 2004) hours prior to implantation. Mice were anesthetized with 2.5% isofluorane, and a midline incision was made at the base of the skull. Using stereotaxic guides, a cannula was implanted into the right lateral ventricle and secured with Loctite adhesive. A catheter attached to an Alzet osmotic mini pump was attached to the cannula, and the pump was placed subcutaneously in the midscapular area. The incision was closed with 5.0 nylon sutures. A similar dosage of CRISPR Cas targeted to Hit may be contemplated for humans in the present invention, for example, about 500 to 1000 g/day CRISPR Cas targeted to Htt may be administered.

[001203] In another example of continuous infusion, Stiles et al. (Experimental Neurology 233 (2012) 463-471) implanted an intraparenchymal catheter with a titanium needle tip into the right putamen. The catheter was connected to a SynchroMed® II Pump (Medtronic Neurological, Minneapolis, MN) subcutaneously implanted in the abdomen. After a 7 day infusion of phosphate buffered saline at 6 pL/day, pumps were re-filled with test article and programmed for

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PCT/US2016/038181 continuous delivery for 7 days. About 2.3 to 11.52 mg/d of siRNA were infused at varying infusion rates of about 0.1 to 0.5 pL/min. A similar dosage of CRISPR Cas targeted to Hit may be contemplated for humans in the present invention, for example, about 20 to 200 mg/day CRISPR Cas targeted to Hit may be administered. In another example, the methods of US Patent Publication No. 20130253040 assigned to Sangamo may also be also be adapted from TALES to the nucleic acid-targeting system of the present invention for treating Huntington’s Disease. [001204] In another example, the methods of US Patent Publication No. 20130253040 (WO2013130824) assigned to Sangamo may also be also be adapted from TALES to the CRISPR Cas system of the present invention for treating Huntington's Disease.

[001205] WO2015089354 Al in the name of The Broad Institute et al., hereby incorporated by reference, describes a targets for Huntington’s Disease (HP). Possible target genes of CRISPR complex in regard to Huntington's Disease: PRKCE; IGF1; EP300; RCOR1; PRKCZ; HDAC4; and TGM2. Accordingly, one or more of PRKCE; 1GF1; EP300; RCOR1; PRKCZ; HDAC4; and TGM2 may be selected as targets for Huntington’s Disease in some embodiments of the present invention.

[001206] Other trinucleotide repeat disorders. These may include any of the following: Category I includes Huntington's disease (HD) and the spinocerebellar ataxias; Category II expansions are phenotypically diverse with heterogeneous expansions that are generally small in magnitude, but also found in the exons of genes; and Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia.

[001207] A further aspect of the invention relates to utilizing the CRISPR-Cas system for correcting defects in the EMP2A and EMP2B genes that have been identified to be associated with Lafora disease. Lafora disease is an autosomal recessive condition which is characterized by progressive myoclonus epilepsy which may start as epileptic seizures in adolescence. A few⁷ cases of the disease may be caused by mutations in genes yet to be identified. The disease causes seizures, muscle spasms, difficulty walking, dementia, and eventually death. There is currently no therapy that has proven effective against disease progression. Other genetic abnormalities associated with epilepsy may also be targeted by the CRISPR-Cas system and the underlying genetics is further described in Genetics of Epilepsy and Genetic Epilepsies, edited by Giuliano Avanzini, Jeffrey L. Noebels, Mariani Foundation Paediatric Neurology:20; 2009).

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PCT/US2016/038181 [001208] The methods of US Patent Publication No. 20110158957 assigned to Sangamo BioSciences, Inc. involved in inactivating T cell receptor (TCR) genes may also be modified to the CRISPR Cas system of the present invention. In another example, the methods of US Patent Publication No. 20100311124 assigned to Sangamo BioSciences, Inc. and US Patent Publication No. 20110225664 assigned to Cellectis, which are both involved in inactivating glutamine synthetase gene expression genes may also be modified to the CRISPR Cas system of the present invention.

[001209] Delivery options for the brain include encapsulation of CRISPR enzyme and guide RNA in the form of either DNA or RNA into liposomes and conjugating to molecular Trojan horses for trans-blood brain barrier (BBB) delivery. Molecular Trojan horses have been shown to be effective for deliver)' of B-gal expression vectors into the brain of non-human primates. The same approach can be used to delivery vectors containing CRISPR enzyme and guide RNA. For instance, Xia CF and Boado RJ, Pardridge WM (Antibody-mediated targeting of siRNA via the human insulin receptor using avidin-biotin technology. Mol Pharm. 2009 MayJun;6(3):747-51. doi: 10.1021/mp800194) describes how delivery' of short interfering RNA (siRNA) to cells in culture, and in vivo, is possible with combined use of a receptor-specific monoclonal antibody (mAb) and avidin-biotin technology. The authors also report that because the bond between the targeting mAh and the siRNA is stable with avidin-biotin technology, and RNAi effects at distant sites such as brain are observed in vivo following an intravenous administration of the targeted siRNA , [001210] Zhang et al. (Mol Ther. 2003 Jan;7(l): 11-8.)) describe how' expression plasmids encoding reporters such as luciferase were encapsulated in the interior of an artificial vims” comprised of an 85 nm pegylated immunoliposome, which was targeted to the rhesus monkey brain in vivo with a monoclonal antibody (MAb) to the human insulin receptor (HIR), The HIRMAb enables the liposome carrying the exogenous gene to undergo transcytosis across the blood-brain hairier and endocytosis across the neuronal plasma membrane following intravenous injection. The level of luciferase gene expression in the brain was 50-fold higher in the rhesus monkey as compared to the rat. Widespread neuronal expression of the beta-galactosidase gene in primate brain was demonstrated by both histochemistry and confocai microscopy. The authors indicate that this approach makes feasible reversible adult transgenics in 24 hours. Accordingly,

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PCT/US2016/038181 the use of immunoliposome is preferred. These may be used in conjunction with antibodies to target specific tissues or cell surface proteins.

Alzheimer’s Disease [001211] US Patent Publication No, 20110023153, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated with Alzheimer’s Disease. Once modified cells and animals may be further tested using known methods to study the effects of the targeted mutations on the development and/or progression of AD using measures commonly used in the study of AD -- such as, without limitation, learning and memory, anxiety, depression, addiction, and sensory motor functions as well as assays that measure behavioral, functional, pathological, metaboloic and biochemical function.

[001212] The present disclosure comprises editing of any chromosomal sequences that encode proteins associated with AD. The AD-related proteins are typically selected based on an experimental association of the AD-related protein to an AD disorder, For example, the production rate or circulating concentration of an AD-related protein may be elevated or depressed in a population having an AD disorder relative to a population lacking the AD disorder. Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the AD-related proteins may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including but not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).

[001213] Examples of Alzheimer’s disease associated proteins may include the very low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene, the ubiquitin-like modifier activating enzyme 1 (UBA1) encoded by the UBA1 gene, or the NEDD8-activating enzyme El catalytic subunit protein (UBE1C) encoded by the UBA3 gene, for example.

[001214] By way of non-limiting example, proteins associated with AD include but are not limited to the proteins listed as follows: Chromosomal Sequence Encoded Protein ALAS2 Deltaaminolevulinate synthase 2 (ALAS2) ABCA1 ATP-binding cassette transporter (ABCA1) ACE Angiotensin I-converting enzyme (ACE) APOE Apolipoprotein E precursor (APOE) APP amyloid precursor protein (APP) AQP1 aquaporin 1 protein (AQP1) BIN! Myc box-dependentinteracting protein 1 or bridging integrator 1 protein (BIN!) BDNF brain-derived neurotrophic

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PCT/US2016/038181 factor (BDNF) BTNL8 Butyrophilin-like protein 8 (BTNL8) C1ORF49 chromosome I open reading frame 49 CDH4 Cadherin-4 CHRNB2 Neuronal acetylcholine receptor subunit beta-2 CKLFSF2 CKLF-like MARVEL transmembrane domain- containing protein 2 (CKLFSF2) CLEC4E C-type lectin domain family 4, member e (CLEC4E) CLU clusterin protein (also known as apoplipoprotein J) CR1 Erythrocyte complement receptor I (CR1, also known as CD35, C3b/C4b receptor and immune adherence receptor) CR1L Erythrocyte complement receptor 1 (CR1L) CSF3R granulocyte colony-stimulating factor 3 receptor (CSF3R) CST3 Cystatin C or cystatin 3 CYP2C Cytochrome P450 2C DAPK1 Death-associated protein kinase 1 (DAPK1) ESR1 Estrogen receptor 1 FCAR Fc fragment of IgA receptor (FCAR, also known as CD89) FCGR3B Fc fragment of IgG, low affinity Illb, receptor (FCGR3B or CD16b) FFA2 Free fatty acid receptor 2 (FFA2) FGA Fibrinogen (Factor 1) GAB2 GRB2-associated-binding protein 2 (GAB2) GAB2 GRB2-associated-binding protein 2 (GAB2) GALP Galanin-like peptide GAPDHS Glyceraidehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) GMPB GMBP HP Haptoglobin (HP) HTR7 S-hydroxytryptamine (serotonin) receptor 7 (adenylate cyclase-coupled) IDE Insulin degrading enzyme IF 127 IF 127 IFI6 Interferon, alpha-inducible protein 6 (IFI6) IFIT2 Interferon-induced protein with tetratricopeptide repeats 2 (1FH'2) IL1RN interleukin-1 receptor antagonist (IL-IRA) IL8RA Interleukin 8 receptor, alpha (IL8RA or CD 181) IL8RB Interleukin 8 receptor, beta (IL8RB) JAG1 Jagged 1 (JAG1) KCNJ15 Potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) LRP6 Low-density lipoprotein receptor-related protein 6 (LRP6) MAPT microtubule-associated protein tau (MAPT) MARK4 MAP/microtubule affinity-regulating kinase 4 (MARK4) MPHOSPH1 M-phase phosphoprotein 1 MTHFR 5,10-methylenetetrahydrofolate reductase MX2 Interferon-induced GTP-binding protein Mx2 NBN Nibrin, also known as NBN NCSTN Nicastrin NIACR2 Niacin receptor 2 (NIACR2, also known as GPR109B) NMNAT3 nicotinamide nucleotide adenyl yl transferase 3 NTM Neurotrimin (or HNT) 0RM1 Orosmucoid 1 (0RM1) or Alpha-1-acid glycoprotein 1 P2RY13 P2Y purinoceptor 13 (P2RY13) PBEF1 Nicotinamide phosphoribosyltransf erase (NAmPRTase or Nampt) also known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin PCK1 Phosphoenolpyruvate carboxykinase PICALM phosphatidylinositol binding clathrin assembly protein (PICALM) PLAU Urokinase-type plasminogen activator (PLAU) PLXNC1 Plexin Cl (PLXNC1) PRNP Prion protein PSEN1 presenilin 1 protein (PSEN1) PSEN2 presenilin 2 protein (PSEN2) PTPRA protein tyrosine phosphatase receptor type A

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PCT/US2016/038181 protein (PTPRA) RALGPS2 Rai GEF with PH domain and SH3 binding motif 2 (RALGPS2) RGSL2 regulator of G-protein signaling like 2 (RGSL2) SELENBP1 Selenium binding protein 1 (SELNBP1) SLC25A37 Mitoferrm-1 SORL1 sortilin-related receptor L(DLR class) A repeatscontaining protein (SORL1) TF Transferrin TFA.M Mitochondrial transcription factor A TNF Tumor necrosis factor TNFRSFIOC Tumor necrosis factor receptor superfamily member 10C (TNFRSFIOC) TNFSF10 Tumor necrosis factor receptor superfamily, (TRAIL) member 10a (TNFSF10) UBA1 ubiquitin-like modifier activating enzyme 1 (UBA1) UBA3 NEDD8activating enzyme El catalytic subunit protein (UBE1C) LJBB ubiquitin B protein (LJBB) UBQLN1 Ubiquilin-1 UCHL1 ubiquitin carboxyl-terminal esterase LI protein (UCHL1) UCHL3 ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3) VLDLR very/ low density lipoprotein receptor protein (VLDLR) [001215] In exemplary/ embodiments, the proteins associated with AD whose chromosomal sequence is edited may be the very low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene, the ubiquitin-like modifier activating enzyme 1 (UBA1) encoded by the UBA1 gene, the NEDD8-activating enzyme El catalytic subunit protein (UBE1C) encoded by the UBA3 gene, the aquaporin 1 protein (AQP1) encoded by the AQP1 gene, the ubiquitin carboxyl-terminal esterase LI protein (UCHL1) encoded by the UCHL1 gene, the ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3) encoded by the UCHL3 gene, the ubiquitin B protein (LJBB) encoded by the UBB gene, the microtubule-associated protein tau (MAPT) encoded by the MAPI' gene, the protein tyrosine phosphatase receptor type A protein (PTPRA) encoded by the PTPRA gene, the phosphatidylinositol binding clathrin assembly protein (PICALM) encoded by the PICALM gene, the clusterin protein (also known as apoplipoprotein J) encoded by the CLU gene, the presenilin 1 protein encoded by the PSEN1 gene, the presenilin 2 protein encoded by the PSEN2 gene, the sortilin-related receptor L(DLR class) A repeats-containing protein (SORL1) protein encoded by the SORL1 gene, the amyloid precursor protein (APP) encoded by the APP gene, the Apolipoprotein E precursor (APOE) encoded by the APOE gene, or the brain-derived neurotrophic factor (BDNF) encoded by the BDNF gene. In an exemplary/ embodiment, the genetically modified animal is a rat, and the edited chromosomal sequence encoding the protein associated with AD is as as follows: APP amyloid precursor protein (APP) NM 019288 AQP1 aquaporin 1 protein (AQP1) NM 012778 BDNF Brain-derived neurotrophic factor NM 012513 CLUJ clusterin protein (also known as

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NM 053021 apoplipoprotein J) MAPT microtubule-associated protein NM 017212 tau (MAPT) PICALM phosphatidylinositol binding NM_053554 clathrin assembly protein (PICALM) PSEN1 presenilin 1 protein (PSEN1) NM 019163 PSEN2 presenilin 2 protein (PSEN2) NM_031087 PTPRA protein tyrosine phosphatase \M 012763 receptor type A protein (PTPRA) SORL1 sortilin-related receptor L(DLR NM 053519, class) A repeats-containing XM_001065506, protein (SORL1) XMJ217115 UBA1 ubiquitin-like modifier activating NM_0Q1014080 enzyme 1 (UBA1) UBA3 NEDD8-activating enzyme El NM_057205 catalytic subunit protein (UBE1C) UBB ubiquitin B protein (UBB) KWl 138895 UCHL1 ubiquitin carboxyl-terminal NM_017237 esterase LI protein (UCHL1) UCHL3 ubiquitin carboxylterminal NM: 001110165 hydrolase isozyme L,3 protein (UCHL3) VLDLR very low density lipoprotein NM_013155 receptor protein (VLDLR) [001216] The animal or cell may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15 or more disrupted chromosomal sequences encoding a protein associated with AD and zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more chromosomally integrated sequences encoding a protein associated with AD.

[001217] The edited or integrated chromosomal sequence may be modified to encode an altered protein associated with AD. A number of mutations in AD-related chromosomal sequences have been associated with AD. For instance, the V7171 (i.e. valine at position 717 is changed to isoleucine) missense mutation in APP causes familial AD. Multiple mutations in the presenilin-1 protein, such as H163R (i.e. histidine at position 163 is changed to arginine), A246E (i.e. alanine at position 246 is changed to glutamate), L286V (i.e. leucine at position 286 is changed to valine) and C410Y (i.e, cysteine at position 410 is changed to tyrosine) cause familial Alzheimer's type 3. Mutations in the preseniIin-2 protein, such as N141 I (i.e. asparagine at position 141 is changed to isoleucine), M239V (i.e. methionine at position 239 is changed to valine), and D439A (i.e. aspartate at position 439 is changed to alanine) cause familial Alzheimer's type 4. Other associations of genetic variants in AD-associated genes and disease are known in the art. See, for example, Waring et al, (2008) Arch. Neurol, 65:329-334, the disclosure of which is incorporated by reference herein in its entirety.

Secretase Disorders [001218] US Patent Publication No. 20110023146, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated with secretase-associated disorders.

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Secretases are essential for processing pre-proteins into their biologically active forms. Defects in various components of the secretase pathways contribute to many disorders, particularly those with hallmark amyloidogenesis or amyloid plaques, such as Alzheimer's disease (AD).

[001219] A secretase disorder and the proteins associated with these disorders are a diverse set of proteins that effect susceptibility for numerous disorders, the presence of the disorder, the severity of the disorder, or any combination thereof. The present disclosure comprises editing of any chromosomal sequences that encode proteins associated with a secretase disorder. The proteins associated with a secretase disorder are typically selected based on an experimental association of the secretase—related proteins with the development of a secretase disorder. For example, the production rate or circulating concentration of a protein associated with a secretase disorder may be elevated or depressed in a population with a secretase disorder relative to a population without a secretase disorder. Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the protein associated with a secretase disorder may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including but not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).

[001220] By way of non-limiting example, proteins associated with a secretase disorder include PSENEN (presenilin enhancer 2 homolog (C. elegans)), CTSB (cathepsin B), PSEN1 (preseniiin I), APP (amyloid beta (A4) precursor protein), APH1B (anterior pharynx defective 1 homolog B (C. elegans)), PSEN2 (presenilin 2 (Alzheimer disease 4)), BACEI (beta-site APP-cleaving enzyme 1), ITM2B (integral membrane protein 2B), CTSD (cathepsin D), NOTCH1 (Notch homolog I, translocation-associated (Drosophila)), TNF (tumor necrosis factor (TNF superfamily, member 2)), INS (insulin), DYT10 (dystonia 10), ADAM 17 (ADAM: metallopeptidase domain 17), APOE (apolipoprotein E), ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1), STN (statin), TP53 (tumor protein p53), 1L6 (interleukin 6 (interferon, beta 2)), NGFR (nerve growth factor receptor (TNFR superfamily, member 16)), IL1B (interleukin 1, beta), ACHE (acetylcholinesterase (Yt blood group)), CTNNB1 (catenin (cadherin-associated protein), beta 1, 88kDa), IGF1 (insulin-like growth factor 1 (somatomedin C)), IFNG (interferon, gamma), NRG1 (neuregulin 1), CASP3 (caspase 3, apoptosis-related

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PCT/US2016/038181 cysteine peptidase), MAPK1 (mitogen-activated protein kinase 1), CDH1 (cadherin 1, type 1, Ecadherin (epithelial)), APBB1 (amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)), HMGCR (3-hydroxy-3-methylglutaryl-Coenzyme A reductase), CREB1 (cAMP responsive element binding protein 1), PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G/Ή synthase and cyclooxygenase)), HES1 (hairy and enhancer of split 1, (Drosophila)), CAT (catalase), TGFB1 (transforming growth factor, beta 1), ENO2 (enolase 2 (gamma, neuronal)), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)), TRAPPC10 (trafficking protein particle complex 10), MAOB (monoamine oxidase B), NGF (nerve growth factor (beta polypeptide)), MMP12 (matrix metallopeptidase 12 (macrophage elastase)), JAG1 (jagged 1 (Alagille syndrome)), CD40LG (CD40 ligand), PPARG (peroxisome proliferator-activated receptor gamma), FGF2 (fibroblast growth factor 2 (basic)), IL3 (interleukin 3 (colony-stimulating factor, multiple)), LRP1 (low⁷ density lipoprotein receptorrelated protein 1), NOTCH4 (Notch homolog 4 (Drosophila)), MAPK8 (mitogen-activated protein kinase 8), PREP (prolyl endopeptidase), NOTCH3 (Notch homolog 3 (Drosophila)), PRNP (prion protein), CTSG (cathepsin G), EGF (epidermal growth factor (beta-urogastrone)), REN (renin), CD44 (CD44 molecule (Indian blood group)), SEEP (selectin P (granule membrane protein 140 kDa, antigen CD62)), GHR (growth hormone receptor), ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary⁷)), IN SR (insulin receptor), GFAP (glial fibrillary acidic protein), MMP3 (matrix metallopeptidase 3 (stromelysin I, progelatinase)), MAPK10 (mitogen-activated protein kinase 10), SP1 (Spl transcription factor), MYC (v-myc myelocytomatosis viral oncogene homolog (avian)), CTSE (cathepsin E), PPARA (peroxisome proliferator-activated receptor alpha), JUN (jun oncogene), TIMP1 (TIMP metallopeptidase inhibitor 1), IL5 (interleukin 5 (colony-stimulating factor, eosinophil)), ILIA (interleukin 1, alpha), MMP9 (matrix metallopeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase)), HTR4 (5-hydroxytryptamine (serotonin) receptor 4), HSPG2 (heparan sulfate proteoglycan 2), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), CYCS (cytochrome c, somatic), SMG1 (SMG1 homolog, phosphatidylinositol 3-kinase-related kinase (C. elegans)), IL1R1 (interleukin 1 receptor, type I), PROK1 (prokineticin 1), MAPK3 (mitogenactivated protein kinase 3), NTRK1 (neurotrophic tyrosine kinase, receptor, type 1), 1L13 (interleukin 13), MME (membrane metallo-endopeptidase), TKT (transketolase), CXCR2 (chemokine (C-X-C motif) receptor 2), IGF1R (insulin-like growth factor 1 receptor), RARA

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PCT/US2016/038181 (retinoic acid receptor, alpha), CREBBP (CREB binding protein), PTGS1 (prostaglandinendoperoxide synthase 1 (prostaglandin G/Ή synthase and cyclooxygenase)), GALT (galactose1-phosphate uridylyltransferase), CHRM1 (cholinergic receptor, muscarinic 1), ATXN1 (ataxin 1), PAWR (PRKC, apoptosis, WT1, regulator), NOTCH2 (Notch homolog 2 (Drosophila)), M6PR (mannose-6-phosphate receptor (cation dependent)), CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1), CSNK1 D (casein kinase 1, delta), MAPK14 (mitogenactivated protein kinase 14), PRG2 (proteoglycan 2, bone marrow (natural killer cell activator, eosinophil granule major basic protein)), PRKCA (protein kinase C, alpha), LI CAM (LI cell adhesion molecule), CD40 (CD40 molecule, TNF receptor superfamily member 5), NR1I2 (nuclear receptor subfamily 1, group I, member 2), JAG2 (jagged 2), CTNND1 (catenin (cadherin-associated protein), delta 1), CDH2 (cadherin 2, type 1, N-cadherin (neuronal)), CMA1 (chymase 1, mast cell), SORT1 (sortilin 1), DLK1 (delta-like 1 homolog (Drosophila)), THEM4 (thioesterase superfamily member 4), JUP (junction piakoglobin), CD46 (CD46 molecule, complement regulatory protein), CCL11 (chemokine (C-C motif) ligand 11), CAV3 (caveolin 3), RNASES (ribonuclease, RNase A family, 3 (eosinophil cationic protein)), HSPA8 (heat shock 70kDa protein 8), CASP9 (caspase 9, apoptosis-related cysteine peptidase), CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4), CCR3 (chemokine (C-C motif) receptor 3), TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)), SCP2 (sterol carrier protein 2), CDK4 (cyclin-dependent kinase 4), HIF1A (hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)), TCF7L2 (transcription factor 7-like 2 (T-cell specific, HMG-box)), IL1R2 (interleukin 1 receptor, type II), B3GALTL (beta 1,3-galactosyltransferase-like), MDM2 (Mdm2 p53 binding protein homolog (mouse)), RELA (v-rel reticuloendotheliosis viral oncogene homolog A (avian)), CASP7 (caspase 7, apoptosis-related cysteine peptidase), IDE (insulin-degrading enzyme), FABP4 (fatty acid binding protein 4, adipocyte), CASK (calcium/calmodulin-dependent serine protein kinase (MAGUK family)), ADCYAP1R1 (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I), ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)), PDGFA (platelet-derived growth factor alpha polypeptide), C21 or £33 (chromosome 21 open reading frame 33), SCG5 (secretogranin V (7B2 protein)), RNF123 (ring finger protein 123), NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1), ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene

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PCT/US2016/038181 homolog (avian)), CAV1 (caveolin 1, caveolae protein, 22 kDa), MMP7 (matrix metallopeptidase 7 (matrilysin, uterine)), TGFA (transforming growth factor, alpha), RXRA (retinoid X receptor, alpha), STX1A (syntaxin 1A (brain)), PSMC4 (proteasome (prosome, macropain) 26S subunit, ATPase, 4), P2RY2 (purinergic receptor P2Y, G-protein coupled, 2), TNFRSF21 (tumor necrosis factor receptor superfamily, member 21), DLG1 (discs, large homolog 1 (Drosophila)), NUMBL (numb homolog (Drosophila)-like), SPN (sialophorin), PLSCR1 (phospholipid scramblase 1), UBQLN2 (ubiquilin 2), UBQLN1 (ubiquilin 1), PCSK7 (proprotein convertase subtilisin/kexin type 7), SPON1 (spondin 1, extracellular matrix protein), SILV (silver homolog (mouse)), QPCT (glutaminyl-peptide cyclotransferase), HESS (hairy and enhancer of split 5 (Drosophila)), GCC1 (GRIP and coiled-coil domain containing 1), and any combination thereof.

[001221] The genetically modified animal or cell may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more disrupted chromosomal sequences encoding a protein associated with a secretase disorder and zero, I, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chromosomally integrated sequences encoding a disiupted protein associated with a secretase disorder.

ALS [001222] US Patent Publication No. 20110023144, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated wdth amyotrophyic lateral sclerosis (ALS) disease. ALS is characterized by the gradual steady degeneration of certain nerve cells in the brain cortex, brain stem, and spinal cord involved in voluntary movement.

[001223] Motor neuron disorders and the proteins associated wdth these disorders are a diverse set of proteins that effect susceptibility for developing a motor neuron disorder, the presence of the motor neuron disorder, the severity of the motor neuron disorder or any combination thereof. The present disclosure comprises editing of any chromosomal sequences that encode proteins associated with ALS disease, a specific motor neuron disorder. The proteins associated with ALS are typically selected based on an experimental association of ALS--related proteins to ALS. For example, the production rate or circulating concentration of a protein associated with ALS may be elevated or depressed in a population with ALS relative to a population without ALS. Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the proteins associated with ALS may be

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PCT/US2016/038181 identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including hut not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).

[001224] By way of non-limiting example, proteins associated with ALS include but are not limited to the following proteins: SOD I superoxide dismutase 1, ALS3 amyotrophic lateral soluble sclerosis 3 SETX senataxin ALS5 amyotrophic lateral sclerosis 5 FUS fused in sarcoma ALS7 amyotrophic lateral sclerosis 7 ALS2 amyotrophic lateral DPP6 Dipeptidyl-peptidase 6 sclerosis 2 NEFH neurofilament, heavy PTGS1 prostaglandin- polypeptide endoperoxide synthase 1 SLC1A2 solute carrier family 1 TNFRSF10B tumor necrosis factor (glial high affinity receptor superfamily, glutamate transporter), member 10b member 2 PRPH peripherin HSP90AA1 heat shock protein 90 kDa alpha (cytosolic), class A member 1 GRIA2 glutamate receptor, IFNG interferon, gamma ionotropic, AMP A 2 SIOOB SI 00 calcium binding FGF2 fibroblast growth factor 2 protein B AOX1 aldehyde oxidase 1 CS citrate synthase TARDBP TAR DNA binding protein TXN thioredoxin RAPH1 Ras association MAP3K5 mitogenactivated protein (RaIGDS/AF-6) and kinase 5 pleckstrin homology domains 1 NBEAL1 neurobeachin-like 1 GPX1 glutathione peroxidase 1 ICA1L islet cell autoantigen RAC1 rasrelated C3 botulinum 1.69 kDa-like toxin substrate 1 MAPT microtubule-associated ITPR2 inositol 1,4,5- protein tau triphosphate receptor, type 2 ALS2CR4 amyotrophic lateral GES glutaminase sclerosis 2 (juvenile) chromosome region, candidate 4 ALS2CR8 amyotrophic lateral CNTFR ciliary neurotrophic factor sclerosis 2 (juvenile) receptor chromosome region, candidate 8 ALS2CR11 amyotrophic lateral FOLH1 folate hydrolase 1 sclerosis 2 (juvenile) chromosome region, candidate 11 FAM117B family with sequence P4HB prolyl 4-hydroxylase, similarity 117, member B beta polypeptide CNTF ciliary neurotrophic factor SQSTM1 sequestosome 1 STRADB STE20-related kinase NAIP NLR family, apoptosis adaptor beta inhibitory protein YWHAQ tyrosine 3- SLC33A1 solute carrier family 33 monooxygenase/tryptoph (acetyl-CoA transporter), an 5-monooxygenase member 1 activation protein, theta polypeptide TRAK2 trafficking protein, FIG. 4 FIG. 4 homolog, SAC1 kinesin binding 2 lipid phosphatase domain containing NIF3L1 NIF3 NGGl interacting INA internexin neuronal factor 3-like 1 intermediate filament protein, alpha PARD3B par-3 partitioning COX8A cytochrome c oxidase defective 3 homolog B subunit VIIIA CDK15 cyclin-dependent kinase HECW1 IIECT, C2 and WW 15 domain containing E3 ubiquitin protein ligase 1 NOS1 nitric

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PCT/US2016/038181 oxide synthase 1 MET met proto-oncogene SOD2 superoxide dismutase 2, HSPB 1 heat shock 27 kDa mitochondrial protein 1 NEFL neurofilament, light CTSB cathepsin B polypeptide ANG angiogenin, HSPA8 heat shock 70 kDa ribonuclease, RNase A protein 8 family, 5 VAPB VAMP (vesicle- ESR1 estrogen receptor 1 associated membrane protein)-associated protein B and C SNCA synuclein, alpha HGF hepatocyte growth factor CAT catalase ACTB actin, beta NEFM neurofilament, medium TH tyrosine hydroxylase polypeptide BCL2 B-cell CLL/lymphoma 2 FAS Fas (TNF receptor superfamily, member 6) CASP3 caspase 3, apoptosis- CLU clusterin related cysteine peptidase SMN1 survival of motor neuron G6PD glucose-6-phosphate 1, telomeric dehydrogenase BAX BCL2-associated X HSF1 heat shock transcription protein factor 1 RNF19A ring finger protein 19A JUN jun oncogene ALS2CR12 amyotrophic lateral HSPA5 heat shock 70 kDa sclerosis 2 (juvenile) protein 5 chromosome region, candidate 12 MAPK14 mitogen-activated protein IL10 interleukin 10 kinase 14 APEX1 APEX nuclease TXNRD1 thioredoxin reductase 1 (multifunctional DNA repair enzyme) 1 NOS2 nitric oxide synthase 2, TIMP1 TIMP metallopeptidase inducible inhibitor 1 CASP9 caspase 9, apoptosis- XIAP Xlinked inhibitor of related cysteine apoptosis peptidase GLG1 golgi glycoprotein 1 EPO erythropoietin VEGFA vascular endothelial ELN elastin growth factor A GDNF glial cell derived NFE2L2 nuclear factor (erythroid- neurotrophic factor derived 2)-like 2 SLC6A3 solute carrier family 6 HSPA4 heat shock 70 kDa (neurotransmitter protein 4 transporter, dopamine), member 3 APOE apolipoprotein E PSMB8 proteasome (prosome, macropain) subunit, beta type, 8 DCTN1 dynactin 1 TIMP 3 TIMP metallopeptidase inhibitor 3 KIFAP3 kinesin-associated SLC1A1 solute carrier family 1 protein 3 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 SMN2 survival of motor neuron CCNC cyclin C 2, centromeric MPP4 membrane protein, STUB1 STIP1 homology and U- palmitoylated 4 box containing protein I ALS2 amyloid beta (A4) PRDX6 peroxiredoxin 6 precursor protein SYP synaptophysin CABIN1 calcineurin binding protein 1 CASP1 caspase 1, apoptosis- GART phosphoribosylglycinami related cysteine de formyltransferase, peptidase phosphoribosylglycinami de synthetase, phosphoribosylaminoimi dazole synthetase CDK5 cyclin-dependent kinase 5 ATXN3 ataxin 3 RTN4 reticulon 4 C1QB complement component 1, q subcomponent, B chain VEGFC nerve growth factor HTT huntingtin receptor PARK7 Parkinson disease 7 XDH xanthine dehydrogenase GFAP glial fibrillary⁷ acidic MAP2 microtubule-associated protein protein 2 CYCS cytochrome c, somatic FCGR3B Fc fragment of

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IgG, low affinity Illb, CCS copper chaperone for UBL5 ubiquitin-like 5 superoxide dismutase MMP9 matrix metallopeptidase SLC18A3 solute carrier family 18 9( (vesicular acetylcholine), member 3 TRPM7 transient receptor HSPB2 heat shock 27 kDa potential cation channel, protein 2 subfamily M, member 7 AKT1 v-akt murine thymoma DERL1 Deri-like domain family, viral oncogene homolog I member 1 CCL2 chemokine (C--C motif) NGRN neugrin, neurite ligand 2 outgrowth associated GSR glutathione reductase TPPP3 tubulin polymerization- promoting protein family member 3 APAF1 apoptotic peptidase BTBD10 BI'B (POZ) domain activating factor 1 containing 10 GLUD1 glutamate CXCR4 chemokine (C—X—C motif) dehydrogenase 1 receptor 4 SLC1A3 solute carrier family 1 FLT1 fms-related tyrosine (glial high affinity glutamate transporter), member 3 kinase 1 PON1 paraoxonase 1 AR androgen receptor LIF leukemia inhibitory factor ERBB3 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 LGALS1 lectin, galactoside- CD44 CD44 molecule binding, soluble, 1 TP53 tumor protein p53 TLR3 toll-like receptor 3 GRIA1 glutamate receptor, GAPDH glyceraldehyde-3- ionotropic, AMP A 1 phosphate dehydrogenase GRIK1 glutamate receptor, DES desmin ionotropic, kainate 1 CHAT choline acetyltransferase FLT4 fms-related tyrosine kinase 4 CHMP2B chromatin modifying BAG1 BCL2-associated protein 2B athanogene MT3 metallothionein 3 CHRNA4 cholinergic receptor, nicotinic, alpha 4 GSS glutathione synthetase BAK1 BCL2antagonist/killer I KDR kinase insert domain GSTP1 glutathione S-transferase receptor (a type III pi I receptor tyrosine kinase) OGGI 8-oxoguanine DNA IL6 interleukin 6 (interferon, glycosylase beta 2).

[001225] The animal or cell may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more disrupted chromosomal sequences encoding a protein associated with ALS and zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chromosomally integrated sequences encoding the disrupted protein associated with ALS. Preferred proteins associated with ALS include SOD1 (superoxide dismutase 1), ALS2 (amyotrophic lateral sclerosis 2), FUS (fused in sarcoma), TARDBP (TAR DNA binding protein), VAGFA (vascular endothelial growth factor A), VAGFB (vascular endothelial growth factor B), and VAGFC (vascular endothelial growth factor C), and any combination thereof. Autism [001226] US Patent Publication No. 20110023145, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated with autism spectrum disorders (ASD). Autism spectrum disorders (ASDs) are a group of disorders characterized by qualitative

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PCT/US2016/038181 impairment in social interaction and communication, and restricted repetitive and stereotyped patterns of behavior, interests, and activities. The three disorders, autism, Asperger syndrome (AS) and pervasive developmental disorder-not otherwise specified (PDD-NOS) are a continuum of the same disorder with varying degrees of severity, associated intellectual functioning and medical conditions. ASDs are predominantly genetically determined disorders with a heritability of around 90%.

[001227] US Patent Publication No. 20110023145 comprises editing of any chromosomal sequences that encode proteins associated with ASD which may be applied to the CRISPR Cas system of the present invention. The proteins associated with ASD are typically selected based on an experimental association of the protein associated with ASD to an incidence or indication of an ASD. For example, the production rate or circulating concentration of a protein associated with ASD may be elevated or depressed in a population having an ASD relative to a population lacking the ASD, Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the proteins associated with ASD may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including but not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (QPCR).

[001228] Non limiting examples of disease states or disorders that may be associated with proteins associated with ASD include autism, Asperger syndrome (AS), pervasive developmental disorder-not otherwise specified (PDD-NOS), Rett's syndrome, tuberous sclerosis, phenylketonuria, Smith-Lemli-Opitz syndrome and fragile X syndrome. By way of non-limiting example, proteins associated with ASD include but are not limited to the following proteins: ATP 10C aminophospholipid- MET MET receptor transporting ATPase tyrosine kinase (ATP10C) BZRAP1 MGLUR5 (GRM5) Metabotropic glutamate receptor 5 (MGLUR5) CDH10 Cadherin-10 MGLUR6 (GRM6) Metabotropic glutamate receptor 6 (MGLUR6) CDH9 Cadherin-9 NLGN1 Neuroligin-1 CNTN4 Contactin-4 NLGN2 Neuroligin-2 CNTNAP2 Contactin-associated SEMA5A Neuroligin-3 protein-like 2 (CNTNAP2) DHCR7 7dehydrocholesterol NLGN4X Neuroligin-4 X- reductase (DHCR7) linked DOC2A Double C2like domain- NLGN4Y Neuroligin-4 Y- containing protein alpha linked DPP6 Dipeptidyl

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NLGN5 Neuroligin-5 aminopeptidase-like protein 6 EN2 engrailed 2 (EN2) NRCAM Neuronal cell adhesion molecule (NRCAM) MDGA2 fragile X mental retardation NRXN1 Neurexin-1 1 (MDGA2) FMR2 (AFF2) AF4/FMR2 family member 2 OR4M2 Olfactory receptor (AFF2) 4M2 FOXP2 Forkhead box protein P2 OR4N4 Olfactory receptor (FOXP2) 4N4 FXR1 Fragile X mental OXTR oxytocin receptor retardation, autosomal (OXTR) homolog I (FXR1) FXR2 Fragile X mental PAH phenylalanine retardation, autosomal hydroxylase (PAH) homolog 2 (FXR2) GABRAl Gamma-aminobutyric acid PTEN Phosphatase and receptor subunit alpha-1 tensin homologue (GABRAl) (PTEN) GABRA5 GABAA (.gamma.-aminobutyric PTPRZ1 Receptor-type acid) receptor alpha 5 tyrosine-protein subunit (GABRA5) phosphatase zeta (PTPRZ1) GABRB1 Gamma-aminobutyric acid RELN Reelin receptor subunit beta-1 (GABRB1) GABRB3 GABAA (.gamma.-aminobutyric RPL10 60S ribosomal acid) receptor .beta.3 subunit protein L10 (GABRB3) GABRG1 Gamma-aminobutyric acid SEMA5A Semaphorin-5A receptor subunit gamma-1 (SEMA5A) (GABRG1) HIRIP3 HIRA-interacting protein 3 SEZ6L2 seizure related 6 homolog (mouse)- like 2 HOXA1 Homeobox protein HoxA1 SHANKS SH3 and multiple (HOXA1) ankyrin repeat domains 3 (SHANK3) 1L6 Interleukin 6 SHBZRAP1 SH3 and multiple ankyrin repeat domains 3 (SHBZRAP1) LAMB1 Laminin subunit beta-1 SLC6A4 Serotonin (LAMB1) transporter (SERT) MAPK3 Mitogen-activated protein TAS2R1 Taste receptor kinase 3 type 2 member 1 TAS2R1 MAZ Myc-associated zinc finger TSC1 Tuberous sclerosis protein protein 1 MDGA2 MAM domain containing TSC2 Tuberous sclerosis glycosylphosphatidylinositol protein 2 anchor 2 (MDGA2) MECP2 Methyl CpG binding UBE3A Ubiquitin protein protein 2 (MECP2) ligase ESA (UBE3A) MECP2 methyl CpG binding WNT2 Wingless-type protein 2 (MECP2) MMTV integration site family, member 2 (WNT2) [001229] The identity of the protein associated with ASD whose chromosomal sequence is edited can and will vary. In preferred embodiments, the proteins associated with ASD whose chromosomal sequence is edited may be the benzodi azapine receptor (peripheral) associated protein 1 (BZRAP1) encoded by the BZRAP1 gene, the AF4/FMR2 family member 2 protein (AFF2) encoded by the AFF2 gene (also termed MFR2), the fragile X mental retardation autosomal homolog 1 protein (FXR1) encoded by the FXR1 gene, the fragile X mental retardation autosomal homolog 2 protein (FXR2) encoded by the FXR2 gene, the MAM domain containing glycosylphosphatidylinositol anchor 2 protein (MDGA2) encoded by the MDGA2

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PCT/US2016/038181 gene, the methyl CpG binding protein 2 (MECP2) encoded by the MECP2 gene, the metabotropic glutamate receptor 5 (MGLUR5) encoded by the MGLUR5-1 gene (also termed GRM5), the neurexin 1 protein encoded by the NRXN1 gene, or the semaphorin-5A protein (SEMA5A) encoded by the SEMA5A gene. In an exemplary embodiment, the genetically modified animal is a rat, and the edited chromosomal sequence encoding the protein associated with ASD is as listed below: BZRAP1 benzodiazapine receptor XM_002727789, (peripheral) associated XM_213427, protein 1 (BZRAP1) XM_002724533, XM_QQ1081125 AFF2 (FMR2) AF4/FMR2 family member 2 XM_219832, (AFF2) XM_001054673 FXR1 Fragile X mental NM_001012179 retardation, autosomal homolog 1 (FXR1) FXR2 Fragile X mental NM 001100647 retardation, autosomal homolog 2 (FXR2) MDGA2 MAM domain containing NM_199269 glycosylphosphatidylinositol anchor 2 (MDGA2) MECP2 Methyl CpG binding NM_022673 protein 2 (MECP2) MGLUR5 Metabotropic glutamate NM_0I7012 (GRM5) receptor 5 (MGLUR5) NRX.N1 Neurexin-1 NM_021767 SEMA.5A Semaphorin-5A (SEMA5A) NM 001107659.

[001230] US Patent Publication No. 20110016540, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated with trinucleotide repeat expansion disorders. Trinucleotide repeat expansion disorders are complex, progressive disorders that involve developmental neurobiology and often affect cognition as well as sensori-motor functions.

[001231] Trinucleotide repeat expansion proteins are a diverse set of proteins associated with susceptibility for developing a trinucleotide repeat expansion disorder, the presence of a trinucleotide repeat expansion disorder, the severity of a trinucleotide repeat expansion disorder or any combination thereof. Trinucleotide repeat expansion disorders are divided into two categories determined by the type of repeat. The most common repeat is the triplet CAG, which, when present in the coding region of a gene, codes for the amino acid glutamine (Q). Therefore, these disorders are referred to as the polyglutamine (polyQ) disorders and comprise the following diseases: Huntington Disease (HD); Spinobulbar Muscular Atrophy (SBMA); Spinocerebellar Ataxias (SCA types 1, 2, 3, 6, 7, and 17); and Dentatorubro-Pallidoluysian Atrophy (DRPLA). The remaining trinucleotide repeat expansion disorders either do not involve the CAG triplet or the CAG triplet is not in the coding region of the gene and are, therefore.

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PCT/US2016/038181 referred to as the non-polyglutamine disorders. The non-polyglutamine disorders comprise Fragile X Syndrome (FRAXA); Fragile XE Mental Retardation (FRAXE); Friedreich Ataxia (FRDA); Myotonic Dystrophy (DM); and Spinocerebellar Ataxias (SCA types 8, and 12). [001232] The proteins associated with trinucleotide repeat expansion disorders are typically selected based on an experimental association of the protein associated with a trinucleotide repeat expansion disorder to a trinucleotide repeat expansion disorder. For example, the production rate or circulating concentration of a protein associated with a trinucleotide repeat expansion disorder may be elevated or depressed in a population having a trinucleotide repeat expansion disorder relative to a population lacking the trinucleotide repeat expansion disorder. Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the proteins associated with trinucleotide repeat expansion disorders may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including but not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).

[001233] Non-limiting examples of proteins associated with trinucleotide repeat expansion disorders include AR (androgen receptor), FMR1 (fragile X mental retardation 1), HTT (huntingtin), DMPK (dystrophia myotonica-protein kinase), FXN (frataxin), ATXN2 (ataxin 2), A TNI (atrophin 1), FEN1 (flap structure-specific endonuclease 1), TNRC6A (trinucleotide repeat containing 6A), PABPNI (poly(A) binding protein, nuclear 1), JPE13 (junctophilin 3), MED15 (mediator complex subunit 15), ATXNI (ataxin 1), ATXN3 (ataxin 3), TBP (TATA box binding protein), CACNA1A (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit), ATXN80S (ATXN8 opposite strand (non-protein coding)), PPP2R2B (protein phosphatase 2, regulatory subunit B, beta), ATXN7 (ataxin 7), TNRC6B (trinucleotide repeat containing 6B), TNRC6C (trinucleotide repeat containing 6C), CELF3 (CUGBP, Elav-like family member 3), MAB21L1 (mab-21-like 1 (C. elegans)), MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)), TMEM185A (transmembrane protein 185A), SIX5 (SIX homeobox 5), CNPY3 (canopy 3 homolog (zebrafish)), FRAXE (fragile site, folic acid type, rare, fra(X)(q28) E), GNB2 (guanine nucleotide binding protein (G protein), beta polypeptide 2), RPL14 (ribosomal protein L14), ATXN8 (ataxin 8), INSR. (insulin receptor), TTR (transthyretin), EP400 (E1A

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PCT/US2016/038181 binding protein p400), GIGYF2 (GRB10 interacting GYF protein 2), OGGI (8-oxoguanine DNA glycosylase), STC1 (stanniocalcin 1), CNDP1 (camosine dipeptidase 1 (metallopeptidase M20 family)), C10orf2 (chromosome 10 open reading frame 2), MAML3 mastermind-like 3 (Drosophila), DKC1 (dyskeratosis congenita 1, dyskerin), PAX1P1 (PAX interacting (with transcription-activation domain) protein I), CASK (calcium/calmodulin-dependent serine protein kinase (MAGUK family)), MAPT (microtubule-associated protein tau), SP1 (Spl transcription factor), POLG (polymerase (DNA directed), gamma), AFF2 (AF4/FMR2 family, member 2), THBS1 (thrombospondin 1), TP53 (tumor protein p53), ESR1 (estrogen receptor 1), CGGBP1 (CGG triplet repeat binding protein 1), ABT1 (activator of basal transcription 1), KLK3 (kallikrein-related peptidase 3), PRNP (prion protein), JUN (jun oncogene), KCNN3 (potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3), BAX (BCL2-associated X protein), FRAXA (fragile site, folic acid type, rare, fra(X)(q27.3) A (macroorchidism, mental retardation)), KBTBD10 (kelch repeat and BTB (POZ) domain containing 10), MBNL1 (muscleblind-like (Drosophila)), RAD51 (RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae)), NCOA3 (nuclear receptor coactivator 3), ERDA1 (expanded repeat domain, CAG/CTG 1), TSC1 (tuberous sclerosis 1), COMP (cartilage oligomeric matrix protein), GCLC (glutamate-cysteine ligase, catalytic subunit), RRAD (Ras-related associated with diabetes), MSI 13 (mutS homolog 3 (E. coli)), DRD2 (dopamine receptor D2), CD44 (CD44 molecule (Indian blood group)), CTCF (CCCTC-binding factor (zinc finger protein)), CCND1 (cyclin DI), CLSPN (claspin homolog (Xenopus laevis)), MEF2A (myocyte enhancer factor 2A), PTPRU (protein tyrosine phosphatase, receptor type, U), GAPDH (glyceraldehyde-3phosphate dehydrogenase), TR1M22 (tripartite motif-containing 22), WT1 (Wilms tumor 1), AHR (aryl hydrocarbon receptor), GPX1 (glutathione peroxidase 1), TPMT (thiopurine Smethyltransferase), NDP (Norrie disease (pseudoglioma)), ARX (aristaless related homeobox), MUS81 (MUS81 endonuclease homolog (S. cerevisiae)), TYR (tyrosinase (oculocutaneous albinism IA)), EGRl (early growth response 1), UNG (uracil-DNA glycosylase), NUMBL (numb homolog (Drosophila)-like), FABP2 (fatty acid binding protein 2, intestinal), EN2 (engrailed homeobox 2), CRYGC (crystallin, gamma C), SRP14 (signal recognition particle 14 kDa (homologous Alu RNA binding protein)), CRYGB (crystallin, gamma B), PDCD1 (programmed cell death 1), HOXA1 (homeobox Al), ATXN2L (ataxin 2-like), PMS2 (PMS2 postaleiotic segregation increased 2 (S. cerevisiae)), GLA (galaetosidase, alpha), CBL (Cas-Br397

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M (murine) ecotropic retroviral transforming sequence), FTH1 (ferritin, heavy polypeptide 1), IL12RB2 (interleukin 12 receptor, beta 2), OTX2 (orthodenticle homeobox 2), HOXA5 (homeobox A5), POLG2 (polymerase (DNA directed), gamma 2, accessory subunit), DLX2 (distal-less homeobox 2), SIRPA (signal-regulatory protein alpha), OTX1 (orthodenticle homeobox 1), AHRR (aryl-hydrocarbon receptor repressor), MANF (mesencephalic astrocytederived neurotrophic factor), TMEM158 (transmembrane protein 158 (gene/pseudogene)), and ENSGGQ000078687.

[001234] Preferred proteins associated with trinucleotide repeat expansion disorders include HTT (Huntingtin), AR (androgen receptor), FXN (frataxin), Atxn3 (ataxin), Atxnl (ataxin), Atxn2 (ataxin), Atxn7 (ataxin), Atxnl0 (ataxin), DMPK (dystrophia myotonica-protein kinase), Atnl (atrophin 1), CBP (creb binding protein), VLDLR (very low density lipoprotein receptor), and any combination thereof.

Treating Hearing Diseases [001235] The present invention also contemplates delivering the CRISPR-Cas system to one or both ears.

[001236] Researchers are looking into whether gene therapy could be used to aid current deafness treatments - namely, cochlear implants. Deafness is often caused by lost or damaged hair cells that cannot relay signals to auditory neurons. In such cases, cochlear implants may be used to respond to sound and transmit electrical signals to the nerve cells. But these neurons often degenerate and retract from the cochlea as fewer growth factors are released by impaired hair cells.

[001237] US patent application 20120328580 describes injection of a pharmaceutical composition into the ear (e.g., auricular administration), such as into the luminae of the cochlea (e.g., the Scala media. Sc vestibulae, and Sc tympani), e.g., using a syringe, e.g., a single-dose syringe. For example, one or more of the compounds described herein can be administered by intratympanic injection (e.g., into the middle ear), and/or injections into the outer, middle, and/or inner ear. Such methods are routinely used in the art, for example, for the administration of steroids and antibiotics into human ears. Injection can be, for example, through the round window of the ear or through the cochlear capsule. Other inner ear administration methods are known in the art (see, e.g., Salt and Plontke, Drug Discovery' Today, 10:1299-1306, 2005).

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PCT/US2016/038181 [001238] In another mode of administration, the pharmaceutical composition can be administered in situ, via a catheter or pump. A catheter or pump can, for example, direct a pharmaceutical composition into the cochlear luminae or the round window of the ear and/or the lumen of the colon. Exemplar}/ drug delivery apparatus and methods suitable for administering one or more of the compounds described herein into an ear, e.g., a human ear, are described by McKenna et al., (U.S. Publication No. 2006/0030837) and Jacobsen et ah, (U.S. Pat. No. 7,206,639). In some embodiments, a catheter or pump can be positioned, e.g., in the ear (e.g., the outer, middle, and/or inner ear) of a patient during a surgical procedure. In some embodiments, a catheter or pump can be positioned, e.g., in the ear (e.g., the outer, middle, and/or inner ear) of a patient without the need for a surgical procedure.

[001239] Alternatively or in addition, one or more of the compounds described herein can he administered in combination with a mechanical device such as a cochlear implant or a hearing aid, winch is worn in the outer ear. An exemplar}' cochlear implant that is suitable for use with the present invention is described by Edge et al., (U.S. Publication No. 2007/0093878).

[001240] In some embodiments, the modes of administration described above may be combined in any order and can be simultaneous or interspersed.

[001241] Alternatively or in addition, the present invention may be administered according to any of the Food and Drug Administration approved methods, for example, as described in CDER Data Standards Manual, version number 004 (which is available at fda. give/cder/dsm/DRG/drg003 01. htm).

[001242] In general, the cell therapy methods described in US patent application 20120328580 can be used to promote complete or partial differentiation of a cell to or towards a mature cell type of the inner ear (e.g., a hair cell) in vitro. Cells resulting from such methods can then be transplanted or implanted into a patient in need of such treatment. The cell culture methods required to practice these methods, including methods for identifying and selecting suitable cell types, methods for promoting complete or partial differentiation of selected cells, methods for identifying complete or partially differentiated cell types, and methods for implanting complete or partially differentiated cells are described below.

[001243] Cells suitable for use in the present invention include, but are not limited to, cells that are capable of differentiating completely or partially into a mature cell of the inner ear, e.g., a hair cell (e.g., an inner and/or outer hair cell), when contacted, e.g., in vitro, with one or more of

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PCT/US2016/038181 the compounds described herein. Exemplary cells that are capable of differentiating into a hair cell include, but are not limited to stem cells (e.g., inner ear stem cells, adult stem ceils, bone marrow derived stem cells, embryonic stem cells, mesenchymal stem cells, skin stem cells, iPS ceils, and fat derived stem cells), progenitor cells (e.g., inner ear progenitor cells), support cells (e.g., Deiters' cells, pillar cells, inner phalangeal cells, tectal cells and Hensen's cells), and/or germ cells. The use of stem cells for the replacement of Inner ear sensory cells is described in Li et al., (U.S. Publication No. 2005/0287127) and Li et al., (U.S. patent Ser. No. 11/953,797). The use of bone marrow derived stem cells for the replacement of inner ear sensory cells is described in Edge et al., PCT/US2007/084654. iPS cells are described, e.g., at Takahashi et al., Cell, Volume 131, Issue 5, Pages 861-872 (2007); Takahashi and Yamanaka, Cell 126, 663-76 (2006), Okita et al., Nature 448, 260-262 (2007); Yu, J. et al., Science 318(5858):1917-1920 (2007), Nakagawa et al., Nat. Biotechnol. 26:101-106 (2008); and Zaehres and Scholer, Cell 131(5):834835 (2007). Such suitable cells can be identified by analyzing (e.g., qualitatively or quantitatively) the presence of one or more tissue specific genes. For example, gene expression can be detected by detecting the protein product of one or more tissue-specific genes. Protein detection techniques involve staining proteins (e.g., using cell extracts or whole cells) using antibodies against the appropriate antigen. In this case, the appropriate antigen is the protein product of the tissue-specific gene expression. Although, in principle, a first antibody (i.e., the antibody that binds the antigen) can be labeled, it is more common (and improves the visualization) to use a second antibody directed against the first (e.g., an anti-IgG). This second antibody is conjugated either with fluorochromes, or appropriate enzymes for colorimetric reactions, or gold beads (for electron microscopy), or with the biotin-avidin system, so that the location of the primary antibody, and thus the antigen, can be recognized.

[001244] The CRISPR Cas molecules of the present invention may be delivered to the ear by direct application of pharmaceutical composition to the outer ear, with compositions modified from US Published application, 20110142917. In some embodiments the pharmaceutical composition is applied to the ear canal. Deliver)' to the ear may also be refered to as aural or otic delivery.

[001245] In some embodiments the RNA molecules of the Invention are delivered in liposome or lipofectin formulations and the like and can be prepared by methods well known to those

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PCT/US2016/038181 skilled in the art. Such methods are described, for example, in U.S. Pat. Nos. 5,593,972, 5,589,466, and 5,580,859, which are herein incorporated by reference.

[001246] Delivery systems aimed specifically at the enhanced and improved deliver}⁷ of siRNA into mammalian cells have been developed, (see, for example, Shen et al FEBS Let, 2003, 539:111-114; Xia et al., Nat. Biotech. 2002, 20:1006-1010; Reich et al., Mol. Vision. 2003, 9: 210-216; Sorensen et al., J. Mol. Biol. 2003, 327: 761-766, Lewis et al,, Nat, Gen. 2002, 32: 107108 and Simeoni et al., NAR 2003, 31, 11: 2717-2724) and may be applied to the present invention. siRNA has recently been successfully used for inhibition of gene expression in primates (see for example. Tolentino et al., Retina 24(4):660 which may also be applied to the present invention.

[001247] Qi et al, discloses methods for efficient siRNA transfection to the inner ear through the intact round window by a novel proteidic deliver}' technology which may be applied to the nucleic acid-targeting system of the present invention (see, e.g., Qi et al.. Gene Therapy (2013), 1-9). In particular, a TAT double stranded RNA-binding domains (TAT-DRBDs), which can transfect Cy3-labeled siRNA into cells of the inner ear, Including the inner and outer hair cells, crista ampullaris, macula utriculi and macula sacculi, through intact round-window permeation was successful for delivering double stranded siRNAs In vivo for treating various inner ear ailments and preservation of hearing function. About 40 μΐ of lOmM RNA may be contemplated as the dosage for administration to the ear.

[001248] According to Rejali et al, (Hear Res, 2007 Jun;228(l-2):180-7), cochlear implant function can be improved by good preservation of the spiral ganglion neurons, which are the target of electrical stimulation by the implant and brain derived neurotrophic factor (BDNF) has previously been shown to enhance spiral ganglion survival in experimentally deafened ears. Rejali et al. tested a modified design of the cochlear implant electrode that includes a coating of fibroblast cells transduced by a viral vector with a BDNF gene insert. To accomplish this type of ex vivo gene transfer, Rejali et al. transduced guinea pig fibroblasts with an adenovirus with a BDNF gene cassette insert, and determined that these cells secreted BDNF and then attached BDNF-secreting cells to the cochlear implant electrode via an agarose gel, and implanted the electrode in the scala tympani. Rejali et al. determined that the BDNF expressing electrodes were able to preserve significantly more spiral ganglion neurons in the basal turns of the cochlea after 48 days of implantation when compared to control electrodes and demonstrated the feasibility of

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PCT/US2016/038181 combining cochlear implant therapy with ex vivo gene transfer for enhancing spiral ganglion neuron survival. Such a system may be applied to the nucleic acid-targeting system of the present invention for delivery to the ear.

[001249] Mukheqea et al. (Antioxidants & Redox Signaling, Volume 13, Number 5, 2010) document that knockdown of NOX3 using short interfering (si) RNA abrogated cisplatin ototoxicity, as evidenced by protection of OHCs from damage and reduced threshold shifts in auditory brainstem responses (ABRs). Different doses of siNOX3 (0.3, 0.6, and 0.9 pg) were administered to rats and N0X3 expression was evaluated by real time RT-PCR. The lowest dose of ΝΌΧ3 siRNA used (0.3 pg) did not show any inhibition of N0X3 mRNA when compared to transtympanic administration of scrambled siRNA or untreated cochleae. However, administration of the higher doses of N0X3 siRNA (0,6 and 0.9 pg) reduced ΝΌΧ3 expression compared to control scrambled siRNA. Such a system may be applied to the CRISPR Cas system of the present invention for transtympanic administration with a dosage of about 2 mg to about 4 mg of CRISPR Cas for administration to a human.

[001250] Jung et al. (Molecular Therapy, vol. 21 no. 4, 834-841 apr. 2013) demonstrate that Hes5 levels in the utricle decreased after the application of siRNA and that the number of hair cells in these utricles was significantly larger than following control treatment. The data suggest that siRNA technology may be useful for inducing repair and regeneration in the inner ear and that the Notch signaling pathway is a potentially useful target for specific gene expression Inhibition. Jung et al. injected 8 pg of Hes5 siRNA in 2 pi volume, prepared by adding sterile normal saline to the lyophilized siRNA to a vestibular epithelium of the ear. Such a system maybe applied to the nucleic acid-targeting system of the present invention for administration to the vestibular epithelium of the ear with a dosage of about 1 to about 30 mg of CRISPR Cas for administration to a human.

Gene Targeting in Non-Dividing Cells (Neurones & Muscle) [001251] Non-dividing (especially non-dividing, fully differentiated) cell types present issues for gene targeting or genome engineering, for example because homologous recombination (HR) is generally supressed in the G1 cell-cycle phase. However, while studying the mechanisms by which cells control normal DNA repair systems, Durocher discovered a previously unknown switch that keeps HR “off’ in non-dividing cells and devised a strategy to toggle this switch back on. Orthwein et al. (Daniel Durocher’s lab at the Mount Sinai Hospital in Ottawa, Canada)

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PCT/US2016/038181 recently reported (Nature 16142, published online 9 Dec 2015) have shown that the suppression of HR can be lifted and gene targeting successfully concluded in both kidney (293T) and osteosarcoma (U2OS) cells. Tumor suppressors, BRCA1, PALB2 and BRAC2 are known to promote DNA DSB repair by HR. They found that formation of a complex of BRCA1 with PALB2 - BRAC2 is governed by a ubiquitin site on PALB2, such that action on the site by an E3 ubiquitin ligase. This E3 ubiquitin ligase is composed of KEAPI (a PALB2 -interacting protein) in complex with cullin-3 (CUL3)-RBX1. PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11, which is itself under cell cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNAend resection is sufficient to induce homologous recombination in Gl, as measured by a number of methods including a CRISPR-Cas9-based gene-targeting assay directed at USPI1 or KEAPI (expressed from a pX459 vector). However, when the BRCA1-PALB2 interaction was restored in resection-competent Gl cells using either KEAPI depletion or expression of the PALB2-KR mutant, a robust increase in gene-targeting events was detected.

[001252] Thus, reactivation of HR in cells, especially non-dividing, fully differentiated cell types is preferred, in some embodiments. In some embodiments, promotion of the BRCA1PALB2 interaction is preferred in some embodiments. In some embodiments, the target ell is a non-dividing cell. In some embodiments, the target cell is a neurone or muscle cell. In some embodiments, the target cell is targeted in vivo. In some embodiments, the cell is in Gl and HR is supressed. In some embodiments, use of KEAP1 depletion, for example inhibition of expression of KEAP1 activity, is preferred. KEAPI depletion may be achieved through siRNA, for example as shown in Orthwein et al. Alternatively, expression of the PALB2-KR mutant (lacking all eight Lys residues in the BRCA1-interaction domain is preferred, either in combination with KEAPI depletion or alone. PALB2-KR interacts with BRCA1 irrespective of cell cycle position. Thus, promotion or restoration of the BRCA1-PALB2 interaction, especially in Gl cells, is preferred in some embodiments, especially where the target cells are non-dividing, or where removal and return (ex vivo gene targeting) is problematic, for example neurone or muscle cells. KEAPI siRNA is available from ThermoFischer. In some embodiments, a BRCAI-PALB2 complex may be delivered to the Gl cell. In some embodiments, PALB2 deubiquitylation may be promoted for example by increased expression of the deubiquitylase

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USPli, so it is envisaged that a construct may be provided to promote or up-regulate expression or activity of the deubiquitylase USP11.

Treating Diseases of the Eye [001253] The present invention also contemplates delivering the CRISPR-Cas system to one or both eyes.

[001254] In particular embodiments of the invention, the CRISPR-Cas system may be used to correct ocular defects that arise from several genetic mutations further described in Genetic Diseases of the Eye, Second Edition, edited by Elias I. Traboulsi, Oxford University Press, 2012. [001255] For administration to the eye, lentiviral vectors, in particular equine infectious anemia viruses (EIAV) are particularly preferred.

[001256] In another embodiment, minimal non-primate lentiviral vectors based on the equine infectious anemia virus (EIAV) are also contemplated, especially for ocular gene therapy (see, e.g., Balagaan, J Gene Med 2006; 8: 275 - 285, Published online 21 November 2005 in Wiley InterScience (wvvw.interscience.wiley.com). DOI: 10.1002/jgm.845). The vectors are contemplated to have cytomegalovirus (CMV) promoter driving expression of the target gene. Intracameral, subretinal, intraocular and intravitreal injections are all contemplated (see, e.g., Balagaan, J Gene Med 2006; 8: 275 -- 285, Published online 21 November 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jgm.845). Intraocular injections may be performed with the aid of an operating microscope. For subretinal and intravitreal injections, eyes may be prolapsed by gentle digital pressure and fundi visualised using a contact lens system consisting of a drop of a coupling medium solution on the cornea covered with a glass microscope slide coverslip. For subretinal injections, the tip of a 10-mm 34-gauge needle, mounted on a 5-μ1 Hamilton syringe may be advanced under direct visualisation through the superior equatorial sclera tangentially towards the posterior pole until the aperture of the needle 'was visible in the subretinal space. Then, 2 μΐ of vector suspension may be injected to produce a superior bullous retinal detachment, thus confirming subretinal vector administration. This approach creates a self-sealing sclerotomy allowing the vector suspension to be retained in the subretinal space until it is absorbed by the RPE, usually within 48 h of the procedure. This procedure may be repeated in the inferior hemisphere to produce an inferior retinal detachment. This technique results in the exposure of approximately 70% of neurosensory retina and RPE to the vector suspension. For intravitreal injections, the needle tip may be advanced through the

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PCT/US2016/038181 sclera 1 mm posterior to the corneoscleral limbus and 2 μ! of vector suspension injected into the vitreous cavity. For intracameral injections, the needle tip may be advanced through a corneoscleral limbal paracentesis, directed towards the central cornea, and 2 μΐ of vector suspension may be injected. For intracameral injections, the needle tip may be advanced through a corneoscleral limbal paracentesis, directed towards the central cornea, and 2 μΐ of vector suspension may be injected. These vectors may be injected at titres of either 1.0-1.4 χ I0^lCI or 1.0-1.4 x 10⁹ transducing units (TU)/ml.

[001257] In another embodiment, RetinoStat®, an equine infectious anemia virus-based lentiviral gene therapy vector that expresses angiostatic proteins endostain and angiostatin that is delivered via a subretinal injection for the treatment of the web form of age-related macular degeneration is also contemplated (see, e.g,, Binley et al., HUMAN GENE THERAPY 23:980991 (September 2012)). Such a vector may be modified for the CRISPR-Cas system of the present invention. Each eye may be treated with either RetinoStat® at a dose of 1.1 x 10⁵ transducing units per eye (TU/eye) in a total volume of 100 μΐ.

[001258] In another embodiment, an E1-, partial E3-, E4-deleted adenoviral vector may be contemplated for delivery to the eye. Twenty-eight patients with advanced neovascular agerelated macular degeneration (AMD) were given a single intravitreous injection of an El-, partial E3-, E4-deleted adenoviral vector expressing human pigment ep- ithelium-derived factor (AdPEDF.ll) (see, e.g., Campochiaro et al., Human Gene Therapy 17:167-176 (February 2006)). Doses ranging from 10⁶ to 10⁹⁵ particle units (PU) were investigated and there were no serious adverse events related to AdPEDF.ll and no dose-limiting toxicities (see, e.g., Campochiaro et al., Human Gene Therapy 17:167-176 (February 2006)). Adenoviral vectormediated ocular gene transfer appears to be a viable approach for the treatment of ocular disorders and could be applied to the CRISPR Cas system.

[001259] In another embodiment, the sd-rxRNA® system of RXi Pharmaceuticals may he used/and or adapted for delivering CRISPR Cas to the eye. In this system, a single intravitreal administration of 3 pg of sd-rxRNA results in sequence-specific reduction of PPIB mRNA levels for 14 days. The the sd-rxRNA® system may be applied to the nucleic acid-targeting system of the present invention, contemplating a dose of about 3 to 20 mg of CRISPR administered to a human.

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PCT/US2016/038181 [001260] Millington-Ward et al. (Molecular Therapy, vol. 19 no. 4, 642-649 apr. 2011) describes adeno-associated virus (AAV) vectors to deliver an RNA interference (RNAi)-based rhodopsin suppressor and a codon-modified rhodopsin replacement gene resistant to suppression due to nucleotide alterations at degenerate positions over the RNAi target site. An injection of either 6.0 x IO⁸ vp or 1.8 x I0^1,J vp AAV were subretinally injected into the eyes by MillingtonWard et al. The AAV vectors of Millington-Ward et al, may be applied to the CRISPR Cas system of the present invention, contemplating a dose of about 2 x 10¹’ to about 6 x 10^!3 vp administered to a human.

[001261] Dalkara et al. (Sci Transl Med 5, 189ra76 (2013)) also relates to in vivo directed evolution to fashion an AAV vector that delivers wild-type versions of defective genes throughout the retina after noninjurious injection into the eyes’ vitreous humor. Dalkara describes a a 7mer peptide display library and an AAV library constructed by DNA shuffling of cap genes from AA.V1, 2, 4, 5, 6, 8, and 9. The rcAAV libraries and rAAV vectors expressing GFP under a CAG or Rho promoter were packaged and and deoxyribonuclease-resistant genomic titers were obtained through quantitative PCR, The libraries were pooled, and two rounds of evolution were performed, each consisting of initial library diversification followed by three in vivo selection steps. In each such step, P30 rho-GFP mice were intravitreally injected with 2 ml of iodixanol-purified, phosphate-buffered saline (PBS)-dialyzed library with a genomic titer of about 1 χ 10“ vg/ml. The AAV vectors of Dalkara et al. may be applied to the nucleic acid-targeting system of the present invention, contemplating a dose of about 1 x 10¹⁵ to about 1 x 10¹⁶ vg/ml administered to a human.

[001262] In a particular embodiment, the rhodopsin gene may be targeted for the treatment of retinitis pigmentosa (RP), wherein the system of US Patent Publication No. 20120204282 assigned to Sangamo BioSciences, Inc. may be modified in accordance of the CRISPR Cas system of the present invention.

[001263] In another embodiment, the methods of US Patent Publication No. 20130183282 assigned to Cellectis, which is directed to methods of cleaving a target sequence from the human rhodopsin gene, may also be modified to the nucleic acid-targeting system of the present invention, [001264] US Patent Publication No. 20130202678 assigned to Academia Sinica relates to methods for treating retinopathies and sight-threatening ophthalmologic disorders relating to

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PCT/US2016/038181 delivering of the Puf-A gene (which is expressed in retinal ganglion and pigmented cells of eye tissues and displays a unique anti-apoptotic activity) to the sub-retinal or intravitreal space in the eye. In particular, desirable targets are zgc: 193933, prdmla, spata2, texlO, rbb4, ddx3, zp2.2, Blimp-1 and HtrA2, all of which may be targeted by the nucleic acid-target!ng system of the present invention.

[001265] Wu (Cell Stem Cell, 13:659-62, 2013) designed a guide RNA that led Cas9 to a single base pair mutation that causes cataracts in mice, where it induced DNA cleavage. Then using either the other wild-type allele or oligos given to the zygotes repair mechanisms corrected the sequence of the broken allele and corrected the cataract-causing genetic defect in mutant mouse. [001266] US Patent Publication No. 20120159653, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated with macular degeration (MD). Macular degeneration (MD) is the primary cause of visual impairment in the elderly, but is also a hallmark symptom of childhood diseases such as Stargardt disease, Sorsby fundus, and fatal childhood neurodegenerative diseases, with an age of onset as young as infancy. Macular degeneration results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. Currently existing animal models do not recapitulate major hallmarks of the disease as it is observed in humans. The available animal models comprising mutant genes encoding proteins associated with MD also produce highly variable phenotypes, making translations to human disease and therapy development problematic.

[001267] One aspect of US Patent Publication No. 20120159653 relates to editing of any chromosomal sequences that encode proteins associated with MD which may be applied to the nucleic acid-targeting system of the present invention. The proteins associated with MD are typically selected based on an experimental association of the protein associated with MD to an MD disorder. For example, the production rate or circulating concentration of a protein associated with MD may be elevated or depressed in a population having an MD disorder relative to a population lacking the MD disorder. Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the proteins associated with MD may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including but not limited to DNA

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PCT/US2016/038181 microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).

[001268] By way of non-limiting example, proteins associated with MD include but are not limited to the following proteins: (ABCA4) ATP-binding cassette, sub-family A (ABO), member 4 ACHM1 achromatopsia (rod monochromacy) I ApoE Apolipoprotein E (ApoE) C1QTNF5 (CTRP5) Clq and tumor necrosis factor related protein 5 (C1QTNF5) C2 Complement component 2 (C2) C3 Complement components (C3) CCL2 Chemokine (C-C motif) Ligand 2 (CCL2) CCR2 Chemokine (C-C motif) receptor 2 (CCR2) CD36 Cluster of Differentiation 36 CEB Complement factor B CFH Complement factor CFH H CFHR1 complement factor H-related 1 CFHR3 complement factor H-related 3 CNGB3 cyclic nucleotide gated channel beta 3 CP ceruloplasmin (CP) CRP C reactive protein (CRP) CST3 cystatin C or cystatin 3 (CST3) CTSD Cathepsin D (CTSD) CX3CR1 chemokine (C-X3-C motif) receptor 1 ELOVL4 Elongation of very long chain fatty acids 4 ER.CC6 excision repair crosscomplementing rodent repair deficiency, complementation group 6 FBLN5 Fibulin-5 FBLN5 Fibulin 5 FBLN6 Fibulin 6 FSCN2 fascin (FSCN2) HMCN1 Hemicentrin 1 HMCN1 hemicentin 1 HTRA1 HtrA serine peptidase 1 (HTRA1) HTRA1 HtrA serine peptidase 1 IL-6 Interleukin 6 IL-8 Interleukin 8 LOC387715 Hypothetical protein PLEKHA1 Pleckstrin homology domaincontaining family A member 1 (PLEKHA1) PROM1 Prominin 1(PROM1 or CD 133) PRPH2 Peripherin-2 RPGR retinitis pigmentosa GTPase regulator SERPING1 serpin peptidase inhibitor, clade G, member 1 (Cl- inhibitor) TCOF1 Treacle T1MP3 Metalloproteinase inhibitor 3 (TIMP3) TLR3 Toll-like receptor 3.

[001269] The identity of the protein associated with MD whose chromosomal sequence is edited can and will vary. In preferred embodiments, the proteins associated with MD whose chromosomal sequence is edited may be the ATP-binding cassette, sub-family A (ABC1) member 4 protein (ABCA4) encoded by the ABCR gene, the apolipoprotein E protein (APOE) encoded by the APOE gene, the chemokine (C-C motif) Ligand 2 protein (CCL2) encoded by the CCL2 gene, the chemokine (C-C motif) receptor 2 protein (CCR2) encoded by the CCR2 gene, the ceruloplasmin protein (CP) encoded by the CP gene, the cathepsin D protein (CTSD) encoded by the CTSD gene, or the metalloproteinase inhibitor 3 protein (TIMP3) encoded by the TIMP3 gene. In an exemplary’ embodiment, the genetically modified animal is a rat, and the edited chromosomal sequence encoding the protein associated with MD may be: (ABCA4)

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ATPbinding cassette, NM 000350 sub-family A (ABC1), member 4 APOE Apolipoprotein E NM_ 138828 (APOE) CCL2 Chemokine (C-C NM_031530 motif) Ligand 2 (CCL2) CCR2 Chemokine (C-C NM 021866 motif) receptor 2 (CCR2) CP ceruloplasmin (CP) NM 012532 CTSD Cathepsin D (CTSD) NMJ34334 TIMP3 Metalloproteinase NM_012886 inhibitor 3 (TIMP3) The animal or cell may comprise 1, 2, 3, 4, 5, 6, 7 or more disrupted chromosomal sequences encoding a. protein associated with MD and zero, 1, 2, 3, 4, 5, 6, 7 or more chromosomally integrated sequences encoding the disrupted protein associated with MD. [001270] The edited or integrated chromosomal sequence may be modified to encode an altered protein associated with MD. Several mutations in MD-related chromosomal sequences have been associated with MD. Non-limiting examples of mutations in chromosomal sequences associated with MD include those that may cause MD including in the ABCR protein, E471K (i.e. glutamate at position 471 is changed to lysine), R1129L (i.e. arginine at position I129 is changed to leucine), T1428M (i.e, threonine at position 1428 is changed to methionine), R1517S (i.e, arginine at position 1517 is changed to serine), Γ1562Τ (i.e. isoleucine at position 1562 is changed to threonine), and G1578R (i.e. glycine at position 1578 is changed to arginine); in the CCR2 protein, V64I (i.e. valine at position 192 is changed to isoleucine); in CP protein, G969B (i.e. glycine at position 969 is changed to asparagine or aspartate); in ΤΓΜΡ3 protein, S156C (i.e. serine at position 156 is changed to cysteine), G166C (i.e. glycine at position 166 is changed to cysteine), G167C (i.e. glycine at position 167 is changed to cysteine), Y168C (i.e. tyrosine at position 168 is changed to cysteine), S170C (i.e. serine at position 170 is changed to cysteine), Y172C (i.e. tyrosine at position 172 is changed to cysteine) and S181C (i.e. serine at position 181 is changed to cysteine). Other associations of genetic variants in MD-associated genes and disease are known in the art.

[001271] CRISPR systems are useful to correct diseases resulting from autosomal dominant genes. For example, CRISPR/Cas9 was used to remove an autosomal dominant gene that causes receptor loss in the eye. Bakondi, B. et al., In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter~3 Rai Model of Autosomal Dominant Retinitis Pigmentosa. Molecular Therapy, 2015; DOI: 10.1038/mt.2015.220.

Treating Circulatory and Muscular Diseases [001272] The present invention also contemplates delivering the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to the heart. For the heart, a myocardium

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PCT/US2016/038181 tropic adena-associated virus (AAVM) is preferred, in particular ΑΑΛ/Μ41 which showed preferential gene transfer in the heart (see, e.g., Lin-Yanga et al., PNAS, March 10, 2009, vol. 106, no. 10). Administration may be systemic or local. A dosage of about 1-10 x 10¹⁴ vector genomes are contemplated for systemic administration. See also, e.g., Eulalio et al. (2012) Nature 492: 376 and Somasuntharam et al. (2013) Biomaterials 34: 7790.

[001273] For example, US Patent Publication No. 20110023139, describes use of zinc finger nucleases to genetically modify cells, animals and proteins associated with cardiovascular disease. Cardiovascular diseases generally include high blood pressure, heart attacks, heart failure, and stroke and ΊΊΑ. Any chromosomal sequence involved in cardiovascular disease or the protein encoded by any chromosomal sequence involved in cardiovascular disease may be utilized in the methods described in this disclosure. The cardiovascular-related proteins are typically selected based on an experimental association of the cardiovascular-related protein to the development of cardiovascular disease. For example, the production rate or circulating concentration of a cardiovascular-related protein may be elevated or depressed in a population having a cardiovascular disorder relative to a population lacking the cardiovascular disorder. Differences in protein levels may be assessed using proteomic techniques including but not limited to Western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, the cardiovascular-related proteins may be identified by obtaining gene expression profiles of the genes encoding the proteins using genomic techniques including hut not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR).

[001274] By way of example, the chromosomal sequence may comprise, but is not limited to, IL1B (interleukin 1, beta), XDH (xanthine dehydrogenase), TP53 (tumor protein p53), PTGIS (prostaglandin 12 (prostacyclin) synthase), MB (myoglobin), IL4 (interleukin 4), ANGPT1 (angiopoietin 1), ABCG8 (ATP-binding cassette, sub-family G (WHITE), member 8), CTSK (cathepsin K), PTGIR (prostaglandin 12 (prostacyclin) receptor (IP)), KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member II), INS (insulin), CRP (C-reactive protein, pentraxin-related), PDGFRB (platelet-derived growth factor receptor, beta polypeptide), CCNA2 (cyclin A2), PDGFB (platelet-derived growth factor beta polypeptide (simian sarcoma viral tvsis) oncogene homolog)), KCNJ5 (potassium inwardly-rectifying channel, subfamily J, member 5), KCNN3 (potassium intermediate/small conductance calcium-activated channel, subfamily N,

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PCT/US2016/038181 member 3), CAPN10 (calpain 10), PTGES (prostaglandin E synthase), ADRA2B (adrenergic, alpha-2B-, receptor), ABCG5 (ATP-binding cassette, sub-family G (WHITE), member 5), PRDX2 (peroxiredoxin 2), CAPN5 (calpain 5), PARP14 (poly (ADP-ribose) polymerase family, member 14), MEX3C (mex-3 homolog C (C, elegans)), ACE angiotensin I converting enzyme (peptidyl-dipeptidase A) 1), TNF (tumor necrosis factor (TNF superfamily, member 2)), IL6 (interleukin 6 (interferon, beta 2)), STN (statin), SERPINE1 (serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1), ALB (albumin), ADIPOQ (adiponectin, C1Q and collagen domain containing), APOB (apolipoprotein B (including Ag(x) antigen)), APOE (apolipoprotein E), LEP (leptin), MTHFR (5,10-methylenetetrahydrofolate reductase (NADPH)), APOA1 (apolipoprotein A-I), EDN1 (endothelin 1), NPPB (natriuretic peptide precursor B), NOS3 (nitric oxide synthase 3 (endothelial cell)), PPARG (peroxisome proliferator-activated receptor gamma), PLAT (plasminogen activator, tissue), PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)), CETP (cholesteryl ester transfer protein, plasma), AGTR1 (angiotensin II receptor, type 1), HMGCR (3-hydroxy-3-methylglutaryl-Coenzyme A reductase), IGF1 (insulin-like growth factor 1 (somatomedin C)), SELE (selectin E), REN (renin), PPARA (peroxisome proliferator-activated receptor alpha), PON1 (paraoxonase 1), KNG1 (kininogen 1), CCL2 (chemokine (C-C motif) ligand 2), LPL (lipoprotein lipase), VWF (von Willebrand factor), F2 (coagulation factor II (thrombin)), ICAMI (intercellular adhesion molecule 1), TGFB1 (transforming growth factor, beta 1), NPPA (natriuretic peptide precursor A), ILIO (interleukin 10), EPO (erythropoietin), SOD1 (superoxide dismutase 1, soluble), VCAM1 (vascular cell adhesion molecule 1), IFNG (interferon, gamma), LPA (lipoprotein, Lp(a)), MPO (myeloperoxidase), ESR1 (estrogen receptor 1), MAPK1 (mitogen-activated protein kinase 1), HP (haptoglobin), F3 (coagulation factor III (thromboplastin, tissue factor)), CST3 (cystatin C), COG2 (component of oligomeric golgi complex 2), MMP9 (matrix metallopeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV coliagenase)), SERPINC1 (serpin peptidase inhibitor, clade C (antithrombin), member 1), F8 (coagulation factor VIII, procoagulant component), HM0X1 (heme oxygenase (decycling) 1), APOC3 (apolipoprotein C-III), IL8 (interleukin 8), PROK1 (prokineticin I), CBS (cystathionine-beta-synthase), NOS2 (nitric oxide synthase 2, inducible), TLR4 (toll-like receptor 4), SELF (selectin P (granule membrane protein 140 kDa, antigen CD62)), ABCA1 (ATP-binding cassette, sub-family A (ABC 1), member 1), AGT (angiotensinogen (serpin

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PCT/US2016/038181 peptidase inhibitor, elade A, member 8)), LDLR (low density lipoprotein receptor), GPT (glutamic-pyruvate transaminase (alanine aminotransferase)), VEGFA (vascular endothelial growth factor A), NR3C2 (nuclear receptor subfamily 3, group C, member 2), IL 18 (interleukin 18 (interferon-gamma-inducing factor)), NOS I (nitric oxide synthase 1 (neuronal)), NR3CI (nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)), FGB (fibrinogen beta chain), HGF (hepatocyte growth factor (hepapoietin A; scatter factor)), ILIA (interleukin 1, alpha), RETN (resistin), AKT1 (v-akt murine thymoma viral oncogene homolog 1), LIPC (lipase, hepatic), HSPD1 (heat shock 60 kDa protein 1 (chaperon!η)), MAPK14 (mitogenactivated protein kinase 14), SPP1 (secreted phosphoprotein 1), ITGB3 (integrin, beta 3 (platelet glycoprotein 111a, antigen CD61)), CAT (catalase), UTS2 (urotensin 2), THBD (thrombomodulin), F10 (coagulation factor X), CP (ceruloplasmin (ferroxidase)), TNFRSF11B (tumor necrosis factor receptor superfamily, member 1 lb), EDNRA (endothelin receptor type A), EGFR (epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)), MMP2 (matrix metallopeptidase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa type IV collagenase)), PEG (plasminogen), NPY (neuropeptide Y), RHOD (ras homolog gene family, member D), MAPK8 (mitogen-activated protein kinase 8), MYC (v-myc myelocytomatosis viral oncogene homolog (avian)), FN1 (libronectin I), CMA1 (chymase 1, mast cell), PLAU (plasminogen activator, urokinase), GNB3 (guanine nucleotide binding protein (G protein), beta polypeptide 3), ADRB2 (adrenergic, beta-2-, receptor, surface), APOA5 (apolipoprotein A-V), SOD2 (superoxide dismutase 2, mitochondrial), F5 (coagulation factor V (proaccelerin, labile factor)), VDR (vitamin D (1,25-dihydroxyvitamin D3) receptor), ALOX5 (arachidonate 5-lipoxygenase), HLA-DRB1 (major histocompatibility complex, class II, DR beta 1), PARP1 (poly (ADP-ribose) polymerase 1), CD40LG (CD40 ligand), PON 2 (paraoxonase 2), ACER (advanced glycosylation end product-specific receptor), IRS1 (insulin receptor substrate 1), PTGS1 (prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)), ECE1 (endothelin converting enzyme 1), F7 (coagulation factor VII (serum prothrombin conversion accelerator)), URN (interleukin 1 receptor antagonist), EPHX2 (epoxide hydrolase 2, cytoplasmic), IGFBP1 (insulin-like growth factor binding protein 1), MAPKIO (mitogen-activated protein kinase 10), FAS (Fas (TNF receptor superfamily, member 6)), ABCB1 (ATP-binding cassette, sub-family B (MDR/TAP), member 1), JUN (jun oncogene), IGFBP3 (insulin-like growth factor binding protein 3), CD14 (CD14 molecule), PDE5A

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PCT/US2016/038181 (phosphodiesterase 5A, cGMP-specific), AGTR2 (angiotensin II receptor, type 2), CD40 (CD40 molecule, TNF receptor superfamily member 5), LCAT (lecithin-cholesterol acyltransferase), CCR5 (chemokine (C-C motif) receptor 5), MMP1 (matrix metallopeptidase 1 (interstitial collagenase)), TIMP1 (TIMP metallopeptidase inhibitor 1), ADM (adrenomedullin), DYT10 (dystonia 10), STATS (signal transducer and activator of transcription 3 (acute-phase response factor)), MMP3 (matrix metallopeptidase 3 (stromelysin 1, progelatinase)), ELN (elastin), USF1 (upstream transcription factor 1), CFH (complement factor H), HSPA4 (heat shock 70 kDa protein 4), MMP12 (matrix metallopeptidase 12 (macrophage elastase)), MME (membrane metallo-endopeptidase), F2R (coagulation factor II (thrombin) receptor), SELL (selectin L), CTSB (cathepsin Β), ANXA5 (annexin A5), ADRB1 (adrenergic, beta-Ι-, receptor), CYBA. (cytochrome b-245, alpha polypeptide), FGA (fibrinogen alpha chain), GGT1 (gammaglutamyltransferase I), LIPG (lipase, endothelial), HIF1A (hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)), CXCR4 (chemokine (C-X-C motif) receptor 4), PROC (protein C (inactivator of coagulation factors Va and Villa)), SCARE! (scavenger receptor class B, member 1), CD79A (CD79a molecule, immunoglobulin-associated alpha), PLTP (phospholipid transfer protein), ADD1 (adducin 1 (alpha)), FGG (fibrinogen gamma chain), SAA1 (serum amyloid Al), K.CNH2 (potassium voltage-gated channel, subfamily H (eag-related), member 2), DPP4 (dipeptidyl-peptidase 4), G6PD (glucose-6phosphate dehydrogenase), NPR1 (natriuretic peptide receptor A/guanylate cyclase A (atrionatriuretic peptide receptor A)), VTN (vitronectin), KIAA0101 (KIAA010I), FOS (FBJ murine osteosarcoma viral oncogene homolog), TLR2 (toll-like receptor 2), PPIG (peptidylprolyl isomerase G (cyclophilin Gj), IL1RI (interleukin 1 receptor, type I), AR (androgen receptor), CYP1A1 (cytochrome P450, family 1, subfamily A, polypeptide 1), SERPTNA1 (serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1), MTR (5methyltetrahydrofolate-homocysteine methyltransferase), RBP4 (retinol binding protein 4, plasma), APOA4 (apolipoprotein A-IV), CDKN2A (cyclin-dependent kinase inhibitor 2A (melanoma, pl6, inhibits CDK4)), FGF2 (fibroblast growth factor 2 (basic)), EDNRB (endothelin receptor type B), ITGA2 (integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)), CABIN 1 (calcineurin binding protein 1), SHBG (sex hormone-binding globulin), HMGB1 (high-mobility group box 1), HSP90B2P (heat shock protein 90 kDa beta (Grp94), member 2 (pseudogene)), CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4),

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PCT/US2016/038181

GJA1 (gap junction protein, alpha 1, 43 kDa), CAV1 (caveolin 1, caveolae protein, 22 kDa), ESR2 (estrogen receptor 2 (ER beta)), LTA (lymphotoxin alpha (TNF superfamily, member 1)), GDF15 (growth differentiation factor 15), BDNF (brain-derived neurotrophic factor), CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6), NGF (nerve growth factor (beta polypeptide)), SP1 (Spl transcription factor), TGIF1 (TGFB-induced factor homeobox 1), SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)), EGF (epidermal growth factor (beta-urogastrone)), PIK3CG (phosphoinositide-3-kinase, catalytic, gamma polypeptide), HLA-A (major histocompatibility complex, class I, A), KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1), CNR1 (cannabinoid receptor 1 (brain)), FBN1 (fibrillin 1), CHKA (choline kinase alpha), BEST1 (bestrophin 1), APP (amyloid beta (A4) precursor protein), CTNNB1 (catenin (cadherin-associated protein), beta 1, 88 kDa), IL2 (interleukin 2), CD36 (CD36 molecule (thrombospondin receptor)), PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalytic subunit), TPO (thyroid peroxidase), ALDH7A1 (aldehyde dehydrogenase 7 family, member Al), CX3CR1 (chemokine (C-X3-C motif) receptor 1), TH (tyrosine hydroxylase), F9 (coagulation factor IX), GH1 (growth hormone 1), TF (transferrin), HFE (hemochromatosis), IL17A (interleukin 17A), PTEN (phosphatase and tensin homolog), GSTM1 (glutathione S-transferase mu 1), DMD (dystrophin), GATA4 (GATA binding protein 4), F13A1 (coagulation factor XIII, Al polypeptide), TTR (transthyretin), FABP4 (fatty acid binding protein 4, adipocyte), PON3 (paraoxonase 3), APOC1 (apolipoprotein C-I), INSR (insulin receptor), TNFRSF1B (tumor necrosis factor receptor superfamily, member IB), HTR2A (5-hydroxytryptamine (serotonin) receptor 2A), CSF3 (colony stimulating factor 3 (granulocyte)), CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9), TXN (thioredoxin), CYP11B2 (cytochrome P450, family 11, subfamily B, polypeptide 2), PTH (parathyroid hormone), CSF2 (colony stimulating factor 2 (granulocyte-macrophage)), KDR (kinase insert domain receptor (a type III receptor tyrosine kinase)), PLA2G2A (phospholipase A2, group HA (platelets, synovial fluid)), B2M (beta-2-microglobulin), THBS1 (thrombospondin 1), GCG (glucagon), RHOA (ras homolog gene family, member A), ALDH2 (aldehyde dehydrogenase 2 family (mitochondrial)), TCF7L2 (transcription factor 7-like 2 (T-cell specific, HMG-box)), BDKRB2 (bradykinin receptor B2), NFE2L2 (nuclear factor (erythroid-derived 2)like 2), NOTCH! (Notch homolog I, translocation-associated (Drosophila)), UGT1A1 (UDP glucuronosyl transferase 1 family, polypeptide Al), IFNA1 (interferon, alpha 1), PPARD

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PCT/US2016/038181 (peroxisome proliferator-activated receptor delta), SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)), GNRH1 (gonadotropin-releasing hormone 1 (luteinizing-releasing hormone)), PAPPA (pregnancy-associated plasma protein A, pappalysin 1), ARR3 (arrestin 3, retinal (X-arrestin)), NPPC (natriuretic peptide precursor C), AHSP (alpha hemoglobin stabilizing protein), PTK2 (PTK2 protein tyrosine kinase 2), IL 13 (interleukin 13), MTOR (mechanistic target of rapamycin (serine/threonine kinase)), ITGB2 (integrin, beta 2 (complement component 3 receptor 3 and 4 subunit)), GSTT1 (glutathione S-transferase theta 1), IL6ST (interleukin 6 signal transducer (gpl30, oncostatin M receptor)), CPB2 (carboxypeptidase B2 (plasma)), CYP1A2 (cytochrome P450, family 1, subfamily A, polypeptide 2), HNF4A (hepatocyte nuclear factor 4, alpha), SLC6A4 (solute carrier family 6 (neurotransmitter transporter, serotonin), member 4), PLA2G6 (phospholipase A2, group VI (cytosolic, calciumindependent)), TNFSFll (tumor necrosis factor (ligand) superfamily, member 11), SLC8A1 (solute carrier family 8 (sodium/calcium exchanger), member 1), F2RL1 (coagulation factor II (thrombin) receptor-like 1), AKR1A1 (aldo-keto reductase family 1, member Al (aldehyde reductase)), ALDH9A1 (aldehyde dehydrogenase 9 family, member Al), BGLAP (bone gammacarboxyglutamate (gla) protein), MTTP (microsomal triglyceride transfer protein), MTRR (5methyltetrahydrofolate-homocysteine methyltransferase reductase), SULT1A3 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 3), RAGE (renal tumor antigen), C4B (complement component 4B (Chido blood group), P2RY12 (purinergic receptor P2Y, G-protein coupled, 12), RNLS (renalase, FAD-dependent amine oxidase), CREB1 (cAMP responsive element binding protein 1), POMC (proopiomelanocortin), RAC I (ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Racl)), LMNA (larnin NC), CD59 (CD59 molecule, complement regulatory protein), SCN5A (sodium channel, voltage-gated, type V, alpha subunit), CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), MIF (macrophage migration inhibitory factor (glycosylation-inhibiting factor)), MMP13 (matrix metallopeptidase 13 (collagenase 3)), TIMP2 (TIMP metallopeptidase inhibitor 2), CYP19A1 (cytochrome P450, family 19, subfamily A, polypeptide 1), CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2), PTPN22 (protein tyrosine phosphatase, non-receptor type 22 (lymphoid)), ΜΑΉ14 (myosin, heavy chain 14, non-muscle), MBL2 (mannose-binding lectin (protein C) 2, soluble (opsonic defect)), SELPLG (selectin P ligand), AOC3 (amine oxidase, copper containing 3 (vascular adhesion protein 1)), CTSL1 (cathepsin Li), PCNA (proliferating

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PCT/US2016/038181 cell nuclear antigen), IGF2 (insulin-like growth factor 2 (somatomedin A)), ITGB1 (integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK 12)), CAST (calpastatin), CXCL12 (chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor I)), IGHE (immunoglobulin heavy constant epsilon), KCNE1 (potassium voltage-gated channel, Iskrelated family, member I), TFRC (transferrin receptor (p90, CD71)), COL1A1 (collagen, type I, alpha 1), COL1A2 (collagen, type I, alpha 2), IL2RB (interleukin 2 receptor, beta), PLA2G10 (phospholipase A2, group X), ANGPT2 (angiopoietin 2), PROCR (protein C receptor, endothelial (EPCR)), NOX4 (NADPH oxidase 4), HAMP (hepcidin antimicrobial peptide), PTPN11 (protein tyrosine phosphatase, non-receptor type 11), SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1), IL2RA (interleukin 2 receptor, alpha), CCL5 (chemokine (C-C motif) ligand 5), IRF1 (interferon regulatory factor I), CFLAR (CASP8 and FADD-like apoptosis regulator), CALCA (calcitonin-related polypeptide alpha), EIF4E (eukaryotic translation initiation factor 4E), GSTP1 (glutathione S-transferase pi 1), JAK2 (Janus kinase 2), CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5), HSPG2 (heparan sulfate proteoglycan 2), CCL3 (chemokine (C-C motif) ligand 3), MYD88 (myeloid differentiation primary response gene (88)), VIP (vasoactive intestinal peptide), SOAT1 (sterol O-acy!transferase 1), ADRBK1 (adrenergic, beta, receptor kinase 1), NR4A2 (nuclear receptor subfamily 4, group A, member 2), MMP8 (matrix metallopeptidase 8 (neutrophil collagenase)), NPR2 (natriuretic peptide receptor B/guanylate cyclase B (atrionatriuretic peptide receptor B)), GCH1 (GTP cyclohydrolase 1), EPRS (glutamyl-prolyl-tRNA synthetase), PPARGC1A (peroxisome proliferator-activated receptor gamma, coactivator I alpha), F12 (coagulation factor ΧΠ (Hageman factor)), PECAM1 (platelet/endothelial cell adhesion molecule), CCL4 (chemokine (C-C motif) ligand 4), SERPINA3 (serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3), CASR (calcium-sensing receptor), GJA5 (gap junction protein, alpha 5, 40 kDa), FABP2 (fatty acid binding protein 2, intestinal), TTF2 (transcription termination factor, RNA polymerase II), PROS! (protein S (alpha)), CTF1 (cardiotrophin 1), SGCB (sarcoglycan, beta (43 kDa dystrophin-associated glycoprotein)), YME1LI (YMEl-like 1 (S. cerevisiae)), CAMP (cathelicidin antimicrobial peptide), ZC3HI2A (zinc finger CCCH-type containing 12A), AKR1B1 (aldo-keto reductase family I, member BI (aldose reductase)), DES (desmin), MMP7 (matrix metallopeptidase 7 (matrilysin, uterine)), AHR (aryl hydrocarbon receptor), CSF1 (colony stimulating factor 1 (macrophage)), HDAC9 (histone deacetylase 9),

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PCT/US2016/038181

CTGF (connective tissue growth factor), KCNMAI (potassium large conductance calciumactivated channel, subfamily M, alpha member 1), UGT1A (UDP glucuronosyltransferase 1 family, polypeptide A complex locus), PRKCA (protein kinase C, alpha), COMT (catechol.beta.-methyltransferase), SIOOB (S100 calcium binding protein B), EGR1 (early growth response 1), PRL (prolactin), IL 15 (interleukin 15), DRD4 (dopamine receptor D4), CAMK2G (calcium/calmodulin-dependent protein kinase II gamma), SLC22A2 (solute carrier family 22 (organic cation transporter), member 2), CCL11 (chemokine (C-C motif) ligand 11), PGF (B321 placental growth factor), THPO (thrombopoietin), GP6 (glycoprotein VI (platelet)), TACR1 (tachykinin receptor 1), NTS (neurotensin), HNF1A (HNF1 homeobox A), SST (somatostatin), KCND1 (potassium voltage-gated channel, Shal-related subfamily, member 1), LOC646627 (phospholipase inhibitor), TBXAS1 (thromboxane A synthase 1 (platelet)), CYP2J2 (cytochrome P450, family 2, subfamily J, polypeptide 2), TBXA2R (thromboxane A2 receptor), ADH1C (alcohol dehydrogenase 1C (class I), gamma polypeptide), ALOX12 (arachidonate 12lipoxygenase), AHSG (alpha-2-HS-glycoprotein), BHMT (betaine-homocysteine methyltransferase), GJA4 (gap junction protein, alpha 4, 37 kDa), SLC25A4 (solute carrier family 25 (mitochondrial carrier; adenine nucleotide transloeator), member 4), ACLY (ATP citrate lyase), ALOX5AP (arachidonate 5-lipoxygenase-activating protein), NUMA1 (nuclear mitotic apparatus protein 1), CYP27B1 (cytochrome P450, family 27, subfamily B, polypeptide 1), CYSLTR2 (cysteinyl leukotriene receptor 2), SOD3 (superoxide dismutase 3, extracellular), LTC4S (leukotriene C4 synthase), UCN (urocortin), GHRL (ghrelin/obestatin prepropeptide), APOC2 (apolipoprotein C-II), CLEC4A (C-type lectin domain family 4, member A), KBTBD10 (kelch repeat and BTB (POZ) domain containing 10), TNC (tenascin C), TYMS (thymidylate synthetase), SHCI (SHC (Src homology 2 domain containing) transforming protein 1), LRP1 (low density lipoprotein receptor-related protein 1), SOCS3 (suppressor of cytokine signaling 3), ADH1B (alcohol dehydrogenase IB (class I), beta polypeptide), KLK3 (kallikrein-related peptidase 3), HSD11B1 (hydroxysteroid (11-beta) dehydrogenase 1), VKORC1 (vitamin K epoxide reductase complex, subunit 1), SERPINB2 (serpin peptidase inhibitor, clade B (ovalbumin), member 2), TNS1 (tensin 1), RNF19A (ring finger protein 19A), EPOR (erythropoietin receptor), ITGAM (integrin, alpha M (complement component 3 receptor 3 subunit)), PITX2 (paired-like homeodomain 2), MAPK7 (mitogen-activated protein kinase 7), FCGR3A (Fc fragment of IgG, low affinity l i la, receptor (CD 16a)), LEPR (leptin receptor),

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PCT/US2016/038181

ENG (endoglin), GPX1 (glutathione peroxidase 1), GOT2 (glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)), HRH1 (histamine receptor Hl), NR112 (nuclear receptor subfamily 1, group I, member 2), CRH (corticotropin releasing hormone), HTR1A (5hydroxytryptamine (serotonin) receptor 1A), VDAC1 (voltage-dependent anion channel 1), HPSE (heparanase), SFTPD (surfactant protein D), TAP2 (transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)), RNF123 (ring finger protein 123), PTK2B (PTK2B protein tyrosine kinase 2 beta), NTRK2 (neurotrophic tyrosine kinase, receptor, type 2), IL6R (interleukin 6 receptor), ACHE (acetylcholinesterase (Yt blood group)), GLP1R (glucagon-like peptide 1 receptor), GHR (growth hormone receptor), GSR (glutathione reductase), NQO1 (NAD(P)H dehydrogenase, quinone 1), NR5A1 (nuclear receptor subfamily 5, group A, member 1), GJB2 (gap junction protein, beta 2, 26 kDa), SLC9A1 (solute carrier family 9 (sodium/hydrogen exchanger), member 1), MAO A (monoamine oxidase A), PCSK9 (proprotein convertase subtilisin/kexin type 9), FCGR2A (Fc fragment of IgG, low affinity Ila, receptor (CD32)), SERPINF1 (serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1), EDN3 (endothelin 3), DHFR (dihydrofolate reductase), GAS6 (growth arrest-specific 6), SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal), UCP2 (uncoupling protein 2 (mitochondrial, proton carrier)), TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)), C4BPA (complement component 4 binding protein, alpha), SERPINF2 (serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 2), TYMP (thymidine phosphorylase), ALPP (alkaline phosphatase, placental (Regan isozyme)), CXCR2 (chemokine (C-X-C motif) receptor 2), SLC39A3 (solute carrier family 39 (zinc transporter), member 3), ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2), ADA (adenosine deaminase), JAK3 (Janus kinase 3), HSPA1A (heat shock 70 kDa protein 1A), FASN (fatty acid synthase), FGF1 (fibroblast growth factor 1 (acidic)), Fll (coagulation factor XT), ATP7A (ATPase, Cu++ transporting, alpha polypeptide), CR1 (complement component (3b/4b) receptor 1 (Knops blood group)), GFAP (glial fibrillary acidic protein), ROCK1 (Rho-associated, coiled-coil containing protein kinase 1), MECP2 (methyl CpG binding protein 2 (Rett syndrome)), MYLK (myosin light chain kinase), BCHE (butyryl cholinesterase), LIFE (lipase, hormone-sensitive), PRDX5 (peroxiredoxin 5), AD0RA1 (adenosine Al receptor), WRN (Werner syndrome, RecQ helicaselike), CXCR3 (chemokine (C-X-C motif) receptor 3), CD81 (CD81 molecule), SMAD7 (SMAD

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PCT/US2016/038181 family member 7), LAMC2 (laminin, gamma 2), MAP3K5 (mitogen-activated protein kinase kinase kinase 5), CHGA (chromogranin A (parathyroid secretory protein 1)), IAPP (islet amyloid polypeptide), RHO (rhodopsin), ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1), PTHLH (parathyroid hormone-like hormone), NRG1 (neuregulin 1), VEGFC (vascular endothelial growth factor C), ENPEP (glutamyl aminopeptidase (aminopeptidase A)), CEBPB (CCAAT/enhancer binding protein (C/EBP), beta), NAGLU (N-acetylglucosaminidase, alpha-), F2RL3 (coagulation factor II (thrombin) receptor-like 3), CX3CL1 (chemokine (C-X3-C motif) ligand 1), BDKRB1 (bradykinin receptor BI), ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13), ELANE (elastase, neutrophil expressed), ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2), CISH (cytokine inducible SH2containing protein), CAST (gastrin), MYOC (myociiin, trabecular meshwork inducible glucocorticoid response), ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide), NF1 (neuroftbromin 1), GJB1 (gap junction protein, beta 1, 32 kDa), MEF2A (myocyte enhancer factor 2A), VCL (vinculin), BMPR2 (bone morphogenetic protein receptor, type II (serine/threonine kinase)), TUBE (tubulin, beta), CDC42 (cell division cycle 42 (GTP binding protein, 25 kDa)), KRT18 (keratin 18), HSF1 (heat shock transcription factor 1), MYB (v-myb myeloblastosis viral oncogene homolog (avian)), PRKAA2 (protein kinase, AMP-activated, alpha 2 catalytic subunit), ROCK2 (Rho-associated, coiled-coil containing protein kinase 2), TFPI (tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor)), PRKG1 (protein kinase, cGMP-dependent, type I), BMP2 (bone morphogenetic protein 2), CTNND1 (catenin (cadherin-associated protein), delta 1), CTH (cystathionase (cystathionine gammalyase)), CTSS (cathepsin S), VAV2 (vav 2 guanine nucleotide exchange factor), NPY2R (neuropeptide Y receptor Y2), IGFBP2 (insulin-like growth factor binding protein 2, 36 kDa), CD28 (CD28 molecule), GSTA1 (glutathione S-transferase alpha 1), PPIA (peptidylprolyl isomerase A (cyciophilin A)), APOH (apolipoprotein H (beta-2-glycoprotein 1)). S100A8 (S100 calcium binding protein A8), IL11 (interleukin 11), ALOX15 (arachidonate 15-lipoxygenase), FBLN1 (fibulin 1), NR1H3 (nuclear receptor subfamily 1, group H, member 3), SCD (stearoyl CoA desaturase (delta-9-desaturase)), GIP (gastric inhibitory polypeptide), CHGB (chromogranin B (secretogranin 1)), PRKCB (protein kinase C, beta), SRD5A1 (steroid-5-alphareductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha I)), HSD11B2 (hydroxysteroid (11-beta) dehydrogenase 2), CALCRL (calcitonin receptor-like),

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GALNT2 (LJDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalaetosaminyltransferase 2 (GalNAc-T2)), ANGPTL4 (angiopoietin-like 4), KCNN4 (potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4), PIK3C2A (phosphoinositide3-kinase, class 2, alpha polypeptide), HBEGF (heparin-binding EGF-like growth factor), CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide I), E1LA-DRB5 (major histocompatibility complex, class II, DR beta 5), BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3), GCKR (glucokinase (hexokinase 4) regulator), S100A12 (SI00 calcium binding protein A12), PADI4 (peptidyl arginine deiminase, type IV), HSPA14 (heat shock 70 kDa protein 14), CXCR1 (chemokine (C-X-C motif) receptor 1), H19 (Hl 9, imprinted maternally expressed transcript (non-protein coding)), KREAP 19-3 (keratin associated protein 19-3), IDDM2 (insulin-dependent diabetes mellitus 2), RAC2 (ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)), RYR1 (ryanodine receptor 1 (skeletal)), CLOCK (clock homolog (mouse)), NGFR (nerve growth factor receptor (TNFR superfamily, member 16)), DBH (dopamine beta-hydroxylase (dopamine beta-monooxygenase)), CHRNA4 (cholinergic receptor, nicotinic, alpha 4), CACNA1C (calcium channel, voltagedependent, L type, alpha 1C subunit), PRKAG2 (protein kinase, AMP-activated, gamma 2 noncatalytic subunit), CHAT (choline acetyltransferase), PTGDS (prostaglandin D2 synthase 21 kDa (brain)), NR1H2 (nuclear receptor subfamily 1, group H, member 2), TEK (TEK tyrosine kinase, endothelial), VEGFB (vascular endothelial growth factor B), MEF2C (myocyte enhancer factor 2C), MAPKAPK2 (mitogen-activated protein kinase-activated protein kinase 2), TNFRSFI1A (tumor necrosis factor receptor superfamily, member Ila, NFKB activator), HSPA9 (heat shock 70 kDa protein 9 (mortalin)), CYSLTR1 (cysteinyl leukotriene receptor 1), ΜΑΤΙΑ (methionine adenosyltransferase I, alpha), OPRL1 (opiate receptor-like 1), IMPA1 (inositol(myo)-l(or 4)monophosphatase I), CLCN2 (chloride channel 2), DLD (dihydrolipoamide dehydrogenase), PSMA6 (proteasome (prosome, macropain) subunit, alpha type, 6), PSMB8 (proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7)), CHI3L1 (chitinase 3-like 1 (cartilage glycoprotein-39)), ALDH1B1 (aldehyde dehydrogenase 1 family, member BI), PARP2 (poly (ADP-ribose) polymerase 2), STAR (steroidogenic acute regulatory protein), EBP (lipopolysaccharide binding protein), ABCC6 (ATP-binding cassette, sub-family C(CFTR/MRP), member 6), RGS2 (regulator of G-protein signaling 2, 24 kDa), EFNB2 (ephrinB2), GJB6 (gap junction protein, beta 6, 30 kDa), APOA2 (apolipoprotein A-II), AMPD1

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PCT/US2016/038181 (adenosine monophosphate deaminase 1), DYSF (dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive)), FDFT1 (famesyl-diphosphate famesyltransferase 1), EDN2 (endothelin 2), CCR6 (chemokine (C-C motif) receptor 6), GJB3 (gap junction protein, beta 3, 31 kDa), IL1RL1 (interleukin 1 receptor-like 1), ENTPD1 (ectonucleoside triphosphate diphosphohydrolase 1), BBS4 (Bardet-Biedl syndrome 4), CELSR2 (cadherin, EGF LAG sevenpass G-type receptor 2 (flamingo homolog, Drosophila)), FUR (FI 1 receptor), RAPGEF3 (Rap guanine nucleotide exchange factor (GEF) 3), HYAL1 (hyaluronoglucosaminidase 1), ZNF259 (zinc finger protein 259), ΑΤΟΧΙ (ATX1 antioxidant protein 1 homolog (yeast)), ATF6 (activating transcription factor 6), KHK (ketohex okinase (fructokinase)), SAIT (spermidine/spermine NI-acetyltransferase 1), GGH (gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)), TIMP4 (TEMP metallopeptidase inhibitor 4), SLC4A4 (solute carrier family 4, sodium bicarbonate cotransporter, member 4), PDE2A (phosphodiesterase 2A, cGMP-stimulated), PDE3B (phosphodiesterase 3B, cGMP-inhibited), FADS1 (fatty acid desaturase 1), FADS2 (fatty acid desaturase 2), TMSB4X (thymosin beta 4, X-linked), TXNIP (thioredoxin interacting protein), LIMS1 (LIM and senescent cell antigen-like domains 1), RHOB (ras homolog gene family, member B), LY96 (lymphocyte antigen 96), FOXO1 (forkhead box 01), PNPLA2 (patatin-like phospholipase domain containing 2), TRH (thyrotropin-releasing hormone), GJC1 (gap junction protein, gamma 1, 45 kDa), SLC17A5 (solute carrier family 17 (anion/sugar transporter), member 5), FTO (fat mass and obesity associated), GJD2 (gap junction protein, delta 2, 36 kDa), PSRC1 (proline/serine-rich coiled-coil I), CASP12 (caspase 12 (gene/pseudogene)), GPBAR1 (G protein-coupled bile acid receptor I), PXK (PX domain containing serine/threonine kinase), IL33 (interleukin 33), TRIB1 (tribbles homolog 1 (Drosophila)), PBX4 (pre-B-cell leukemia homeobox 4), NUPR1 (nuclear protein, transcriptional regulator, 1), 15-Sep(15 kDa selenoprotein), CILP2 (cartilage intermediate layer protein 2), TERC (telomerase RNA component), GGT2 (gamma-glutamyltransferase 2), MTCO1 (mitochondrially encoded cytochrome c oxidase I), and UOX (urate oxidase, pseudogene). Any of these sequences, may be a target for the CRISPR-Cas system, e.g., to address mutation. [001275] In an additional embodiment, the chromosomal sequence may further be selected from Ponl (paraoxonase 1), LDLR (LDL receptor), ApoE (Apolipoprotein E), Apo B-100 (Apolipoprotein B-100), ApoA (Apolipoprotein(a)), ApoAl (Apolipoprotein Al), CBS (Cystathione B-synthase), Glycoprotein Ilb/IIb, MTHRF (5,10-methylenetetrahydrofolate

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PCT/US2016/038181 reductase (NADPH), and combinations thereof In one iteration, the chromosomal sequences and proteins encoded by chromosomal sequences involved in cardiovascular disease may be chosen from CacnalC, Sodl, Pten, Ppar(alpha), Apo E, Leptin, and combinations thereof as target(s) for the CRISPR-Cas system.

Treating Diseases of the Liver and Kidney [001276] The present invention also contemplates delivering the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to the liver and/or kidney. Delivery strategies to induce cellular uptake of the therapeutic nucleic acid include physical force or vector systems such as viral-, lipid- or complex- based delivery, or nanocarriers. From the initial applications with less possible clinical relevance, when nucleic acids were addressed to renal cells with hydrodynamic high pressure injection systemically, a wide range of gene therapeutic viral and non-viral carriers have been applied already to target posttranscriptional events in different animal kidney disease models in vivo (Csaba Revesz and Peter Hamar (2011). Delivery Methods to Target RNAs in the Kidney, Gene Therapy Applications, Prof. Chunsheng Kang (Ed.), ISBN: 978-953-307-541-9, InTech, Available from:

http:/7www.intechopen.cotn/books/gene-therapy-appiications/deliveiy-methods-to-target-masinthe-kidney). Delivery methods to the kidney may include those in Yuan et al. (Am J Physiol Renal Physiol 295: F605-F617, 2008) investigated whether in vivo deliver}⁷ of small interfering RNAs (siRNAs) targeting the 12/15-lipoxygenase (12/15-LO) pathway of arachidonate acid metabolism can ameliorate renal injury and diabetic nephropathy (DN) in a streptozotocininjected mouse model of type I diabetes. To achieve greater in vivo access and siRNA expression in the kidney, Yuan et al. used double-stranded 12/15-LO siRNA oligonucleotides conjugated with cholesterol. About 400 pg of siRNA was injected subcutaneously into mice. The method of Yuang et al. may be applied to the CRISPR Cas system of the present invention contemplating a 1-2 g subcutaneous injection of CRISPR Cas conjugated with cholesterol to a human for delivery to the kidneys.

[001277] Molitoris et al. (J Am Soc Nephrol 20: 1754-1764, 2009) exploited proximal tubule cells (PTCs), as the site of oligonucleotide reabsorption within the kidney to test the efficacy of siRNA targeted to p53, a pivotal protein in the apoptotic pathway, to prevent kidney injury. Naked synthetic siRNA to p53 injected intravenously 4 h after ischemic injury maximally protected both PTCs and kidney function. Molitoris et al.’s data indicates that rapid delivery of

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PCT/US2016/038181 siRNA to proximal tubule cells follows intravenous administration. For dose-response analysis, rats were injected with doses of siP53, 0.33; 1, 3, or 5mg/kg, given at the same four time points, resulting in cumulative doses of 1.32; 4, 12, and 20 mg/kg, respectively. All siRNA doses tested produced a SCr reducing effect on day one with higher doses being effective over approximately five days compared with PBS-treated ischemic control rats. The 12 and 20 mg/kg cumulative doses provided the best protective effect. The method of Molitoris et al. may be applied to the nucleic acid-targeting system of the present invention contemplating 12 and 20 mg/kg cumulative doses to a human for delivery to the kidneys.

[001278] Thompson et al. (Nucleic Acid Therapeutics, Volume 22, Number 4, 2012) reports the toxicological and pharmacokinetic properties of the synthetic, small interfering RNA I5NP following intravenous administration in rodents and nonhuman primates, I5NP is designed to act via the RNA interference (RNAi) pathway to temporarily inhibit expression of the pro-apoptotic protein p53 and is being developed to protect cells from acute ischemia/reperfusion injuries such as acute kidney injury that can occur during major cardiac surgery and delayed graft function that can occur following renal transplantation. Doses of 800mg/kg I5NP in rodents, and 1,000 mg/kg I5NP in nonhuman primates, were required to elicit adverse effects, which in the monkey were isolated to direct effects on the blood that included a sub-clinical activation of complement and slightly increased clotting times. In the rat, no additional adverse effects were observed with a rat analogue of I5NP, indicating that the effects likely represent class effects of synthetic RNA duplexes rather than toxicity related to the intended pharmacologic activity of I5NP. Taken together, these data support clinical testing of intravenous administration of I5NP for the preservation of renal function following acute ischemia/reperfusion injury'. The no observed adverse effect level (NOAEL) in the monkey was 500 mg/kg. No effects on cardiovascular, respiratory, and neurologic parameters were observed in monkeys following i.v. administration at dose levels up to 25 mg/kg. Therefore, a similar dosage may be contemplated for intravenous administration of CRISPR Cas to the kidneys of a human.

[001279] Shimizu et al, (J Am Soc Nephrol 21: 622-633, 2010) developed a system to target delivery of siRNAs to glomeruli via poly(ethylene glycol)-poly(L-lysine)-based vehicles. The siRNA/nanocarrier complex was approximately 10 to 20 nm in diameter, a size that would allow it to move across the fenestrated endothelium to access to the mesangium. After intraperitoneal injection of fluorescence-labeled siRNA/nanocarrier complexes, Shimizu et al. detected siRNAs

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PCT/US2016/038181 in the blood circulation for a prolonged time. Repeated intraperitoneal administration of a mitogen-activated protein kinase 1 (MAPK1) siRNA/nanocarrier complex suppressed glomerular MAPK1 mRNA and protein expression in a mouse model of glomerulonephritis. For the investigation of siRNA accumulation, Cy5-labeled siRNAs compiexed with PIC nanocarriers (0.5 ml, 5 nmol of siRNA content), naked Cy5-labeled siRNAs (0.5 ml, 5 nmol), or Cy5-labeled siRN As encapsulated in HVJ-E (0.5 ml, 5 nmol of siRNA content) were administrated to BALBc mice. The method of Shimizu et al. may he applied to the nucleic acid-targeting system of the present invention contemplating a dose of about of 10-20 pmol CRISPR Cas compiexed with nanocarriers in about 1-2 liters to a human for intraperitoneal administration and delivery to the kidneys.

[001280] Delivery' methods to the kidney' are summarized as follows:

Delivery method	Carrier	Target RNA	Disease	Model	Functional assays	Author
Hydrodyna mic / Lipid	TransIT In Vivo Gene Delivery System, DOTAP	p85a	Acute renal injury	Ischemia- reperfusion	Uptake, biodistribution	Larson et al., Surgery, (Aug 2007), Vol. 142, No. 2, pp, (262-269)
Hydrodyna mic / Lipid	Lipofectamine 2000	Fas	Acute renal injury	Isehemia- reperfusion	Blood urea nitrogen, Fas Immunohistoch emistryy apoptosis, histological scoring	Hamar et al., Proc Natl Acad Sci, (Oct 2004), Vol. 101, No. 41, pp.(1488314888)
Hydrodyna mic	n.a.	Apoptosis cascade elements	Acute renal injury	Ischemia- reperfusion	n.a.	Zheng et al., Am J Pathol, (Oct 2008), Vol. 173, No. 4, pp.(973-980)
Hydrodyna mic	n.a.	Nuclear factor kappa-b (NFkB)	Acute renal injury'	Ischemia- reperfusion	n.a.	Feng et al., Transplantation, (May 2009), Vol. 8 /, No. 9, pp.(1283— 1289)
Hydrodyna mic / Viral	Lipofectamine 2000	Apoptosis antagonizin g transcription factor (AATF)	Acute renal injury	Ischemia- reperfusion	Apoptosis, oxidative stress, caspase activation, membrane lipid peroxidation	Xie & Guo, Am Soc Nephrol, (Dec 2006), Vol. 17, No. 12, pp.(3336' 3346)

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Delivery method	Carrier	Target RNA	Disease	Model	Functional assays	Author
Hydrodyna mic	pBAsi mU6 Neo/ TransITEE Hydrodynamic Delivery System	Gremlin	Diabetic nephropath y	Streptozoto zin - induced diabetes	Proteinuria, serum, creatinine, glomerular and tubular diameter, collagen type IV/BMP7 expression	Q. Zhang et al., PloS ONE, (Jul 2010), Vol. 5, No. 7, el 1709, PP- (1-13)
Viral/Lipid	pSUPER vector/Lipofect amine	TGF-β type II receptor	Interstitial renal fibrosis	Unilateral urethral obstruction	a-SMA expression, collagen content.	Kushibikia et al., J Controlled Release, (Jul 2005), Vol. 105, No. 3, pp. (318-331)
Viral	Adeno- associated virus-2	Mineral corticoid receptor	Hyper- tension caused renal damage	Cold- induced hypertensi on	blood pressure, serum albumin, serum urea nitrogen, serum. creatinine, kidney weight, urinary sodium	Wang et al.. Gene Therapy, (Jul 2006), Vol. 13, No. 14, pp. (1097-1103)
Hydrodyna mic· /Viral	pU6 vector	Luciferase	n.a.	n.a.	uptake	Kobayashi et al., Journal of Pharmacology and Experimental Therapeutics, (Feb 2004), Vol. 308, No. 2, pp.(688-693)
Lipid	Lipoproteins, albumin	apoBl, apoM	n.a.	n.a.	Uptake, binding affinity to lipoproteins and albumin	Wolfram et al., Nature Biotechnology, (Sep 2007), Vol. 25, No. 10, pp. (1149-1.157)
Lipid	Lipofectamine2 000	p53	Acute renal injury	Ischemic and cisplatin- induced acute injury	Histological scoring, apoptosis	Molitoris et al., J Am Soc Nephrol, (Aug 2009), Vol, 20, No. 8, pp.(1754-1764)
Lipid	DOTAP/DOPE, DOTAP/DO PE/DOPE- PEG2000	COX-2	Breast adeno- carcinoma	MDA-MB- 231 breast cancer xenograft-	Cell viability, uptake	Mikhaylova et al., Cancer Gene Therapy, (Mar 2011), Vol. 16,

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Delivery method	Carrier	Target RNA	Disease	Model	Functional assays	Author
				bearing mouse		No. 3, pp. (217226)
Lipid	Cholesterol	12/15- lipoxygenas e	Diabetic nephro- pathy	Streptozoto cin induced diabetes	Albuminuria, urinary creatinine, histology, type I and I V collagen, TGF- β, fibronectin, plasminogen activator inhibitor 1	Yuan et al., Am J Physiol Renal Physiol, (Jun 2008), Vol. 295,pp. (F605F617)
Lipid	Lipofectamine 2000	Mitochondri al membrane 44 (TIM44)	Diabetic nephro- pathy	Streptozoto cin induced diabetes	Cell proliferation and apoptosis, histology, ROS,' mitochondrial import of MnSOD and glutathione peroxidase, cellular membrane polarization	Y. Zhang et al., J Am Soc Nephrol, (Apr 2006), Vol. 17, No. 4, pp. (1090-1101)
Hydrodyna mic / Lipid	Proteolipo- some	RLIP76	Renal carcinoma	Caki-2 kidney cancer xenograft- bearing mouse	uptake	Singhal et al., Cancer Res, (May 2009), Vol. 69, No. 10, pp.(4244-4251)
Polymer	PEGylated PEI	Luciferase pGL3	n.a.	n.a.	Uptake, biodistribution, erythrocyte aggregation	Malek et al., Toxicology and Applied Pharmacology, (Apr 2009), Vol. 236, No. 1, pp.(97-108)
Polymer	PEGylated poly-L-lysine	MAPK1	Lupus glomerulo- nephritis	Glomerulo - nephritis	Proteinuria, glomeruloscler osis, TGF- β, fibronectin, plasminogen activator inhibitor 1	Shimizu et al., J Am Soc Nephrology, (Apr 2010), Vol. 2.1, No. 4, pp.(622-633)
Polymer/Na no particle	Hyaluronic acid/ Quantum	VEGF	Kidney cancer/	B16F1 melanoma	Biodistribution , citotoxicity,	Jiang et al,, Molecular

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Delivery method	Carrier	Target RNA	Disease	Model	Functional assays	Author
	dot/ PEI		melanoma	tumor- bearing mouse	tumor volume, endocytosis	Pharmaceutics, (Mav-Jun 2009), Vol. 6, No. 3, pp. (727737)
Polymer/Na no particle	PEGylated polycapro- iactone nanofiber	GAPDH	n.a.	n.a.	cell viability, uptake	Cao et al, J Controlled Release, (Jun 2010), Vol. 144, No. 2, pp. (203-212)
Aptamer	Spiegelmer mNOX-E36	CC chemokine ligand 2	Glomerulo sclerosis	Uninephre cto- mized mouse	urinary' albumin, urinary' creatinine, histopathology, glomerular filtration rate, macrophage count, serum Cel2, Mac- 2+, Ki-67+	Ninichuk et al., Am J Pathol, (Mar 2008), Vol. 172, No. 3, pp.(628-637)
Aptamer	Aptamer NQXF37	vasopressin (AVP)	Congestive heart failure	n.a.	Binding affinity to DAVP, Inhibition of AVP Signaling, Urine osmolality and sodium concentration,	Purschke et al., Proc Natl Acad Sci, (Mar 2006), Vol. 103, No. 13, pp. (5173-5178)

[001281] Targeting liver cells is provided. This may he in vitro or in vivo. Hepatocytes are preferred. Delivery of the CRISPR protein, such as Cpfl herein may be via viral vectors, especially AAV (and in particular AAV2/6) vectors. These may be administered by intravenous injection.

[001282] A preferred target for liver, whether in vitro or in vivo, is the albumin gene. This is a so-called ‘safe harbor” as albumin is expressed at very high levels and so some reduction in the production of albumin following successful gene editing is tolerated. It is also preferred as the high levels of expression seen from the albumin promoter/enhancer allows for useful levels of

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PCT/US2016/038181 correct or transgene production (from the inserted donor template) to be achieved even if only a small fraction of hepatocytes are edited.

[001283] Intron 1 of albumin has been shown by Wechsler et al. (reported at the 57th Annual Meeting and Exposition of the American Society of Hematology - abstract available online at https://ash.confex.com/ash/2015/webprogram/Paper86495.htmi and presented on 6th December 2015) to be a suitable target site. Their work used Zn Fingers to cut the DNA at this target site, and suitable guide sequences can be generated to guide cleavage at the same site by a CRISPR protein.

The use of targets within highly-expressed genes (genes with highly active enhancers/promoters) such as albumin may also allow a promoterless donor template to be used, as reported by Wechsler et al, and this is also broadly applicable outside liver targeting. Other examples of highly-expressed genes are known.

Other disease of the liver [001284] In particular embodiments, the CRISPR proteins of the present invention are used in the treatment of liver disorders such as transthyretin amyloidosis (ATTR), alpha-1 antitrypsin deficiency and other hepatic-based inborn errors of metabolism. FAP is caused by a mutation in the gene that encodes transthyretin (TTR). While it ia an autosomal dominant disease, not al carriers develop the disease. There are over 100 mutations in the TTR gene known to be associated with the disease. Examples of common mutations include V30M. The principle of treatment of TTR based on gene silencing has been demonstrated by studies with iRNA (Ueda et al. 2014 Transl Neurogener. 3:19). Wilson’s Disease (WD) is caused by mutations in the gene encoding ATP7B, which is found exclusively in the hepatocyte. There are over 500 mutations associated with WD, with increased prevalence in specific regions such as East .Asia. Other examples are A1ATD (an autosomal recessive disease caused by mutations in the SERPINA1 gene) and PKU (an autosomal recessive disease caused by mutations in the phenylalanine hydroxylase (PAH) gene).

Liver-Associated Blood Disorders, especially Hemophilia and in particular Hemophilia B [001285] Successful gene editing of hepatocytes has been achieved in mice (both in vitro and in vivo) and in non-human primates (in vivo), showing that treatment of blood disorders through gene editing/genome engineering in hepatocytes is feasible. In particular, expression of the

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PCT/US2016/038181 human F9 (hF9) gene in hepatocytes has been shown in non-human primates indicating a treatment for Hemophilha B in humans.

[001286] Wechsler et al. reported at the 57th Annual Meeting and Exposition of the American Society of Hematology (abstract presented 6th December 2015 and available online at https://ash.confex.com/ash/2015/webprograni/Paper86495.htnil) that they has successfully expressed human F9 (hF9) from hepatocytes in non-human primates through in vivo gene editing. This was achieved using 1) two zinc finger nucleases (ZFNs) targeting intron 1 of the albumin locus, and 2) a human F9 donor template construct. The ZFNs and donor template were encoded on separate hepatotropic adeno-associated virus serotype 2/6 (AAV2/6) vectors injected intravenously, resulting in targeted insertion of a corrected copy of the hF9 gene into the albumin locus in a proportion of liver hepatocytes, [001287] The albumin locus was selected as a “safe harbor” as production of this most abundant plasma protein exceeds 10 g/day, and moderate reductions in those levels are welltolerated. Genome edited hepatocytes produced normal hFIX (hF9) in therapeutic quantities, rather than albumin, driven by the highly active albumin enhancer/promoter. Targeted integration of the hF9 transgene at the albumin locus and splicing of this gene into the albumin transcript was shown.

[001288] Mice studies: C57BL/6 mice were administered vehicle (n=20) or AAV2/6 vectors (n=25) encoding mouse surrogate reagents at 1.0 xl013 vector genome (vg)/kg via tail vein injection. ELISA analysis of plasma hFIX in the treated mice showed peak levels of 50-1053 ng/mL that were sustained for the duration of the 6-month study. Analysis of FIX activity from mouse plasma confirmed bioactivity commensurate with expression levels, [001289] Non-human primate (NHP) studies: a single intravenous co-infusion of AAV2/6 vectors encoding the NHP targeted albumin-specific ZFNs and a human F9 donor at 1.2x1013 vg/kg (n=5/group) resulted in >50 ng/mL (>1% of normal) in this large animal model. The use of higher AAV2/6 doses (up to 1.5x1014 vg/kg) yielded plasma hFIX levels up to 1000 ng/ml (or 20% of normal) in several animals and up to 2000 ng/ml (or 50% of normal) in a single animal, for the duration of the study (3 months).

[001290] The treatment was well tolerated in mice and NI TPs, with no significant toxicological findings related to AAV2/6 ZEN + donor treatment in either species at therapeutic doses.

Sangamo (CA, USA) has since applied to the FDA, and been granted, permission to conduct the

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PCT/US2016/038181 world’s first human clinical trial for an in vivo genome editing application. This follows on the back of the EMEA’s approval of the Glybera gene therapy treatment of lipoprotein lipase deficiency.

[001291] Accordingly, it is preferred, in some embodiments, that any or all of the following are used:

* AAV (especially AAV2/6) vectors, preferably administered by intravenous injection;

« Albumin as target for gene editing/insertion of transgene/template- especially at intron 1 of albumin;

« human F9 donor template; and/or ® a promoterless donor template.

Hemophilia B [001292] Accordingly, in some embodiments, it is preferred that the present invention is used to treat Hemophilia B. As such it is preferred that a template is provided and that this is the human F9 gene. It will be appreciated that the hF9 template comprises the wt or ‘correct’ version of hF9 so that the treatment is effective.

[001293] In an alternative embodiment, the hemophilia B version of F9 may be delivered so as to create a model organism, cell or cell line (for example a murine or non-human primate model organism, cell or cell line), the model organism, cell or cell line having or carrying the Hemophilia B phenotype, i.e. an inability to produce wt F9.

Hemophilia A [001294] In some embodiments, the F9 (factor IX) gene may be replaced by the F8 (factor VIII) gene described above, leading to treatment of Hemophilia A (through provision of a correct F8 gene) and/or creation of a Hemophilia A model organism, cell or cell line (through provision of an incorrect, Hemophilia A version of the F8 gene).

Hemophilia C [001295] In some embodiments, the F9 (factor IX) gene may be replaced by the FI 1 (factor XI) gene described above, leading to treatment of Hemophilia C (through provision of a correct FI I gene) and/or creation of a Hemophilia C model organism, cell or cell line (through provision of an incorrect, Hemophilia C version of the F I I gene).

Treating Epithelial and Lung Diseases

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PCT/US2016/038181 [001296] The present invention also contemplates delivering the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to one or both lungs.

[001297] Although AAV-2-based vectors were originally proposed for CFTR delivery to CF airways, other serotypes such as AAV-1, AA.V-5, AAV-6, and AAV-9 exhibit improved gene transfer efficiency in a variety of models of the lung epithelium (see, e.g., Li et al., Molecular Therapy, vol. 17 no. 12, 2067-2077 Dec 2009). AAV-1 was demonstrated to be ~l()()-fold more efficient than AAV-2 and AAV-5 at transducing human airway epithelial cells in vitro,5 although AAV-1 transduced murine tracheal airway epithelia in vivo with an efficiency equal to that of AAV-5. Other studies have shown that AAV-5 is 50-fold more efficient than AAV-2 at gene delivery to human airway epithelium (HAE) in vitro and significantly more efficient in the mouse lung airway epithelium in vivo, AAV-6 has also been shown to be more efficient than AAV-2 in human airway epithelial cells in vitro and murine airways in vivo.8 The more recent isolate, AAV-9, was shown to display greater gene transfer efficiency than AAV-5 in murine nasal and alveolar epithelia in vivo with gene expression detected for over 9 months suggesting AAV may enable long-term gene expression in vivo, a desirable property for a CFTR gene delivery vector. Furthermore, it was demonstrated that AAV-9 could be readministered to the murine lung with no loss of CFTR expression and minimal immune consequences. CF and nonCF HAE cultures may be inoculated on the apical surface with 100 μί of AAV vectors for hours (see, e.g., Li et al., Molecular Therapy, vol. 17 no. 12, 2067-2077 Dec 2009). The MOI may vary from 1 x 1()⁵ to 4 χ 10³ vector genomes/cell, depending on virus concentration and purposes of the experiments. The above cited vectors are contemplated for the delivery⁷ and/or administration of the invention.

[001298] Zamora et al. (Am J Respir Crit Care Med Vol 183. pp 531-538, 2011) reported an example of the application of an RNA interference therapeutic to the treatment of human infectious disease and also a randomized trial of an antiviral drug in respiratory syncytial virus (RSV)-infected lung transplant recipients. Zamora et al. performed a randomized, double-blind, placebocontrolled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN-RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. This study demonstrates that an RNAi therapeutic targeting RSV can be safely administered to LTX recipients with RSV infection. Three daily doses of ALN-RSV01 did not result in any exacerbation of respiratory tract symptoms or impairment of

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PCT/US2016/038181 lung function and did not exhibit any systemic proinflammatory effects, such as induction of cytokines or CRP. Pharmacokinetics showed only low', transient systemic exposure after inhalation, consistent with preclinical animal data showing that ALN-RSV01, administered intravenously or by inhalation, is rapidly cleared from the circulation through exonucleasemediated digestion and renal excretion. The method of Zamora et al. may be applied to the nucleic acid-targeting system of the present invention and an aerosolized CRISPR Cas, for example with a dosage of 0.6 mg/kg, may be contemplated for the present invention.

[001299] Subjects treated for a lung disease may for example receive pharmaceutically effective amount of aerosolized AAV vector system per lung endobronchially delivered while spontaneously breathing. As such, aerosolized delivery is preferred for AAV delivery in general. An adenovirus or an AAV particle may be used for delivery. Suitable gene constructs, each operably linked to one or more regulatory sequences, may be cloned into the delivery vector. In this instance, the following constructs are provided as examples; Cbh or EFla promoter for Cas (Cpfl), U6 or HI promoter for guide RNA),: A preferred arrangement is to use a CFTRdelta508 targeting guide, a repair template for deltaF508 mutation and a codon optimized Cpfl enzyme, with optionally one or more nuclear localization signal or sequence(s) (NLS(s)), e.g., two (2) NLSs. Constructs without NLS are also envisaged.

Treating Diseases of the Muscular System [001300] The present invention also contemplates delivering the CRISPR-Cas system described herein, e.g, Cpfl effector protein systems, to muscle(s).

[001301] Bortolanza et al. (Molecular Therapy vol. 19 no. 11, 2055-2064 Nov. 2011) shows that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of facioscapulohumeral muscular dystrophy (FSHD), led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Bortolanza et al. found that a single intravenous injection of 5 χ 10¹² vg of rAAV6-shlFRGl rescues muscle histopathology and muscle function of FRG1 mice. In detail, 200 ul containing 2 χ 10^u or 5 χ 10¹² vg of vector in physiological solution were injected into the tail vein using a 25-gauge Terumo syringe. The method of Bortolanza et al. may be applied to an AAV expressing CRISPR Cas and injected into humans at a dosage of about 2 χ 10¹³ or 2 χ 1()¹⁶ vg of vector.

[001302] Dumonceaux et al. (Molecular Therapy vol. 18 no. 5, 881-887 May 2010) inhibit the myostatin pathway using the technique of RNA interference directed against the myostatin

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PCT/US2016/038181 receptor AcvRIIb mRNA (sh-AcvRIIb). The restoration of a quasi-dystrophin was mediated by the vectorized U7 exon-skipping technique (U7-DYS). Adeno-associated vectors carrying either the sh-Acvrllb construct alone, the U7-DYS construct alone, or a combination of both constructs were injected in the tibiaiis anterior (TA) muscle of dystrophic mdx mice. The injections were performed with 10¹¹ AAV viral genomes. The method of Dumonceaux et al. may be applied to an AAV expressing CRISPR Cas and injected into humans, for example, at a dosage of about 10^l4 to about 10¹⁵ vg of vector.

[001303] Kinouchi et al. (Gene Therapy (2008) 15, 1126-1130) report the effectiveness of in vivo siRNA delivery into skeletal muscles of normal or diseased mice through nanoparticle formation of chemically unmodified siRNAs with atelocollagen (ATCOL). ATCOL-mediated local application of siRNA targeting myostatin, a negative regulator of skeletal muscle growth, in mouse skeletal muscles or intravenously, caused a marked increase in the muscle mass within a few weeks after application. These results imply that ATCOL-mediated application of siRNAs is a powerful tool for future therapeutic use for diseases including muscular atrophy. MstsiRNAs (final concentration, 10 mM) were mixed with ATCOL (final concentration for local administration, 0.5%) (AteloGene, Kohken, Tokyo, Japan) according to the manufacturer’s instructions. After anesthesia of mice (20-week-old male C57BL/6) by Nembutal (25 mg/kg, i.p.), the Mst-siRNA/ATCOL complex was injected into the masseter and biceps femoris muscles. The method of Kinouchi et al. may be applied to CRISPR Cas and injected into a human, for example, at a dosage of about 500 to 1000 ml of a. 40 μΜ solution into the muscle. Hagstrom et al. (Molecular Therapy Vol. 10, No. 2, August 2004) describe an intravascular, nonviral methodology that enables efficient and repeatable delivery of nucleic acids to muscle cells (myofibers) throughout the limb muscles of mammals. The procedure involves the injection of naked plasmid DNA or siRNA into a distal vein of a limb that is transiently isolated by a tourniquet or blood pressure cuff. Nucleic acid delivery to myofibers is facilitated by its rapid injection in sufficient volume to enable extravasation of the nucleic acid solution into muscle tissue. High levels of transgene expression in skeletal muscle were achieved in both small and large animals with minimal toxicity. Evidence of siRNA delivery to limb muscle was also obtained. For plasmid DNA intravenous injection into a. rhesus monkey, a threeway stopcock was connected to two syringe pumps (Model PHD 2000; Harvard Instruments), each loaded with a single syringe. Five minutes after a papaverine injection, pDNA (15.5 to 25.7 mg in 40 -100

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PCT/US2016/038181 ml saline) was injected at a rate of 1.7 or 2.0 ml/s. This could be sealed up for plasmid DNA expressing CRISPR Cas of the present invention with an injection of about 300 to 500 mg in 800 to 2000 ml saline for a human. For adenoviral vector injections into a rat, 2 x 10⁹ infectious particles were injected in 3 ml of normal saline solution (NSS). This could be scaled up for an adenoviral vector expressing CRISPR Cas of the present invention with an injection of about I x I0¹³ infectious particles were injected in 10 liters of NSS for a human. For siRNA, a rat was injected into the great saphenous vein with 12.5 pg of a siRNA and a primate was injected injected into the great saphenous vein with 750 pg of a siRNA. This could be scaled up for a CRISPR Cas of the present invention, for example, with an injection of about 15 to about 50 mg into the great saphenous vein of a human.

[001304] See also, for example, WO2013163628 A2, Genetic Correction of Mutated Genes, published application of Duke University describes efforts to correct, for example, a frameshift mutation which causes a premature stop codon and a truncated gene product that can be corrected via nuclease mediated non-homologous end joining such as those responsible for Duchenne Muscular Dystrophy, (DMD) a recessive, fatal, X-linked disorder that results in muscle degeneration due to mutations in the dystrophin gene. The majority of dystrophin mutations that cause DMD are deletions of exons that disrupt the reading frame and cause premature translation termination in the dystrophin gene. Dystrophin is a cytoplasmic protein that provides structural stability to the dystroglycan complex of the cell membrane that is responsible for regulating muscle cell integrity and function. The dystrophin gene or DMD gene as used interchangeably herein is 2.2 megabases at locus Xp21. The primary' transcription measures about 2,400 kb with the mature mRNA being about 14 kb, 79 exons code for the protein which is over 3500 amino acids. Exon 51 is frequently adjacent to frame-disrupting deletions in DMD patients and has been targeted in clinical trials for oligonucleotide-based exon skipping. A clinical trial for the exon 51 skipping compound eteplirsen recently reported a significant functional benefit across 48 weeks, with an average of 47% dystrophin positive fibers compared to baseline. Mutations in exon 51 are ideally suited for permanent correction by NHEJ-based genome editing.

[001305] The methods of US Patent Publication No. 20130145487 assigned to Cellectis, which relates to meganuclease variants to cleave a target sequence from the human dystrophin gene (DMD), may also be modified to for the nucleic acid-targeting system of the present inventi on.

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Treating Diseases of the Skin [001306] The present invention also contemplates delivering the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to the skin.

[001307] Hickerson et al. (Molecular Therapy—Nucleic Acids (2013) 2, e!29) relates to a motorized microneedle array skin deliver}⁷ device for delivering self-delivery (sd)-siRNA to human and murine skin. The primary challenge to translating siRNA-based skin therapeutics to the clinic is the development of effective deliver}⁷ systems. Substantial effort has been invested in a variety of skin delivery technologies with limited success. In a clinical study in which skin was treated with siRNA, the exquisite pain associated with the hypodermic needle injection precluded enrollment of additional patients in the trial, highlighting the need for improved, more “patient-friendly” (i.e., little or no pain) delivery approaches. Microneedles represent an efficient way to deliver large charged cargos including siRNAs across the primary barrier, the stratum corneum, and are generally regarded as less painful than conventional hypodermic needles. Motorized “stamp type” microneedle devices, including the motorized microneedle array (MMNA) device used by Hickerson et al., have been shown to be safe in hairless mice studies and cause little or no pain as evidenced by (i) widespread use in the cosmetic industry and (ii) limited testing in which nearly all volunteers found use of the device to be much less painful than a flushot, suggesting siRNA delivery using this device will result in much less pain than was experienced in the previous clinical trial using hypodermic needle injections. The MMNA device (marketed as Triple-M or Tri-M by Bomtech Electronic Co, Seoul, South Korea) was adapted for delivery of siRNA to mouse and human skin. sd-siRNA solution (up to 300 μΐ of 0.1 mg/ml RNA) was introduced into the chamber of the disposable Tri-M needle cartridge (Bomtech), which was set to a depth of 0.1 mm. For treating human skin, deidentified skin (obtained immediately following surgical procedures) was manually stretched and pinned to a cork platform before treatment. All intradermal injections were performed using an insulin syringe with a 28-gauge 0.5-inch needle. The MMNA device and method of Hickerson et al. could be used and/or adapted to deliver the CRISPR Cas of the present invention, for example, at a dosage of up to 300 μΐ of 0.1 mg/ml CRISPR Cas to the skin.

[001308] Leachman et al. (Molecular Therapy, vol. 18 no. 2, 442-446 Feb. 2010) relates to a phase lb clinical trial for treatment of a rare skin disorder pachyonychia congenita (PC), an autosomal dominant syndrome that includes a disabling plantar keratoderma, utilizing the first

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PCT/US2016/038181 short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) NI? IK mutant mRNA without affecting wild-type K6a mRNA.

[001309] Zheng et al. (PNAS, July 24, 2012, vol, 109, no. 30, 11975-11980) show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Zheng et al. demonstrated that a single application of 25 n.M epidermal growth factor receptor (EGFR) SNA-NCs for 60 h demonstrate effective gene knockdown in human skin. A similar dosage may be contemplated for CRISPR Cas immobilized in SNA-NCs for administration to the skin.

[001310] In some embodiments, the treatment, prophylaxis or diagnosis of cancer is provided. The target is preferably one or more of the FAS, BID, CTLA4, PDCD1, CBLB, PTPN6, TRAC or TRBC genes. The cancer may be one or more of lymphoma, chronic lymphocytic leukemia (CLL), B cell acute lymphocytic leukemia (B-ALL), acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma (NHL), diffuse large ceil lymphoma (DLCL), multiple myeloma, renal cell carcinoma (RCC), neuroblastoma, colorectal cancer, breast cancer, ovarian cancer, melanoma, sarcoma, prostate cancer, lung cancer, esophageal cancer, hepatocellular carcinoma, pancreatic cancer, astrocytoma, mesothelioma, head and neck cancer, and medulloblastoma. This may be implemented with engineered chimeric antigen receptor (CAR) T cell. Tins is described in WO2015161276, tire disclosure of which is hereby incorporated by reference and described herein below.

[001311] Target genes suitable for the treatment or prophylaxis of cancer may include, in some embodiments, those described in WO2015048577 the disclosure of which is hereby incorporated by reference.

Usher Syndrome or retinitis pigmentosa-39 [001312] In some embodiments, the treatment, prophylaxis or diagnosis of Usher Syndrome or retinitis pigmentosa-39 is provided. The target is preferably the USH2A gene. In some embodiments, correction of a G deletion at position 2299 (2299delG) is provided. This is described in WO2015134812A1, the disclosure of which is hereby incorporated by reference. Cystic Fibrosis (CF)

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PCT/US2016/038181 [001313] In some embodiments, the treatment, prophylaxis or diagnosis of cystic fibrosis is provided. The target is preferably the SCNN1A or the CFTR gene. This is described in WO2015157070, the disclosure of which is hereby incorporated by reference.

[001314] Schwank et al. (Cell Stem Cell, 13:653-58, 2013) used CRISPR-Cas9 to correct a defect associated with cystic fibrosis in human stem cells. The team’s target was the gene for an ion channel, cystic fibrosis transmembrane conductor receptor (CFTR), A deletion in CFTR causes the protein to misfold in cystic fibrosis patients. Using cultured intestinal stem cells developed from cell samples from two children with cystic fibrosis, Schwank et al. were able to correct the defect using CRISPR along with a donor plasmid containing the reparative sequence to be inserted. The researchers then grew⁷ the cells into intestinal “organoids,” or miniature guts, and showed that they functioned normally. In this case, about half of clonal organoids underwent the proper genetic correction.

HIV and AIDS [001315] In some embodiments, the treatment, prophylaxis or diagnosis of HIV and AIDS is provided. The target is preferably the CCR5 gene In HIV. This is described in WO2015148670A1, the disclosure of which is hereby incorporated by reference.

Beta Thalassaemia [001316] In some embodiments, the treatment, prophylaxis or diagnosis of Beta Thalassaemia is provided. The target is preferably the BCL11A gene. This is described in WO2015148860, the disclosure of which is hereby incorporated by reference.

Sickle Ceil Disease (SCD) [001317] In some embodiments, the treatment, prophylaxis or diagnosis of Sickle Cell Disease (SCD) is provided. The target is preferably the HBB or BCL11A gene. This is described in WO2Q15148863, the disclosure of which is hereby incorporated by reference.

Herpes Simplex Virus 1 and 2 [001318] In some embodiments, the treatment, prophylaxis or diagnosis of HSV-1 (Herpes Simplex Virus 1) is provided. The target is preferably the UL19, UL30, UL48 or UL50 gene in HSV-1. This is described in WO2015153789, the disclosure of which is hereby incorporated by reference.

[001319] In other embodiments, the treatment, prophylaxis or diagnosis of HSV-2 (Herpes Simplex Virus 2) is provided. The target is preferably the UL19, UL30, UL48 or UL50 gene In

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HSV-2. This is described in WO2015153791, the disclosure of which is hereby incorporated by reference.

[001320] In some embodiments, the treatment, prophylaxis or diagnosis of Primary' Open Angle Glaucoma (POAG) is provided. The target is preferably the MYOC gene. This is described in WO2015153780, the disclosure of which is hereby incorporated by reference. Adoptive Cell Therapies [001321] The present invention also contemplates use of the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to modify cells for adoptive therapies. Aspects of the invention accordingly involve the adoptive transfer of immune system cells, such as T cells, specific for selected antigens, such as tumor associated antigens (see Mans et al., 2014, Adoptive Immunotherapy for Cancer or Viruses, Annual Review of Immunology, Vol. 32: 189-225, Rosenberg and Restifo, 2015, Adoptive cell transfer as personalized immunotherapy for human cancer. Science Vol, 348 no. 6230 pp. 62-68; and, Restifo et al., 2015, Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12(4): 269-281; and Jenson and Riddell, 2014, Design and implementation of adoptive therapy with chimeric antigen receptormodified T cells. Immunol Rev. 257(1): 127-144). Various strategies may for example be employed to genetically modify T cells by altering the specificity of the T cell receptor (TCR) for example by introducing new TCR a and β chains with selected peptide specificity (see U.S. Patent No. 8,697,854; PCT Patent Publications: W02003020763, W02004033685,

W02004044004, W02005114215, W02006000830, W02008038002, W02008039818, W02004074322, W02005113595, WO2006125962, WO2013166321, WO2013039889, WO2014018863, WO2014083173; U.S, Patent No, 8,088,379).

[001322] As an alternative to, or addition to, TCR modifications, chimeric antigen receptors (CARs) may be used in order to generate immunoresponsive cells, such as T cells, specific for selected targets, such as malignant cells, with a wide variety of receptor chimera constructs having been described (see U.S. Patent Nos. 5,843,728; 5,851,828; 5,912,170; 6,004,811; 6,284,240; 6,392,013; 6,410,014; 6,753,162; 8,211,422; and, PCT Publication WO9215322). Alternative CAR constructs may be characterized as belonging to successive generations. Firstgeneration CARs typically consist of a single-chain variable fragment of an antibody specific for an antigen, for example comprising a VL linked to a VH of a specific antibody, linked by a flexible linker, for example by a CD8a hinge domain and a CD8a transmembrane domain, to the

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PCT/US2016/038181 transmembrane and intracellular signaling domains of either (Τ)3ζ or FcRy (3θΡν-€03ζ or scFvFcRy; see U.S. Patent No. 7,741,465; U.S. Patent No. 5,912,172; U.S. Patent No. 5,906,936). Second-generation CARs incorporate the intracellular domains of one or more costimulatory molecules, such as CD28, 0X40 (CD 134), or 4-IBB (CD 137) within the endodomain (for example 3θΡν-0028/ΌΧ40/4-ΙΒΒΤ03ζ; see U.S. Patent Nos. 8,911,993; 8,916,381; 8,975,071; 9,101,584, 9,102,760; 9,102,761). Third-generation CARs include a combination of costimulatory endodomains, such a €Ώ3ζ-ο1ιηϊη, CD97, GDI la-CD18, CD2, ICOS, CD27, CD 154, CDS, 0X40, 4-1BB, or CD28 signaling domains (for example 5θΡν-ί'Ώ28-4~1ΒΒΤ03ζ or scFv-CD28-OX40-CD3G see U.S. Patent No. 8,906,682; U.S. Patent No. 8,399,645; U.S. Pat. No. 5,686,281; PCT Publication No. WO2014134165; PCT Publication No. WO2012079000). Alternatively, costimulation may be orchestrated by expressing CARs in antigen-specific T cells, chosen so as to be activated and expanded following engagement of their native apTCR, for example by antigen on professional antigen-presenting cells, with attendant costimulation. In addition, additional engineered receptors may be provided on the immunoresponsive cells, for example to improve targeting of a T-cell attack and/or minimize side effects.

[001323] Alternative techniques may be used to transform target immunoresponsive cells, such as protoplast fusion, lipofection, transfection or electroporation. A wide variety of vectors may be used, such as retroviral vectors, lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, plasmids or transposons, such as a Sleeping Beauty transposon (see U.S. Patent Nos. 6,489,458, 7,148,203; 7,160,682; 7,985,739; 8,227,432), may be used to introduce CARs, for example using 2nd generation antigen-specific CARs signaling through CD3ζ and either CD28 or CD137. Viral vectors may for example include vectors based on HIV, SV40, EBV, HSV or BPV.

[001324] Cells that are targeted for transformation may for example include T cells, Natural Killer (NK) cells, cytotoxic T lymphocytes (CTL), regulator)' T cells, human embryonic stem cells, tumor-infiltrating lymphocytes (TIL) or a pluripotent stem cell from which lymphoid cells may be differentiated. T cells expressing a desired CAR may for example be selected through coculture with γ-irradiated activating and propagating cells (AaPC), which co-express the cancer antigen and co-stimulatory molecules. The engineered CAR T-cells may be expanded, for example by co-culture on AaPC in presence of soluble factors, such as IL-2 and IL-21. This expansion may for example be carried out so as to provide memory CAR+ T cells (which may

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PCT/US2016/038181 for example be assayed by non-enzymatic digital array and/or multi-panel flow cytometry). In this way, CAR T cells may he provided that have specific cytotoxic activity against antigenbearing tumors (optionally in conjunction with production of desired chemokines such as interferon-γ). CAR T cells of this kind may for example be used in animal models, for example to threat tumor xenografts.

[001325] Approaches such as the foregoing may be adapted to provide methods of treating and/or increasing survival of a subject having a disease, such as a neoplasia, for example by administering an effective amount of an immunoresponsive cell comprising an antigen recognizing receptor that binds a selected antigen, wherein the binding activates the immunoreponsive cell, thereby treating or preventing the disease (such as a neoplasia, a pathogen infection, an autoimmune disorder, or an allogeneic transplant reaction). Dosing in CAR T cell therapies may for example involve administration of from 106 to 109 cells/kg, with or without a course of lymphodepletion, for example with cyclophosphamide.

[001326] In one embodiment, the treatment can be administrated into patients undergoing an immunosuppressive treatment. The cells or population of cells, may be made resistant to at least one immunosuppressive agent due to the inactivation of a gene encoding a receptor for such immunosuppressive agent. Not being bound by a theory, the immunosuppressive treatment should help the selection and expansion of the immunoresponsive or T cells according to the invention within the patient.

[001327] The administration of the cells or population of cells according to the present invention may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The cells or population of cells may be administered to a patient subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous or intralymphatic injection, or intraperitoneally. In one embodiment, the cell compositions of the present invention are preferably administered by intravenous injection.

[001328] The administration of the cells or population of cells can consist of the administration of IO⁴- 10⁹ cells per kg body weight, preferably 10⁵ to 10° cells/kg body weight including all integer values of cell numbers within those ranges. Dosing in CAR T cell therapies may for example involve administration of from 10⁶ to 10^y cells/kg, with or without a course of lymphodepletion, for example with cyclophosphamide. The cells or population of cells can be

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PCT/US2016/038181 administrated in one or more doses. In another embodiment, the effective amount of cells are administrated as a single dose, in another embodiment, the effective amount of cells are administrated as more than one dose over a period time. Timing of administration is within the judgment of managing physician and depends on the clinical condition of the patient. The cells or population of cells may be obtained from any source, such as a blood bank or a donor. While individual needs vary, determination of optimal ranges of effective amounts of a given cell type for a particular disease or conditions are within the skill of one in the art. An effective amount means an amount which provides a therapeutic or prophylactic benefit. The dosage administrated will be dependent upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.

[001329] In another embodiment, the effective amount of cells or composition comprising those cells are administrated parenterally. The administration can be an intravenous administration. The administration can be directly done by injection within a tumor, [001330] To guard against possible adverse reactions, engineered immunoresponsive cells may be equipped with a transgenic safety switch, in the form of a transgene that renders the cells vulnerable to exposure to a specific signal. For example, the herpes simplex viral thymidine kinase (TK) gene may be used in this way, for example by introduction into allogeneic T lymphocytes used as donor lymphocyte infusions following stem cell transplantation (Greco, et al., Improving the safety of cell therapy with the TK-suicide gene. Front. Pharmacol. 2015; 6: 95). In such cells, administration of a nucleoside prodrug such as ganciclovir or acyclovir causes cell death. Alternative safety switch constructs include inducible caspase 9, for example triggered by administration of a small-molecule dimerizer that brings together two nonfunctional icasp9 molecules to form the active enzyme. A wide variety of alternative approaches to implementing cellular proliferation controls have been described (see U.S. Patent Publication No. 20130071414; PCT Patent Publication WO2011146862; PCT Patent Publication WO2014OI1987; PCT Patent Publication W02013040371; Zhou et al. BLOOD, 2014, 123/25:3895 - 3905; Di Stasi et al., The New England Journal of Medicine 2011; 365:16731683; Sadelain M, The New⁷ England Journal of Medicine 2011; 365:1735-173; Ramos et al., Stem Cells 28(6):1107-15 (2010)).

[001331] In a further refinement of adoptive therapies, genome editing with a CRISPR-Cas system as described herein may be used to tailor immunoresponsive cells to alternative

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PCT/US2016/038181 implementations, for example providing edited CAR T cells (see Poirot et al., 2015, Multiplex genome edited T-cell manufacturing platform for off-the-shelf' adoptive T-cell immunotherapies, Cancer Res 75 (18): 3853). For example, immunoresponsive cells may be edited to delete expression of some or all of the class of HLA type II and/or type I molecules, or to knockout selected genes that may inhibit the desired immune response, such as the PD I gene. [001332] Cells may be edited using any CRISPR system and method of use thereof as described herein. CRISPR systems may be delivered to an immune cell by any method described herein. In preferred embodiments, cells are edited ex vivo and transferred to a subject in need thereof. Immunoresponsive cells, CAR T cells or any cells used for adoptive cell transfer may be edited. Editing may be performed to eliminate potential alloreactive T-cell receptors (TCR), disrupt the target of a chemotherapeutic agent, block an immune checkpoint, activate a T cell, and/or increase the differentiation and/or proliferation of functionally exhausted or dysfunctional CD8+ T-cells (see PCT Patent Publications: WO2013176915, WO2014059173,

WO2014172606, WO2014184744, and WO2014191128). Editing may result in inactivation of a gene.

[001333] By inactivating a gene it is intended that the gene of interest is not expressed in a functional protein form. In a particular embodiment, the CRISPR system specifically catalyzes cleavage in one targeted gene thereby inactivating said targeted gene. The nucleic acid strand breaks caused are commonly repaired through the distinct mechanisms of homologous recombination or non-homologous end joining (NHEJ). However, NHEJ is an imperfect repair process that often results in changes to the DNA sequence at the site of the cleavage. Repair via non-homologous end joining (NHEJ ) often results in small insertions or deletions (Indel) and can be used for the creation of specific gene knockouts. Cells in which a cleavage induced mutagenesis event has occurred can be identified and/or selected by well-known methods in the art.

[001334] T cell receptors (TCR) are cell surface receptors that participate in the activation of T cells in response to the presentation of antigen. The TCR is generally made from two chains, a and β, which assemble to form a heterodimer and associates with the CD3-transducing subunits to form the T cell receptor complex present on the cell surface. Each a and β chain of the TCR consists of an immunoglobulin-like N-terminal variable (V) and constant (C) region, a hydrophobic transmembrane domain, and a short cytoplasmic region. As for immunoglobulin

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PCT/US2016/038181 molecules, the variable region of the a and β chains are generated by V(D)J recombination, creating a large diversity of antigen specificities within the population of T cells. However, in contrast to immunoglobulins that recognize intact antigen, T cells are activated by processed peptide fragments in association with an MHC molecule, introducing an extra dimension to antigen recognition by T cells, know'll as MHC restriction. Recognition of MHC disparities between the donor and recipient through the T cell receptor leads to T cell proliferation and the potential development of graft versus host disease (GVHD). The inactivation of TCRa or TCRP can result in the elimination of the TCR from the surface of T ceils preventing recognition of alloantigen and thus GVHD. However, TCR disruption generally results in the elimination of the CDS signaling component and alters the means of further T cell expansi on.

[001335] Allogeneic cells are rapidly rejected by the host immune system. It has been demonstrated that, allogeneic leukocytes present in non-irradiated blood products will persist for no more than 5 to 6 days (Boni, Muranski et al, 2008 Blood 1;112( 12):4746-54). Thus, to prevent rejection of allogeneic cells, the host's immune system usually has to be suppressed to some extent. However, in the case of adoptive cell transfer the use of immunosuppressi ve drugs also have a detrimental effect on the introduced therapeutic T ceils. Therefore, to effectively use an adoptive immunotherapy approach in these conditions, the introduced cells would need to be resistant to the immunosuppressive treatment. Thus, in a particular embodiment, the present invention further comprises a step of modifying T cells to make them resistant to an immunosuppressive agent, preferably by inactivating at least one gene encoding a target for an immunosuppressive agent. An immunosuppressive agent is an agent that suppresses immune function by one of several mechanisms of action. An immunosuppressive agent can be, but is not limited to a calcineurin inhibitor, a target of rapamycin, an interleukin-2 receptor a-chain blocker, an inhibitor of inosine monophosphate dehydrogenase, an inhibitor of dihydrofolic acid reductase, a corticosteroid or an immunosuppressive anti metabolite. The present invention allows conferring immunosuppressive resistance to T ceils for immunotherapy by inactivating the target of the immunosuppressive agent in T cells. As non-limiting examples, targets for an immunosuppressive agent can be a receptor for an immunosuppressive agent such as: CD52, glucocorticoid receptor (GR), a FKBP family gene member and a cyclophilin family gene member.

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PCT/US2016/038181 [001336] Immune checkpoints are inhibitory⁷ pathways that slow down or stop immune reactions and prevent excessive tissue damage from uncontrolled activity of immune cells. In certain embodiments, the immune checkpoint targeted is the programmed death-1 (PD-1 or CD279) gene (PDCDl). In other embodiments, the immune checkpoint targeted is cytotoxic Tlymphocyte-associated antigen (CTLA-4). In additional embodiments, the immune checkpoint targeted is another member of the CD28 and CTLA4 Ig superfamily such as BTLA, LAG3, ICOS, PDL1 or KIR. In further additional embodiments, the immune checkpoint targeted is a member of the TNFR superfamily such as CD40, 0X40, CD137, GITR, CD27 or TIM-3. [001337] Additional immune checkpoints include Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) (Watson IIA, et al., SHP-1: the next checkpoint target for cancer immunotherapy? Biochem Soc Trans. 2016 Apr I5;44(2):356-62). SHP-1 is a widely expressed inhibitory protein tyrosine phosphatase (PTP). In T-cells, it is a negative regulator of antigendependent activation and proliferation. It is a cytosolic protein, and therefore not amenable to antibody-mediated therapies, but its role in activation and proliferation makes it an attractive target for genetic manipulation in adoptive transfer strategies, such as chimeric antigen receptor (CAR) T cells. Immune checkpoints may also include T cell immunoreceptor with Ig and ΠΤΜ domains (TIGIT/Vstm3/WUCAM/VSIG9) and VISTA (Le Mercier I, et al., (2015) Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front. Immunol. 6:418). [001338] WO2014172606 relates to the use of MT1 and/or MT1 inhibitors to increase proliferation and/or activity of exhausted CD8+ T-cells and to decrease CD8+ T-cell exhaustion (e.g., decrease functionally exhausted or unresponsive CD8+ immune cells). In certain embodiments, metallothioneins are targeted by gene editing in adoptively transferred T cells. [001339] In certain embodiments, targets of gene editing may be at least one targeted locus involved in the expression of an immune checkpoint protein. Such targets may include, but are not limited to CTLA4, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, ICOS (CD278), PDL1, KIR, LAGS, HAVCR2, BTLA, CD160, TIGIT, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244 (2B4), TNFRSF10B, TNFRSF10A, CASP8, CASP10, CASP3, CASP6, CASP7, FADE), FAS, TGFBRII, TGFRBRI, SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, 1L10RA, IL10RB, HM0X2, IL6R, IL6ST, E1F2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, VISTA, GUCY1A2, GUCY1A3, GUCY1B2, GUCYIB3, MT1, MT2, CD40, 0X40, CD137, GITR, CD27, SHP-1 or TIM-3. In preferred embodiments, the gene locus involved in

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PCT/US2016/038181 the expression of PD-1 or CTLA-4 genes is targeted. In other preferred embodiments, combinations of genes are targeted, such as but not limited to PD-1 and TIGIT.

[001340] In other embodiments, at least two genes are edited. Pairs of genes may include, but are not limited to PD1 and TCRa, PD1 and TCRp, CTLA-4 and TCRa, CTLA-4 and TCRp, LAGS and TCRa, LAGS and TCRP, Tim3 and TCRa, Tim3 and TCRP, BTLA and TCRa, BTLA and TCRp, BY55 and TCRa, BY55 and TCRfl, TIGIT and TCRa, TIGIT and TCRp, B7H5 and TCRa, B7H5 and TCRp, LAIR1 and TCRa, LAIR1 and TCRp, SIGLEC10 and

TCRa, SIGLEC 10 and TCRp, 2B4 and TCRa, 2B4 and TCRp.

[001341] Whether prior to or after genetic modification of the T cells, the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694, 6,534,055, 6,905,680, 5,858,358, 6,887,466, 6,905,681, 7,144,575, 7,232,566, 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and 7,572,631. T cells can be expanded in vitro or in vivo.

[001342] The practice of the present invention employs, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See MOLECULAR CLONING: A LABORATORY MANUAL, 2nd edition (1989) (Samhrook, Fritsch and Maniatis); MOLECULAR CLONING: A LABORATORY MANUAL, 4th edition (2012) (Green and Sambrook); CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (1987) (F. M. Ausubel, et al. eds.); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.); PCR 2: A PRACTICAL APPROACH (1995) (M.J. MacPherson, B.D. Flames and G.R. Taylor eds.); ANTIBODIES, A LABORATORY MANUAL (1988) (Harlow and Lane, eds.); ANTIBODIES A LABORATORY MANUAL, 2nd edition (2013) (E.A. Greenfield ed.); and ANIMAL CELL CULTURE (1987) (R.I. Freshney, ed.).

[001343] The practice of the present invention employs, unless otherwise indicated, conventional techniques for generation of genetically modified mice. See Marten H. Hofker and Jan van Deursen, TRANSGENIC MOUSE METHODS AND PROTOCOLS, 2nd edition (2011).

Gene Drives [001344] The present invention also contemplates use of the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to provide RNA-guided gene drives, for example in

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PCT/US2016/038181 systems analogous to gene drives described in PCT Patent Publication WO 2015/105928. Systems of this kind may for example provide methods for altering eukaryotic germline cells, by introducing into the germline cell a nucleic acid sequence encoding an RNA-guided DNA nuclease and one or more guide RNAs. The guide RNAs may be designed to be complementary to one or more target locations on genomic DNA of the germline cell. The nucleic acid sequence encoding the RNA guided DNA nuclease and the nucleic acid sequence encoding the guide RNAs may be provided on constructs between flanking sequences, with promoters arranged such that the germline cell may express the RNA guided DNA nuclease and the guide RNAs, together with any desired cargo-encoding sequences that are also situated between the flanking sequences. The flanking sequences will typically include a sequence which is identical to a corresponding sequence on a selected target chromosome, so that the flanking sequences work with the components encoded by the construct to facilitate insertion of the foreign nucleic acid construct sequences into genomic DNA at a target cut site by mechanisms such as homologous recombination, to render the germline cell homozygous for the foreign nucleic acid sequence. In this way, gene-drive systems are capable of introgressing desired cargo genes throughout a breeding population (Gantz et al., 2015, Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles Stephens!, PNAS 2015, published ahead of print November 23, 2015, doi:10.1Q73/pnas.1521077112; Esvelt et al., 2014, Concerning RNA-guided gene drives for the alteration of wild populations eLife 2014;3:e03401), In select embodiments, target sequences may be selected which have few potential off-target sites in a genome. Targeting multiple sites within a target locus, using multiple guide RNAs, may increase the cutting frequency and hinder the evolution of drive resistant alleles. Truncated guide RNAs may reduce off-target cutting. Paired nickases may be used instead of a single nuclease, to further increase specificity. Gene drive constructs may include cargo sequences encoding transcriptional regulators, for example to activate homologous recombination genes and/or repress non-homologous end-joining. Target sites may be chosen within an essential gene, so that non-homologous end-joining events may cause lethality rather than creating a drive-resistant allele. The gene drive constructs can be engineered to function in a range of hosts at a range of temperatures (Cho et al. 2013, Rapid and Tunable Control of Protein Stability in Caenorhabditis elegans Using a Small Molecule, PLoS ONE 8(8): e72393. doi: 10.13 71 /j ournal .pone. 00723 93).

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Xenotransplantation [001345] The present invention also contemplates use of the CRISPR-Cas system described herein, e.g. Cpfl effector protein systems, to provide RNA-guided DNA nucleases adapted to be used to provide modified tissues for transplantation. For example, RNA-guided DNA nucleases may be used to knockout, knockdown or disrupt selected genes in an animal, such as a transgenic pig (such as the human heme oxygenase-1 transgenic pig line), for example by disrupting expression of genes that encode epitopes recognized by the human immune system, i.e. xenoantigen genes. Candidate porcine genes for disruption may for example include a(l,3)galactosyltransferase and cytidine monophosphate-N-acetylneuraminic acid hydroxylase genes (see PCT Patent Publication WO 2014/066505). In addition, genes encoding endogenous retroviruses may be disrupted, for example the genes encoding all porcine endogenous retroviruses (see Yang et al., 2015, Genome-wide inactivation of porcine endogenous retroviruses (PERVs), Science 27 November 2015: Vol, 350 no. 6264 pp. 1101-1104). In addition, RNA-guided DNA nucleases may be used to target a site for integration of additional genes in xenotransplant donor animals, such as a human CD55 gene to improve protection against hyperacute rejection.

[001346] Examples of disease-associated genes and polynucleotides amd disease specific information is available from McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.), available on the World Wide Web.

[001347] Mutations in these genes and pathways can result in production of improper proteins or proteins in improper amounts which affect function. Further examples of genes, diseases and proteins are hereby incorporated by reference from US Provisional application 61/736,527 filed December 12, 2012. Such genes, proteins and pathways may be the target polynucleotide of a CRISPR complex of the present invention. Examples of disease-associated genes and polynucleotides are listed in Tables A and B, Examples of signaling biochemical pathwayassociated genes and polynucleotides are listed in Table C.

[001348] Table A

DISEASE/D1SORDER |GENE(S) I

S

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Neoplasia	PTEN; ATM; A'TR; EGFR; ERBB2; ERBB3; ERBB4;
	Notch 1; Notch2; Notch3; Notch4; AKT; AKT2; AKT3; HIF;
	HIFla; HIF3a; Met; HRG; Bcl2; PPAR alpha; PPAR
	gamma; WT1 (Wilms Tumor); FGF Receptor Family
	members (5 members: 1, 2, 3, 4, 5), CDKN2a; APC; RB
	(retinoblastoma); MEN1; VHL; BRCA1; BRCA2; AR
	(Androgen Receptor); TSG101; IGF; IGF Receptor, Igfl (4
	variants); Igf2 (3 variants); Igf 1 Receptor, Igf 2 Receptor;
	Bax; Bcl2; caspases family (9 members:
	1,2,3,4, 6, 7, 8, 9, 12); Kras; Ape
Age-related Macular	Abcr; Ccl2; Cc2; cp (ceruloplasmin); Timp3; cathepsinD;
Degeneration	Vldlr; Ccr2
Schizophrenia	Neuregulinl (Nrgl); Erb4 (receptor for Neuregulin);
	Complexinl (Cplxl); Tphl Tryptophan hydroxylase; Tph2
	Tryptophan hydroxylase 2; Neurexin 1; GSK3; GSK3a;
	GSK3b
Disorders	5-HTT (Slc6a4); COM T; DRD (Drdla); SLC6A3; DAO A,
	DTNBP1; Dao (Daol)
Trinucleotide Repeat	HTT (Huntington’s Dx); SBMA/SMAX1/AR (Kennedy’s
Disorders	Dx); FXN/X25 (Friedrich’s Ataxia); ATX3 (Machado-
	Joseph’s Dx); ATXNI and ATXN2 (spinocerebellar
	ataxias); DMPK (myotonic dystrophy); Atrophin-1 and Atnl
	(DRPLA Dx); CBP (Creb-BP - global instability); VLDLR
	(Alzheimer’s), Atxn, AtxnlO
Fragile X Syndrome	FMR2; FXR1; FXR2; mGLURS
Secretase Related	APH-1 (alpha and beta); Presenilin (Psenl); nicastrin
Disorders	(Ncstn); PEN-2
Others	Nos I; Parpl, Natl; Nat2
Prion - related disorders	Prp
ALS	SOD1; ALS2; STEX; FUS; TARDBP; VEGF (VEGF-a;
	VEGF-b; VEGF-c)
Drug addiction	Prkce (alcohol); Drd2; Drd4; ABAT (alcohol); GRIA2;
	Grni5; Grinl; Htrlb; Grin2a; Drd3, Pdyn; Grial (alcohol)
Autism	Mecp2; BZRAP1; MDGA2; SemaSA; Neurexin 1, Fragile X
	(FMR2 (AFF2); FXR1; FXR2; Mglur5)
Alzheimer’s Disease	El; CHIP; UCH; UBB; Tau; LRP; PICALM; Clusterin; PSI;
	SORL1, CR1; Vldlr; Ubal; Uba3; CHIP28 (Aqpl,
	Aquaporin 1); Uchll; Uchl3; APP
Inflammation	IL-10; IL-1 (IL-la; IL-lb); IL-13; IL-17 (IL-17a (CTLA8); IL-
	17b; IL-T7c; IL-17d; IL-171); 11-23; Cx3crl; ptpn22; TNFa;
	NOD2/CARD15 for IBD; IL-6; IL-12 (IL-12a; IL-12b);
	CTLA4; Cx3cll
Parkinson’s Disease	x-Synuclein; DJ-1; LRRK2; Parkin; PINKl

[001349] Table B:

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Blood and coagulation diseases and disorders	Anemia (CDAN1, CDA1, RPS19, DBA, PKLR, PK1, NT5C3, UMPH1, PSN1, RHAG, RH50A, NRAMP2, SPTB, ALAS2, ANH1, ASB, ABCB7, ABC7, ASAT); Bare lymphocyte syndrome (TAPBP, TPSN, TAP2, ABCB3, PSF2, RINGlfi MHC2TA, C2TA, RFX5, RFXAP, RFX5), Bleeding disorders (TBXA2R, P2RX1, P2X1); Factor H and factor H-like 1 (HFI, CFH, HUS); Factor V and factor VIII (MCFD2); Factor VII deficiency (F7); Factor X deficiency (FI 0); Factor XI deficiency (FI 1); Factor XII deficiency (FI2, HAF); Factor XIIIA. deficiency (F13A1, F13A); Factor XIIIB deficiency (F13B); Fanconi anemia (FANCA, FACA, FA1, FA, FAA, FAAP95, FAAP90, FLJ34064, FANCB, FANCC, FACC, BRCA2, FANCD 1, FANCD2, FANCD, FACD, FAD, FANCE, FACE, FANCF, XRCC9, FANCG, BRIP1, BACH1, FANCJ, PHF9, FANCL, FANCM, ΚΙ AA 1596); Hemophagocytic lymphohistiocytosis disorders (PRF1, HPLH2, UNC13D,MUNC13-4, HPLH3J4LH3, FHL3); Hemophilia A (F8, F8C, HEMA), Hemophilia B (F9, HEMB), Hemorrhagic disorders (PI, ATT, F5); Leukocyde deficiencies and disorders (ITGB2, CD 18, LCAMB, LAD, EIF2B1, E1F2BA, EIF2B2, EIF2B3, E1F2B5, LVWM, CACH, CLE, EIF2B4); Sickle cell anemia (HBB); Thalassemia (HBA2, HBB, HBD, LCRB, HBA1).
Cell dysregulation and oncology diseases and disorders	B-cell non-Hodgkin lymphoma (BCL7A, BCL7); Leukemia (TALI, TCL5, SCL, TAL2, FLT3, NBS1, NBS, ZNFN1A1, 1K1, LYF1, 110X1)4, HOX4B, BCR, CML, PHI,, ALL, ARNT, KRAS2, RASK2, GMPS, AF10, ARHGEF12, LARG, KIAA0382, CALM, CLTH, CEBPA, CEBP, CHIC2, BTL, FLT3, KIT, PBT, LPP, NPM1, NUP214, D9S46E, CAN, CAIN, RUNX1, CBFA2, AMLI, WHSC1L1, NSD3, 11.13, AF1Q, NPM1, NUMA 1, ZNF145, PLZF, PML, MYL, STAT5B, AF 10, CALM, CLTH, ARL11, AJRLTS1, P2RX7, P2X7, BCR, CML, Pi IF. ALL, GRAF, NFI, VRNF, WSS, NFNS, PTPN11, PTP2C, SHP2, NS1, BCL2, CCND1, PRAD1, BCL1, TCRA, GATA1, GF1, ERYF1, NFE1, ABLE NQO1, DIA4, NMORI, NUP2I4, D9S46E, CAN, CAIN).
Inflammation and immune related diseases and disorders	AIDS (KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1, IFNG, CXCLI2, SDFI); Autoimmune lymphoproliferative syndrome (TNFRSF6, ΑΡΤΙ, FAS, CD95, ALPS1A); Combined immunodeficiency, (IL2RG, SCIDX1, SCIDX, IMD4); HIV-1 (CCL5, SCYA5, D17S136E, TCP228), HIV susceptibility or infection (ILIO, CSIF, CMKBR2, CCR2, CMKBR5, CCCKR5 (CCR5)); immunodeficiencies (CD3E, CD3G, AICDA, AID, HIGM2, TNFRSF5, CD40, UNG, DGU, HIGM4, TNFSF5, CD40LG, HIGMl, IGM, FOXP3. IPEX, AHD, XPID, PIDX, TNFRSF14B, TAC1); Inflammation (IL-10, IL-1 ill.-la, IL-lb), IL-13, IL-17 (IL-I7a (CTLA8), IL-17b, IL-17c, IL-17d, IL-17f), 11-23, Cx3crl, ptpn22, TNFa, NOD2/CARD15 for IBD, IL-6, IL-12 (IL-12a, IL-12b), CTLA4, CxScll); Severe combined immunodeficiencies (SCIDs)(JAK3, JAKL, DCLRE1C, ARTEMIS, SODA, RAG1, RAG2, ADA, PTPRC,

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	CD45, LCA, IL7R, CD3D, T3D, IL2RG, SCIDX1, SCIDX, IMD4).
Metabolic, liver, kidney and protein diseases and disorders	Amyloid neuropathy (TTR, PALB); Amyloidosis (APOA1, APP, AAA, CVAP, ADI, GSN, FGA, LYZ, TTR, PALB); Cirrhosis (KRT18, KRT8, CIRH1A, NAIC, TEX292, KIAA1988); Cystic fibrosis (CFIR, ABCC7, CF, MRP7); Glycogen storage diseases (SLC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGE, GDE, GBE1, GYS2, PYGL, PFKM); Hepatic adenoma, 142330 (TCF1, HNF1A, M0DY3), Hepatic failure, early onset, and neurologic disorder (SCOD1, SCO 1), Hepatic lipase deficiency (LIPC), Hepatoblastoma, cancer and carcinomas (CTNNB1, PDGFRL, PDGRL, PRLTS, ΑΧΙΝΕ AXIN, CTNNB1, TP53, P53, LFS1, IGF2R, MPRI, MET, (ASPS, MCH5; Medullary cystic kidney disease (UMOD, HNFJ, FJHN, MCKD2, ADMCKD2); Phenylketonuria (PAH, PKU1, QDPR, DHPR, PTS); Polycystic kidney and hepatic disease (FCYT, PKHD1, ARPKD, PKD1, PKD2, PKD4, PKDTS, PRKCSH, G19P1, PCI I). SEC63).
Muscular / Skeletal diseases and disorders	Becker muscular dystrophy (DMD, BMD, MYF6), Duchenne Muscular Dystrophy (DMD, BMD); Emery-Dreifuss muscular dystrophy (LMNA, LMN1, EMD2, FPLD, {AID IA 11GPS, LGMD1B, LMNA, LMN1, EMD2, FPLD, CMD1A); Facioscapulohumeral muscular dystrophy (FSHMD1A, FSHD1A); Muscular dystrophy (FKRP, MDC1C, LGMD2I, LAMA2, LAMM, LARGE, KIAA0609, MDCID, FCMD, TTID, MYOT, CAPN3, CANP3, DYSF, LGMD2B, SGCG, LGMD2C, DMDA1, SCG3, SGCA, ADL, DAG2, LGMD2D, DMDA2, SGCB, LGMD2E, SGCD, SGD, LGMD2F, CMD1L, TCAP, LGMD2G, CMD1N, TRIM32, HT2A, LGMD2H, FKRP, MDC 1C, LGMD2I, TTN, CMD1G, TMD, LGMD2J, POMT1, CAV3, LGMD1C, SEPN1, SEEN, RSMD1, PLEC1, PLTN, EBS1); Osteopetrosis (LRP5, BMND1, LRP7, LR3, OPPG, VBCH2, CLCN7, CLC7, OPTA2, OSTML GL, TCIRG1, TIRC7, 0016, OPTB1); Muscular atrophy (VAPB, VAPC, ALS8, SMN1, SMA1, SMA2, SMA3, SMA4, BSCL2, SPG17, GARS, SMAD1, CMT2D, HEXB, IGHMBP2, SMUBP2, CATF1, SMARD1).
Neurological and neuronal diseases and disorders	ALS (SODI, ALS2, STEX, FUS, TARDBP, VEGF (VEGF-a, VEGF-b, VEGF-c); Alzheimer disease (APP, AAA, CVAP, ADI, APOE, AD2, PSEN2, AD4, STM2, APBB2, FE65L1, NOS3, PLAU, URK, ACE, DCP1, ACE1, MPO, PACIP1, PAXIP1L, PTIP, A2M, BLMH, BMH, PSEN1, AD3); Autism (Mecp2, BZRAP1, MDGA2, SemaSA, Neurexin I, GL01, MECP2, RTT, PPMX, MRXI6, MRX79, NLGN3, NLGN4, ΚΙΛΑ 1260, AUTSX2); Fragile X Syndrome (FMR2, FXR1, FXR2, mGLUR5); Huntington’s disease and disease like disorders (HD, IT15, PRNP, PRIP, JPH3, JP3, HDL2, TBP, SCA 17); Parkinson disease (NR4A2, NURR.1, NOT, T1NUR, SNCAIP, TBP, Si A17, SNCA, NACP, PARK1, PARK4, DJI, PARK7, LRRK2, PARKS, PINK 1, PARK6, UCHL1, PARKS, SNCA, NACP, PARK i, PARK. 4, PRKN,

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	PARK2, PDJ, DBH, NDUFV2); Rett syndrome (MECP2, RTT, PPMX, MRX16, MRX79, CDKL5, STK9, MECP2, RTT, PPMX, MRX16, MRX79, x-Synuclein, DJ-1); Schizophrenia (Neuregulinl (Nrgl), Erb4 (receptor for Neuregulin), Complexinl (Cplxl), Tphl Tryptophan hydroxylase, Tph2, Tryptophan hydroxylase 2, Neurexin 1, GSK3, GSK3a, GSK3b, 5-HTT (Skoal)' COMT, DRD (Drdla), SLC6A3, DAOA, DTNBP1, Dao (Daol)); Secretase Related Disorders (APH-1 (alpha and beta), Presentlin (Psenl), nieastrin, (Ncstn), PEN-2, Nosl, Parpl, Natl, Nat2); Trinucleotide Repeat Disorders (HTT (Huntington’s Dx), SBMA/SMAX1/AR (Kennedy’s Dx), FXN/X25 (Friedrich’s” Ataxia), ATX3 (Machado- Joseph’s Dx), ATXN1 and ATXN2 (spinocerebellar ataxias), DMPK (myotonic dystrophy), Atrophin-1 and Atnl (DRPI.A Dx), CBP (Creb-BP - global instability), VLDLR (Alzheimer’s), Atxn7, AtxnlO).
Occular diseases and disorders	Age-related macular degeneration (Abcr, Ccl2, Cc2, cp (ceruloplasmin), Timp3, cathepsinD, Vldlr, Ccr2); Cataract (CRYAA, CRYA1, CRYBB2, CRYB2, PITX3, BFSP2, CP49, CP47, CRYAA, CRYAI, PAX6, AN2, MGDA, CRYBA1, CRYB1, CRYGC, CRYG3, CCL, LIM2, MP 19, CRYGD, CRYG4, BFSP2, CP49, CP47, HSF4, CTM, HSF4, CTM, MIP, AQP0, CRYAB, CRYA2, CTPP2, CRYBB1, CRYGD, CRYG4, CRYBB2, CRYB2, CRYGC, CRYG3, CCL, CRYAA, CRYAI, GJA8, CX50, CAEI, GJ A3, CX46, CZP3, CAE3, CCM1, CAM, KRITl); Corneal clouding and dystrophy (APOA1, TGFBI, CSD2, CDGG1, CSD, BIGH3, CDG2, TACSTD2, TROP2, M1S1, VSX1, RINX, PPCD, PPD, KTCN, COL8A2, FECD, PPCD2, P1P5K3, CFD); Cornea plana congenital (KERA, CNA2); Glaucoma (MYOC, TIGR, GLC1A, JOAG, GPOA, OP TN, GLC1E, FIP2, HYPE, NRP, CYP1B1, GLC3A, OPA1,' NTG, NPG, CYP1B1, GLC3A); Leber congenital amaurosis (CRB1, RP12, CRX, CORD2, CRD, RPGRIP1, LCA6, CORD9, RPE65, RP20, A1PL1, LCA4, GUCY2D, GUC2D, LCA1, CORD6, RDH12, LCA3), Macular dystrophy (ELOVL4, ADMD, STGD2, STGD3, RDS, RP7, PRPH2, PRPH, AVMD, AOFMD, VMD2).

[001350] [001351] Table C:

CELLULAR FUNCTION	GENES
ΡΪ3Κ/ΑΚΤ Signaling	PRKCE; ETGAM; ITGA5; EaKI; PRKAA2; EIF2AK2;
	PTEN; EIF4E; PRKCZ; GRK6; MARK E. TSC1; PLK1;
	AKT2; IKBKB, PIK3CA; CDK8, CDKN1B; NFKB2; BCL2;
	PIK3CB; PPP2R1A; MARKS; BCL2L1; MAPK3; TSC2;
	ITGA1; KRAS; EIF4EBP1; RELA; PRKCD; NOS3;
	PRKAAl; MAPK9; CDK2; PPP2CA; P1M1; ITGB7;
	YVVHAZ; ILK; TP53; RAF'1; IKBKG; RELB; DYRK1A;
	CDKN1A; TfGBl; MAP2K2; JAKE AKT1; JAK2; PIK3R1;

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	( HEK: PDPK1; PPP2R5C; CTNNB1; ΜΛΡ2Κ1; NFKB1;
	PAK3; ITGB3; CCND1; GSK3A; FRAP1; SFN; ITGA2;
	TTK; CSNK1A1; BRAF; GSK3B; AKT3; FOXO1; SGK;
	HSP90AA1; RPS6KB1
ERK/MAPK Signaling	PRKCE; ITGAM; ITGA5; HSPB1; IRAKI, PRKAA2;
	EIF2AK2, RAC1; RAP1A; TLN1, EIF4E; ELK 1; GRK6;
	ΜΑΡΚΕ RAC2; PLK1; AKT2; PIK3CA, CDK8; GREBE
	PRKCI; PTK2, FOS; RPS6KA4; PIK3CB; PPP2R1A;
	PIK3C3; MARKS; MAPK3; ITGA1; EISI: KRAS; MYCN;
	EIF4EBP1; PPARG; PRKCD; PRKAA1; ΜΑΡΚΟ; SRC;
	CDK2; PPP2CA; PIM1; PIK3C2A; ITGB7; YWHAZ;
	PPP1CC; KSR1; PXN; RAF1; FYN; DYRK1A; ITGB1;
	MAP2K2; PAK4; PIK3R1; STAT3; PPP2R5C; MAP2K1;
	PAK3; ITGB3; ESRE ITGA2; MYC; TTK; CSNK1 Al;
	CRKL; BRAF; ATF4; PRKCA; SRF; STAFF. SGK
Glucocorticoid Receptor	RACl, TAF4B; EP300; SMAD2; TRAF6, PCAF; ELK1;
Signaling	MAPK1; SMAD3; AKT2; IKBKB, NCOR2; UBE2I;
	PIK3CA; CREB1; FOS; HSPA5; NFKB2; BCL2;
	MAP3K14; STAT5B; PIK3CB; PIK3C3; MAPK8; BCL2L1;
	MAPK3; TSC22D3; MAPK 10: NRIP1; KRAS; MAPK13;
	RELA; STAT5A; MAPK9; NOS2A; PBX1; NR3C1;
	PIK3C2A; CDKNIC; TRAF2; SERPINEl; NCOA3;
	MAPK 14; TNF; RAF1; IKBKG; MAP3K7; CREBBP;
	CDKN1A; ΜΆΡ2Κ2; JAKE IL8; NCOA2; AKT1, JAK2,
	PIK3R1; CHUK; STAT3; MAP2K1, NFKB1, TGFBR1;
	ESR1, SMAD4; CEBPB; JUN; AR; AKT3; CC1.2: MMRI:
	STATE IL6, HSP90AA1
Axonal Guidance Signaling	PRKCE; ITGAM: ROCK 1; ITGA5; C.XCR.4; ADAM 12;
	IGF1; RAC1; RAP1A; EIF4E, PRKCZ; NRP1, NTRK2;
	ARHGEF7; SMO ROCK 2: MAPK P. PGF; RAC2;
	PTPNI1; GNAS; AKT2, PIK3CA; ERBB2, PRKCI; PTK2;
	CFL1; GNAQ; PIK3CB; CXCL12; PIK3C3; WNT11;
	PRKD1; GNB2LE ABLE MAPK3; ITGA1; KRAS; RHOA;
	PRKCD; PIK3C2A; ITGB7; GLI2; PXN; VASP; RAPE
	FYN; ITGB1; MAP2K2; PAK4; ADAM17; AKT1; PIK3R1;
	GLU; WNT5A; ADAM10; MAP2K1; PAK3; ITGB3;
	CDC42; VEGFA; ITGA2, EPHA8; CRKL; RND1; GSK3B;
	AKT3; PRKCA
Ephrin Receptor Signaling	PRKCE; ITGAM; ROCKI; ITGA5; CXCR4; IRAKI;
	PRKAA2; EIF2AK2; RACE RAP!A; GRK6; ROCK2;
	MAPKi; PGF; RAC 2; PTPNI E GNAS; PLK1, AKT2;
	DOK1; CDK8; CREB1, PTK2; CFL1, GNAQ; MAP3KI4;

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	CXCL12; MAPK8; GNB2L1; ABL1; MAPK3; ITGA1;
	KRAS; RHOA; PRKCD; PRKAAi; MAPK9; SRC; CDK2;
	PIM1; ITGB7; PXN; RAF1; FYN; DYRK1A; ITGB1;
	MAP2K2; PAK4; AKT1; JAK2; STATS; ADAM10;
	MAP2K1; PAK3; ITGB3; CDC42; VEGFA; ITGA2,
	EPHA8; TTK; CSNK1A1; CRKL; BRAF; PTPNI 3; ATF4;
	AKT3; SGK
Actin Cytoskeleton	ACTN4; PRKCE, ITGAM; ROCK1; ITGA5; IRAKI;
Signaling	PRKAA2; EIF2AK2; RAC1; INS; ARHGEF7; GRK6;
	ROCK2; MAPK1; RAC'2; PLK1; AKT2; PIK3CA; CDK8;
	PTK2; CELL PIK3CB; ΜΥΉ9; DIAPH1; PIK3C3; MAPK8;
	F2R; MAPK3; SLC9AI; ITGA1; KRAS; RHOA; PRKCD;
	PRKAAi; MAPK9; CDK2; PIM1; PIK3C2A; ITGB7;
	PPP1CC; PXN; VIL2; RAF1; GSN; DYRK1A; ITGB1;
	MAP2K2; PAK4; PIP5K1A; PIK3R1, MAP2K1; PAK3;
	ITGB3; CDC42, APC; ITGA2; TTK; CSNK1A1; CRKL;
	BRAF; VAV3; SGK
Huntington’s Disease	PRKCE, IGF1; EP300; RCOR1; PRKCZ; HDAC4; TGM2;
Signaling	MAPK1; CAPNS1; AKT2; EGFR; NCOR2; SP1; CAPN2;
	PIK3CA; HDACS; CREB1; PRKCI; HSPA5; REST;
	GNAQ; PIK3CB; PIK3C3; MAPK8; IGFIR; PRKDi;
	GNB2LI; BCL2L1; CAPN1; MAPK3; CASP8; HDAC2;
	HDAC7A; PRKCD; HDACI1; MAPK9; HDAC9; PIK3C2A;
	HDAC3; TP53; CASP9; CREBBP; AKT1; PIK3R1;
	PDPK1, CASP1; APAF1; FRAP1; CASP2; JUN; BAX;
	ATF4; AKT3; PRKCA; CLTC, SGK; HDAC6, CASP3
Apoptosis Signaling	PRKCE, ROCK1, BID; IRAKI; PRKAA2; EIF2AK2; BAK1;
	BIRC4; GRK6; MAPKI; CAPNS1; PLK1; AK4 2: IKBKB;
	CAPN2; CDK8; FAS; NFKB2; BCL2; MAP3K14; MAPK8;
	BCL2L1; CAPN1; MAPK3; CASP8; KRAS; RELA;
	PRKCD; PRKAAI; MAPK9; CDK2; PIM1; TP53; TNF;
	RAF1; IKBKG; RELB; CASP9; DYRK1A; MAP2K2;
	CHUK; APAF1; MAP2K1; NFKB1; PAK3, LMNA; CASP2;
	BIRC2; TTK, CSNK1A1; BRAF; BAX, PRKCA, SGK;
	CASP3; BER.C3; PARP1
B Cell Receptor Signaling	RAC1, PTEN; LYN, ELK1; MAPKI; RAC2; PTPNI 1;
	AKT2; IKBKB, PIK3CA; CREB1, SYK; NFKB2; CAMK2A;
	MAP3K14; PIK3CB, PIK3C3, MAPK8; BCL2L1, ABL1;
	MAPK3; ETS1; KRAS; MAPK13; RELA; PTPN6; MAPK9;
	EGR1; PIK3C2A; BTK; MAPKI4; RAF1; IKBKG, RELB;
	MAP3K7; MAP2K2; AKT1; PIK3R1; CHUK; ΜΛΡ2Κ1;
	NFKB1; CDC42; GSK3A; FRAP1; BCL6; BCL10; JUN;
	GSK3B; ATF4; AKT3; VAV3; RPS6KB1

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Leukocyte Extravasation	ACTN4; ¢1)44: PRKCE; ITGAM; ROCK1; CXCR4; CYBA;
Signaling	RAC1; RAP1A; PRKCZ; ROCK2; RAC2; PTPNI 1;
	MMP14; PIK3CA; PRKCI; PTK2; PIK3CB; CXCL12;
	PIK3C3; MAPK8; PRKD1; ABL1; MAPK10; CYBB;
	MAPK13; RHOA; PRKCD; MAPK9, SRC, PIK3C2A; BTK,
	MARK 14; NOXI; PXN; VIL2; VASP; ITGB1; MAP2K2;
	CTNND1; PIK3R1; CTNNB1; CLDN1; CDC42; FUR, ΪΤΚ;
	CRKL, VAV3, CTTN; PRKCA; MMP1; MMP9
Integrin Signaling	ACTN4; ITGAM; ROCK 1; ITGA5; RAC1; PTEN; RAP1A;
	TEN 1; ARHGEF7; MAPK1; RAC2; CAPNS1; AKT2;
	CAPN2; PIK3CA; PTK2; PIK3CB; PIK3C3; MAPK8;
	CAV1; CAPN1; ABL1; MAPK3; ITGA1; KRAS; RHOA;
	SRC; PIK3C2A; ITGB7; PPP1CC; ILK; PXN; VASP;
	RAF1; FYN, ITGB1, MAP2K2; PAK4; AKT1; PIK3R1;
	TNK2; MAP2K1; PAK3, ITGB3; CDC42; RND3, ITGA2;
	CRKL; BRAE GSK3B; AKT3
Acute Phase Response	IRAKI; 8()1)2: MYD88; TRAF6; ELK1; MAPK1; PTPNI 1;
Signaling	AKT2; IKBKB; PIK3CA; FOS; NFKB2; MAP3K14;
	PIK3CB; MAPK8; RIPK1; MAPK3; HAST; KRAS;
	MAPK13; IL6R; RELA; S0CS1; MAPK9; 1-14.: NR3C1;
	TRAF2; SERPINEi; MAPK14; TNF; RAF1; PDK1;
	IKBKG; RELB; MAP3K7; MAP2K2; AKT1; JAK2; PIK3RI;
	CHUK; STATS; MAP2K1; NFKB1; FRAP1; CEBPB; JUN;
	AKT3; IE! R!. IL6
PTEN Signaling	ITGAM; ITGA5; RACE PTEN, PRKCZ; BCL2L11,
	MAPK1; RAC'2. AKT2; EGFR; IKBKB; ('BE; PIK3CA;
	CDKN1B, PTK2; NFKB2; BCL2; PIK3CB; BCL2LI,
	MAPK3; ITGA1; KRAS; ITGB7; ILK; PDGFRB; INSR;
	RAH: IKBKG; CASP9; CDKN1A; ITGB1; MAP2K2;
	ANTE PIK3R1; CHUK; PDGFRA: PDPK1; MAP2K1;
	NFKB1; ITGB3; CDC42; CCND1; GSK3A; ITGA2;
	GSK3B; AKT3; FOXO1; CASP3; RPS6KB1
p53 Signaling	PTEN, EP300, BBC3, PCAF; FASN, BRCA1; GADD45A;
	BIRC5; AKT2; PIK3CA, CHEK1; TP53INP1; BCL2,
	PIK3CB; P1K3C3; MAPK8; THBS1; ATR; BCL2L1, E2F1;
	PMAIPI; CHEK2; TNFRSF10B; TP73; RBI; HDAC9;
	CDK2; PIK3C2A; MAPK14; TP53; LRDD; CDKN1A;
	HIPK2; AKTl; PIK3R1; RRM2B; APAF1; CTNNB1;
	SIRT1; CCND1; PRKDC; ATM; SEN; CDKN2A; JUN;
	SNAI2; GSK3B; ΒΑΧ; AKT3
Aryl Hydrocarbon Receptor	HSPB1; EP300; FASN; TGM2; RXRA; MAPK1; NQO1;
Signaling	NCOR2; SP1; ARNE CDKN1B; FOS; CHEK1;
	SMARCA4; NFKB2; MAPK8; ALDH1A1; ATR; E2F1;

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	MAPK3; NRIP1; CHEK2; RELA; TP73; GSTP1; RBI;
	SRC; CDK2; AHR; NFE2L2; NCOA3; TP53; TNF;
	CDKN1A; NCOA2; APAF1; NFKB1; CCND1; ATM; ESR1;
	CDKN2A; MYC; JUN; ESR2; BAX; IL6; CYP1B1;
	HSP90AA1
Xenobiotic Metabolism	PRKCE; EP300; PRKCZ, RXRA; MAPK1, NQO1,
Signaling	NCOR2; PIK3CA; ARNT, PRKCI; NFKB2; CAMK2A;
	PIK3CB; PPP2RI A; PIK3C3; MAPK8; PRKD1,
	ALDH1A1; MAPK3; NRIP1; KRAS; MAPK13; PRKCD;
	GSTP1; MAPK9; NOS2A; ABCB1; AHR; PPP2CA; FTL;
	NFE2L2; PIK3C2A; PPARGC1A; MAPK14; TNF; RAFl;
	CREBBP; MAP2K2; PIK3R1; PPP2R5C; MAP2K1;
	NFKB1; KEAP1; PRKCA; EIF2AK3; IL6; CYP1B1;
	HSP90AA1
SAPK/JNK Signaling	PRKCE; IRAKI; PRKAA2; EIF2AK2; RACE ELK1;
	GRK6; MAPK1; GADD45A; RAC2; PLK1; AKT2; PIK3CA;
	FADE); CDK8; PIK3CB; P1K3C3; MAPK8, R1PK1;
	GNB2L1; IRS1; MAPK3; MAPK10; DAXX; KRAS;
	PRKCD; PRKAA1; ΜΑΡΚΑ CDK2; PIM1; PIK3C2A;
	TRAF2; TP53; LCK; MAP3K7; DYRK1A; MAP2K2;
	PIK3R1; MAP2K1; PAK3; CDC42; JUN; TTK; CSNKIA1;
	CRKL; BRAF; SGK
PPAr/RXR Signaling	PRKAA2; EP300; INS; SMAD2; TRAF6; PPARA; FASN;
	RXRA; MAPK 1; SMAD3; GNAS, IKBKB; NCOR2;
	ABCA1; GNAQ; NFKB2, MAP3K14; STAT5B; MAPK8;
	IRS1; MAPK3; KRAS; RELA; PRKAA1, PPARGC1A;
	NCOA3; MAPK14; 1NSR, RAFl; 1KBKG; RELB; MAP3K7;
	CREBBP; MAP2K2; JAK2; CHUK; MAP2K1; NFKB1;
	TGFBR1; SMAD4; JUN; IL1R1; PRKCA; IL6; HSP90AA1;
	ADIPOQ
NF-KB Signaling	IRAKI; EFF2AK2; EP300; INS; MYD88; PRKCZ; TRAF6;
	TBKI; AKT2; EGFR; IKBKB; PIK3CA; BTRC; NFKB2;
	MAP3K14, PIK3CB; PIK3C3; MAPK8, RIPK1; HDAC2;
	KRAS; RELA; PIK3C2A; TRAF2, TLR4, PDGFRB; TNF;
	INSR; LCK; 1KBKG; RELB; MAP3K7; CREBBP; AKTL
	PIK3R1; CHUK; PDGFRA; NFKB1; TLR2; BCL10;
	GSK3B; AKT3; TNFAIP3; IL1R1
Neuregulin Signaling	ERBB4; PRKCE; iTGAM; ITGA5; PTEN; PRKCZ; ELK1;
	M APK 1; PTPN11; AKT2; EGFR; ERBB2; PRKCI;
	CDKN1B; STAT5B; PRKD1; MAPK3; ITGAI; KRAS;
	PRKCD; STAT5A; SRC; ITGB7; RAFl; ITGB1; MAP2K2;
	ADAM 17; AKT1; PIK3R1; PDPK1; MAP2K1; ITGB3;
	EREG; FRAP1; PSEN1, ITGA2; MYC, NRG1; CRKL;
	AKT3; PRKCA; HSP90AA1; RPS6KB1

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Writ & Beta catenin	CD44; EP300; LRP6; DVL3; CSNK1E; GJA1; SMQ;
Signaling	AKT2; ΡΙΝΙ; CDH1; BTRC; GNAQ; MARK2; PPP2R1A;
	WNT11; SRC; DKKI; PPP2CA; SOX6; SFRP2; ILK;
	LEF1; SOX9; TP53; MAP3K7; CREBBP; TCF7L2; AKT1;
	PPP2R5C, WNT5A; LRP5, CTNNB1; TGFBR1, CCND1,
	GSK3A; DVL1; APC; CDKN2A, MYC; CSNK1A1; GSK3B;
	AKT3; SOX2
Insulin Receptor Signaling	PTEN, INS; EIF4E, PTPN1; PRKCZ, MAPKI; TSC1;
	PTPN11; AKT2; CBL, PIK3CA; PRKCI, P1K3CB; PIK3C3;
	MARKS: IRSI; MAPK3; TSC2; KRAS; EIF4EBP1;
	SLC2A4; PIK3C2A; PPP1CC; INSR; RAF1; FYN;
	MAP2K2; JAK1; AKT1, JAK2; P1K3R1; PDPK1, MAP2K1;
	GSK3A; FRAP1; CRKL; GSK3B; AKT3; FOXO1; SGK;
	RPS6KB1
IL-6 Signaling	HSPB1; TRAF6; MAPKAPK2; ELK1; MAPKI; PTPN11;
	IKBKB; FOS; NFKB2; MAP3K14; MAPK8; MAPK3;
	MARK 10; IL6ST; KRAS; MARK 13; IL6R; RELA; SOCS1;
	MAPK9; ABCB1; TRAF2, MARK 14; TNF; RAF1; IKBKG;
	RELB; MAP3K7; MAP2K2; ILS; JAK2; CHUK; STAT3,
	MAP2K1; NFKB1; CEBPB; JUN; ILIRl; SRF; IL6
Hepatic Cholestasis	PRKCE; IRAKI; INS; MYD88; PRKCZ; TRAF6; PPARA,
	RXRA; IKBKB; PRKCI; NFKB2; MAP3K14; MAPK8;
	PRKD1; MARK 10; RELA; PRKCI); ΜΑΡΚΑ ABC Bi:
	TRAF2; TLR4; TNF; INSR; IKBKG; RELB; MAP3K7; ILS;
	CHUK; NR1H2; TJP2; NFKB1; ESRI; SREBF1; FGFR4;
	JUN; IL1RI; PRKCA; IL6
IGF-1 Signaling	IGF'1, PRKCZ; ELK 1, MAPKI; PTPN11; NEDD4; AKT2;
	PIK3CA; PRKCI, PTK2; FOS, P1K3CB; PIK3C3; MAPK8,
	IGF1R; IRSI; MAPK3; IGFBP7, KRAS, P1K3C2A;
	YWHAZ; PXN; RAH. CASP9, MAP2K2; AKT1, PIK3R1;
	PDPK1, MAP2K1; IGFBP2; SFN; JUN; CYR61; AKT3;
	FOXO1; SRI·; CTGF; RPS6KB1
NRF'2-mediated Oxidative	PRKCE; EP300; SOD2; PRKCZ; MAPKI; SQSTM1;
Stress Response	NQO1, PIK3CA; PRKCI, FOS; PIK3CB; PIK3C3; MAPK8;
	PRKD1; MAPK3; KRAS; PRKCD; GSTP1; MAPK9; FTL;
	NFE2L2; PIK3C2A; MAPKI4; RAF1; MAP3K7; CREBBP;
	MAP2K2; AKT1; PIK3R1; MAP2K1; PPIB; JUN; KEAP1;
	GSK3B; ATF4; PRKCA; EIF2AK3; HSP90AA1
Hepatic Fibrosis/Hepatic	EDN1; IGF1; KDR; FLT1; SMAD2; FGFR1; MET; PGF;
Stellate Cell Activation	SMAD3, EGFR; FAS; CSF1; NFKB2; BCI.2; MYIT9;
	IGF1R; IL6R; RELA; TLR4, PDGFRB; TNF; RELB, IL8;
	PDGFRA; NFKB1; TGFBR1; SMAD4; VEGFA; BAX;

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	IL1R1; CCL2; HGF; MMP1; STAT1; IL6; CTGF; MMP9
PPAR Signaling	EP300; INS; TRAF6; PPARA; RXRA; MAPK1; IKBKB;
	NCOR2; FOS; NFKB2; MAP3K14; STAT5B; MAPK3;
	NRIPI; KRAS; PPARG; RELA; ST ATS A; TRAF2;
	PPARGC1 A, PDGFRB; TNF; INSR, RAF1; IKBKG;
	RELB; MAP3K7; CREBBP; MAP2K2; CHUK; PDGF'RA;
	MAP2K1; NFKB1; JUN; IL1R1; HSP90AA1
Fc Epsilon RI Signaling	PRKCE; RACE PRKCZ; LYN; MAPK1; RAC2; PTPN11,
	AKT2; P1K3CA; SYK; PRKCI; PIK3CB; PIK3C3; MAPK8;
	PRKD1; MAPK3; MAPK10; KRAS; M APK1.L PRKCD;
	MAPK9; PIK3C2A; BTK; MAPK14; TNF; RAFT; FYN;
	MAP2K2; AKTI; PIK3R1; PDPK1; MAP2K1; AKT3;
	VAV3; PRKCA
G-Protein Coupled	PRKCE, RAPi A; RGSI6; MAPK1; GY AS: AKT2, IKBKB;
Receptor Signaling	PIK3CA; CREB1, GNAQ; NFKB2; CAMK2A; PIK3CB,
	PIK3C3; MAPK3; KRAS, RELA; SRC; PIK3C2A; RAFT;
	IKBKG; RELB; FYN; MAP2K2, AKTI: PIK3R1, CHUK,
	PDPK1, STAT3; MAP2K1; NFKB1; BRAF; ATF4; AKT3;
	PRKCA
Inositol Phosphate	PRKCE; IRAKI; PRKAA2; EIF2AK2; PTEN; GRK6;
Metabolism	MAPK1; PLK1; AKT2; PIK3CA; CDK8; PIK3CB; PIK3C3;
	MAPK8; MAPK3; PRKCD; PRKAA1; MAPK9; CDK2;
	PIM1; PIK3C2A; DYRKIA; MAP2K2; PIP5K1A; PIK3R1;
	MAP2K1; PAK3; ATM, TTK; CSNK1A1, BRAF; SGK
PDGF Signaling	EIF2AK2; ELK1; ABL2, MAPK1; PIK3CA; FOS; PIK3CB;
	PIK3C3; M APK8; CAV1; ABL1; M APK3; KRAS; SRC;
	PIK3C2A; PDGFRB; RAF1; MAP2K2; JAK1; JAK2;
	PIK3R1; PDGFRA; STAT3; SPHK1; MAP2K1; MYC;
	JUN; CRKL; PRKCA; SRF; S' TA T1; SPHK2
VEGF Signaling	ACTN4; ROCK 1; KDR; FLT1; ROCK2; MAPK1; PGF;
	AKT2; PIK3CA; ARNT; PTK2; BCL2; PFK3CB; PIK3C3;
	BCL2L1; MAPK3; KRAS; HFF1A; NOS3; PIK3C2A; PXN;
	RAF I; MAP2K2; ELAVL1; AKTI; PIK3R1; MAP2K1, SEN;
	VEGF A; AKT3; FOXO1; PRKCA
Natural Killer Cell Signaling	PRKCE; RACE PRKCZ; MAPK1; RAC2, PTPN11,
	KIR2DL3; AKT2; PIK3CA; SYK; PRKCI; PIK3CB;
	PIK3C3, PRKD1; MAPK3; KRAS; PRKCD; PTPN6;
	PIK3C2A, LCK; RAFT: FYN, MAP2K2; PULL AKTI;
	PIK3R1; MAP2K1; ΡΛΚ3: AKT3; VAV3; PRKCA
Cell Cycle: Gl/S	HDAC4; SMAD3; SUV39H1; HDAC5; CDKN1B; BTRC,
Checkpoint Regulation	A TIL ABLE E2F1; HDAC2; HDAC7A; RBI; HDAC11;
	HDAC9; CDK2; E2F2; HDAC3; TP53; CDKN1A; CCND1;
	1121-4: ATM; RBL2; SMAD4; CDKN2A; MYC; NRG1;

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	GSK3B; RBL1; HDAC6
T Cell Receptor Signaling	RAC1; ELKI; MAPK1; IKBKB; CBL; PIK3CA; FOS;
	NFKB2; PIK3CB; PIK3C3; ΜΛΡΚ8: MAPK3; KRAS:
	RELA; PIK3C2A; BTK; LCK; RAFF IKBKG; RELB; FYN;
	MAP2K2; PIK3R1; CHEIK; ΜΛΡ2Κ1; NFKB1; ITK; BCL10;
	JUN; VAV3
Death Receptor Signaling	CRADD; HSPBi; BID; BIRC4; TBKi; IKBKB; FADD;
	FAS, NFKB2, BCL2; MAP3K14; MAPK8; RIPK1; CASP8;
	DAXX, TNFRSF10B; RELA; TRAF2; TNF; IKBKG; RELB,
	CASP9; CHUK; APAF1; NFKB'l; CASP2; BIRC2; CASP3;
	BIRC3
FGF Signaling	RAC1; FGFR1; MET, MAPKAPK2, ΜΆΡΚΕ PTPNI1;
	AKT2; PIK3CA; GREBE PIK3CB; PIK3C3; MAPK8;
	MAPK3; MAPK13; PTPN6; PIK3C2A; MAPK14; RAFT;
	AKT1; PIK3R1; STATS; MAP2K1; FGFR4; CRKL; ATF4;
	AKT3; PRKCA; HGF
GM-CSF Signaling	LYN; ELKi; MAPK1; PTPNI1; AKT2; PIK3CA; CAMERA;
	STAT5B; PIK3CB; PIK3C3; GNB2L1, BCL2L1; MAPK3,
	ETS1; KRAS; RUNX1; PIM1; PIK3C2A; RAPE MAP2K2;
	ΛΚΤΕ JAK2; P1K3R1; STATS; MAP2K1; CCND1, AKT3;
	STAT1
Amyotrophic Lateral	BID; IGF1; RAC1; BIRC4; PGF; CAPNS1; CAPN2;
Sclerosis Signaling	PIK3CA; BCL2; PIK3CB; PIK3C3; BCL2L1; CAPN1;
	PIK3C2A; TP53; CASP9; PIK3R1; RAB5A; CASP1;
	APAF1; VEGF A; BIRC2; ΒΑΧ; AKT3; CASP3; BIRC3
JAK/Stat Signaling	PTPNi; MAPK1; PTPNI 1; AKT2; PIK3CA; STAT5B;
	PIK3CB; PIK3C3; MAPK3; KRAS; SOCSi; STAT5A;
	PTPN6; PIK3C2A, RAF!; CDKN1A; MAP2K2, JAK1,
	AKT1, JAK2; PIK3R1; STATS; MAP2K1; FRAP1; AKT3;
	STAT1
Nicotinate and Nicotinamide	PRKCE; IRAKI; PRKAA2; EIF2AK2; GRK6; MAPK1;
Metabolism	PLK1; AKT2; CDK8; MAPK8; MAPK3; PRKCD; PRKAA1,
	PBEF1, M APK9; CDK2; PIM1; DYRK1A; MAP2K2;
	MAP2K1; PAK3; NT5E; TTK; CSNK1 Al; BRAF, SGK
Chemokine Signaling	CXCR4; ROCK2; ΜΑΡΚΕ PTK2; FOS; CFL1; GNAQ;
	CAMK2A; CXCL12; MAPK8; MAPK3; KRAS; MAPK13;
	RHOA; CCR3; SRC; PPP1CC; MAPK14; NOX1; RAF 1;
	MAP2K2; MAP2K1; JUN; CCL2; PRKCA
IL-2 Signaling	ELKI; MAPK1; PTPNi 1; AKT2; PIK3CA; SYK; FOS;
	STAT5B; PIK3CB; PIK3C3; MAPK8; MAPK3; KRAS;
	SOCSI; STAT5A; PIK3C2A, LCK; RAF1; MAP2K2,
	JAK1; AKT1; PIK3R1; MAP2K1; JUN, AKT3

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Synaptic Long Term	PRKCE; IGF 1; PRKCZ; PRDX6; LYN; MAPK 1; GN AS;
Depression	PRKCI; GNAQ; PPP2R1A; IGF1R; PRKDI; MAPK3;
	KRAS; GRN; PRKCD; NOSS; NOS2A; PPP2CA;
	YWHAZ; RAF1; MAP2K2; PPP2R5C; MAP2K1; PRKCA
Estrogen Receptor	TAF4B, EP300, CARMI; PCAF; MAPK1; NCOR2,
Signaling	SMARCA4, MAPK3; NRIP1, KRAS, SRC; NR3C1;
	HDAC3; PPARGC1A, RBM9; NCOA3; RAF1; CREBBP;
	MAP2K2; NCOA2, MAP2K1; PRKDC; ESR1; ESR2
Protein Ubiquitination	TRAF6; SMURF 1; BIRC4; BRCA1; UCHL1; NEDD4;
Pathway	CBL; UBE2I; BTRC; HSPA5; USP7; USP10; FBXW7;
	USP9X; STUB1; USP22; B2M; BIRC2; PARK2; USP8;
	USPI; VHL; HSP90AA1; BIRC3
IL-10 Signaling	TRAF6; CCR1; ELK1; IKBKB; SP1; FOS; NFKB2;
	MAP3K14; MAPK8; MAPK13; RELA, MAPK14; TNF;
	IKBKG; RELB; MAP3K7, JAK1, CHUK, STATS. NFKB!,
	JUN; IL1R1, IL6
VDR/RXR Activation	PRKCE; EP300; PRKCZ, RXRA; GADD45A; HES1,
	NCOR2; SP1; PRKCI; CDKN1B; PRKDI; PRKCD,
	RUNX2; KLF4; YY1; NCOA3; CDKNT A; NCQA2; SPP1;
	LRP5; CEBPB; FOXO1; PRKCA
TGF-beta Signaling	EP300; SMAD2; SMURF'1; MAPK1; SMAD3; SMAD1;
	FOS; MAPK8; MAPK3; KRAS; MAPK9; RUNX2;
	SERPINE1; RAF I; MAP3K7; CREBBP; MAP2K2;
	MAP2K1; TGFBR1; SMAD4; JUN; SMAD5
Toll-like Receptor Signaling	IRAKI; EIF2AK2; MYD88; TRAF6; PPARA; ELK 1;
	IKBKB; FOS; NFKB2; MAP3K14; MAPK8; MAPK13;
	RELA; TLR4; MAPK14; IKBKG, RELB; MAP3K7, CHUK,
	NFKB1; TLR2; JEN
p38 MAPK Signaling	HSPB1; IRAKI; TRAF6; MAPKAPK2; ELK 1; FADD; FAS;
	CREB1; DDIT3; RPS6KA4; DAXX; MAPK 13; TRA.F2;
	MAPK14; TNF; MAP3K7; TGFBR1; MYC; ATF4; IL1R1;
	SRF; STAT1
N eurotrophin/TRK Signaling	NTRK2; MAPK1; PTPN11; PIK3CA; CREB1; FOS;
	PIK3CB, PIK3C3; MAPK8; MAPK3; KRAS; PIK3C2A;
	RAF'l; MAP2K2; AKT1; PIK3R1; PDPK1; MAP2K1;
	CDC42; JUN; ATF4
FXRZRXR Activation	INS; PPARA; F'ASN; RXRA; AKT2; SDC1; MAPK8;
	APOB; MAPK10; PPARG; MTTP; MAPK9; PPARGC1A;
	TNF; CREBBP; AKT1; SREBF1; FGFR4; AKT3; FOXO1
Synaptic Long Term	PRKCE, RAP1A; EP300, PRKCZ; MAPK 1. CREB1;
Potentiation	PRKCI; GNAQ; CAMK2A; PRKDI, MAPK3; KRAS;
	PRKCD; PPP1CC, RAF1; CREBBP; MAP2K2; MAP2K1,

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	ATF4; PRKCA
Calcium Signaling	RAPIA; EP300; HDAC4; MAPK1; HD ACS; CREBI;
	CAMK2A; MYH9; MAPK3; HDAC2; HDAC7A; HD AC 11;
	HDAC9; HDAC3; CREBBP; CALR; CAMKK2; ATF4;
	HDAC6
EGF Signaling	ELK I; MAPK1; EGFR; PIK3CA; FOS; PIK3CB; PIK3C3,
	MAPK8; MAPK3; PIK3C2A; RAF1; JAK1; PIK3RI;
	STAT3; MAP2K1; JEN: PRKCA; SRF, STAT1
Hypoxia Signaling in the	EDN1; PTEN; EP300; NQO1; UBE2I; CREBI; ARNT;
Cardiovascular System	f nil A; SLC2A4; NOS3; TP53; LDHA; AKIT; ATM;
	VEGFA; JUN; ATF4; VHL; HSP90AA1
LPS/IL-1 Mediated Inhibition	IRAKI; MYD88; TRAF6; PPARA; RXRA; ABCAI;
of RXR Function	MAPK8; ALDH1A1; GS 1 Pl: MAPK9; ABCB1; TRAF'2;
	TLR4; TNF; MAP3K7; NR1H2; SREBFI; JUN; IL1R1
LXR/RXR Activation	FASN; RXRA; NCOR2; .ABCAI; NFKB2; IRF3; RELA;
	NOS2A; TLR4; TNF; RELB; LDLR; NR1H2; NFKB1;
	SREBFI; IL1R1; CCL2; IL6; MMP9
Amyloid Processing	PRKCE; CSNK1E; MAPK1; CAPNS1, AKT2; CAPN2;
	CAPN1; MAPK3; MAPK13; MAPT, MAPK14; AKT1;
	PSEN1; CSNK1AI, GSK3B, AKT3; APP
IL-4 Signaling	AKT2; PIK3CA; PIK3CB; PIK3C3; 1RS1; KRAS; SOCS1;
	PTPN6; NR3C1; PIK3C2A; JAK1; AKIT; JAK2; P1K3R1;
	FRAPI; AKT3; RPS6KB1
Cell Cycle: G2/M DNA	EP300; PCAF; BRCA1; GADD45A; PLK1; BTRC;
Damage Checkpoint	CHEK1; ATR; CHEK2; YWHAZ; TP53; CDKN1A;
Regulation	PRKDC; ATM; SFN; CDKN2A
Nitric Oxide Signaling in the	KDR; FLT1; PGF; AKT2; PIK3CA; PIK3CB; PIK3C3;
Cardiovascular System	CAV1; PRKCD; NOS3; PIK3C2A; AKT1; PIK3R1;
	VEGFA; AKT3; HSP90AA1
Purine Metabolism	NME2: SMARCA4; MYH9; RRM2; ADAR; EIF2AK4;
	PKM2; ENTPD1; RAD51, RRM2B; TJP2; RADS 1C;
	NT5E; POLD1; NME1
cAMP-mediated Signaling	RAPIA; ΜΑΡΚΕ GN AS: CREBI; CAMK2A; MAPK3;
	SRC; RAF1; MAP2K2; STAT3; MAP2K1; BRAF; ATF4
Mitochondrial Dysfunction	SOD2; MAPK8, CASP8; MAPK10; MAPK9; C ASP9;
	PARK7; PSEN1; PARK2; APP; CASP3
Notch Signaling	HES1; JAG1; NUMB; NOTCH4; ADAM17; NOTCH2;
	PSEN1; NOTCH3; NOTCHI; DLL4
Endoplasmic Reticulum	HSPA5, MAPK8; XBP1, TRAF2; ATF6; CASP9; ATF4,
Stress Pathway	EIF2AK3, CASP3
Pyrimidine Metabolism	NME2, A1CDA, RRM2; E1F2AK4; ENTPD1, RRM2B;

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	NT5E; POLD1; NME1
Parkinson’s Signaling	UCHLI; MAPK8; MAPKI3; MAPK14; CASP9; PARK?;
	PARK2; CASP3
Cardiac & Beta Adrenergic	GNAS; GNAQ; PPP2R1A; GNB2L1; PPP2CA; PPP1CC;
Signaling	PPP2R5C
Glycoly si s/Gluconeogene sis	HK2; GCK; GPI; ALDH1A1; PKM2; LDHA; HK1
Interferon Signaling	IRF'l; SOCS1; JAK1; JAK2; IFITMl; STATE IFIT3
Sonic Hedgehog Signaling	ARRB2; SMO; GLI2; DYRK1A; GLI1; GSK3B; DYRK1B
Glycerophospholipid	PLD1; GRN; GPAM; YWHAZ; SPHK1; SPHK2
Metabolism
Phospholipid Degradation	PRDX6; PLD1; GRN; YWHAZ; SPHK1; SPHK2
Tryptophan Metabolism	SIAH2; PRMT5, NEDD4; ALDH1A1; CYP1B1, SIAH1
Lysine Degradation	SUV39H1; EHMT2, NSD1, SETD7, PPP2R5C
Nucleotide Excision Repair	ERCC5; ERCC4; XPA; XPC; ERCC1
Pathway
Starch and Sucrose	UCHLI, HK2; GCK, GPI; HKI
Metabolism
Aminosugars Metabolism	NQO1; HK2; GCK; HKI
Arachidonic Acid	PRDX6; GRN; YWHAZ; CYP1B1
Metabolism
Circadian Rhythm Signaling	CSNK1E; CREB1; ATF4; NRID1
Coagulation System	BDKRB1; F2R; SERPINEl; F3
Dopamine Receptor	PPP2R1A; PPP2CA; PPP1CC; PPP2R5C
Signaling
Glutathione Metabolism	IDH2; GSTP1; ANPEP; IDH1
Glycerolipid Metabolism	ALDH1A1; GPAM, SPHK1; SPHK2
Linoleic Acid Metabolism	PRDX6; GRN; YWHAZ; CYP1B1
Methionine Metabolism	DNMT1; DNMT3B; AHCY; DNMT3A
Pyruvate Metabolism	GLO1, ALDH 1 Al; PKM2; LDHA
Arginine and Proline	AL Di11A1; NOS3; NOS2A
Metabolism
Eicosanoid Signaling	PRDX6; GRN; YWHAZ
Fructose and Mannose	HK2, GCK; HKI
Metabolism
Galactose Metabolism	HK2; GCK; HKI
Stilbene, Coumarine and	PRDX6; PRDX1; TYR
Lignin Biosynthesis
Antigen Presentation	CALR; B2M

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Pathway
Biosynthesis of Steroids	NQO1; DHCR7
Butanoate Metabolism	ALDH1A1; NLGNI
Citrate Cycle	IDH2; IDH1
Fatty Acid Metabolism	ALDH1A1, CYP1B1
Glycerophospholipid	PRDX6; CHKA
Metabolism
Histidine Metabolism	PRMT5; ALDH1A1
Inositol Metabolism	ERO1L; APEX1
Metabolism of Xenobiotics	GSTP1; CYP1B1
by Cytochrome p450
Methane Metabolism	PRDX6; PRDXI
Phenylalanine Metabolism	PRDX6; PRDX1
Propanoate Metabolism	ALDH1A1; LDHA
Selenoamino Acid	PRMT5, AHCY
Metabolism
Sphingolipid Metabolism	SPHK1; SPHK2
Aminophosphonate	PRMT5
Metabolism
Androgen and Estrogen	PRMT5
Metabolism
Ascorbate and Aldarate	ALDH1A1
Metabolism
Bile Acid Biosynthesis	ALDH1AI
Cysteine Metabolism	LDHA
Fatty Acid Biosynthesis	FASN
Glutamate Receptor	GNB2L1
Signaling
NRF2-mediated Oxidative	PRDXI
Stress Response
Pentose Phosphate	GPI
Pathway
Pentose and Glucuronate	UCHL1
Interconversions
Retinol Metabolism	ALDH1A1
Riboflavin Metabolism	TYR
Tyrosine Metabolism	PRMT5, TYR
Ubiquinone Biosynthesis	PRMT5
Valine, Leucine and	ALDH1A1
Isoleucine Degradation
Glycine, Serine and	CHKA
Threonine Metabolism

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Lysine Degradation	ALDH1A1
Pain/Taste	TRPM5; TRPA1
Pain	TRPM7; TRPC5; TRPC6; TRPC1; Cnrl; cnr2; Grk2;
	Trpal; Pome; Cgrp; Crf; Pka; Era; Nr2b; TRPM5; Prkaca;
	Prkacb; Prkarla, Prkar2a
Mitochondrial Function	AIF; CytC; SMAC (Diablo); Aifm~l; Aifm-2
Developmental Neurology	BMP-4; Chordin (Chrd); Noggin (Nog), WNT (Wnt2;
	Wnt2b; Wnt3a; Wnt4; Wnt5a; Wnt6; Wnt7b; Wnt8b;
	Wnt9a; Wnt9b; WntlOa; WntlOb; Wntl6); beta-catenin;
	Dkk-1; Frizzled related proteins; Otx-2; Gbx2; FGF-8;
	Reelin; Dahl, unc-86 (Pou4fl or Brn3a); Numb, Rein

[001352] Embodiments of the invention also relate to methods and compositions related to knocking out genes, amplifying genes and repairing particular mutations associated with DNA repeat instability and neurological disorders (Robert D. Wells, Tetsuo Ashizawa, Genetic Instabilities and Neurological Diseases, Second Edition, Academic Press, Oct 13, 2011 Medical). Specific aspects of tandem repeat sequences have been found to be responsible for more than twenty human diseases (New insights into repeat instability: role of RNA’DNA hybrids. Mclvor El, Polak U, Napierala M. RNA Biol. 2010 Sep-Oct;7(5):551-8). The present effector protein systems may be harnessed to correct these defects of genomic instability. [001353] Several further aspects of the invention relate to correcting defects associated with a wide range of genetic diseases which are further described on the website of the National Institutes of Health under the topic subsection Genetic Disorders (website at health.nih.gov/topic/GeneticDisorders). The genetic brain diseases may include but are not limited to Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Aicardi Syndrome, Alpers' Disease, Alzheimer's Disease, Barth Syndrome, Batten Disease, CADASIL, Cerebellar Degeneration, Fabry's Disease, Gerstmann-Straussler-Scheinker Disease, Huntington’s Disease and other Triplet Repeat Disorders, Leigh's Disease, Lesch-Nyhan Syndrome, Menkes Disease, Mitochondrial Myopathies and NINDS Colpocephaly. These diseases are further described on the website of the National Institutes of Health under the subsection Genetic Brain Disorders. Cash Development and Use [001354] The present invention may he further illustrated and extended based on aspects of CRISPR-Cas9 development and use as set forth in the following articles and particularly as

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PCT/US2016/038181 relates to delivery of a CRISPR protein complex and uses of an RNA guided endonuclease in cells and organisms:

> Multiplex genome engineering using CRISPR/Cas systems. Cong, L., Ran, F.A., Cox, D., Lin, S,, Barretto, R., Habib, N., Hsu, P.D., Wu, X., Jiang, W., Marraffini, L.A., & Zhang, F. Science Feb 15;339(6121):819-23 (2013);

> RNA-guided editing of bacterial genomes using CRISPR-Cas systems. Jiang W,, Bikard D., Cox D., Zhang F, Marraffini LA. Nat Biotechnol Mar;31(3):233-9 (2013);

> One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/CasMediated Genome Engineering. Wang H., Yang H., Shivalila CS., Dawlaty MM., Cheng AW., Zhang F., Jaenisch R. Cell May 9; 153(4):910-8 (2013);

> Optical control of mammalian endogenous transcription and epigenetic states. Konermann S, Brigham MD, Trevino AE, Hsu PD, Heidenreich M, Cong L, Platt RJ, Scott DA, Church GM, Zhang F. Nature. Aug 22,500(7463):472-6. doi: 10,1038,/Nature12466. Epub 2013 Aug 23 (2013);

> Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity. Ran, FA., Hsu, PD., Lin, CY., Gootenberg, JS., Konermann, S., Trevino, AE., Scott, DA., Inoue, A., Matoba, S., Zhang, Y., & Zhang, F. Cell Aug 28. pii: S0092-8674(13)01015-5 (2013-A);

> DNA targeting specificity of RNA-guided Cas9 nucleases. Hsu, P., Scott, D., Weinstein, J., Ran, FA., Konermann, S., Agarwala, V,, Li, Y., Fine, E,, Wu, X., Shalem, 0,, Cradick, TJ., Marraffini, LA., Bao, G., & Zhang, F. Nat Biotechnol doi: 10.1038/nbt.2647 (2013);

> Genome engineering using the CRISPR-Cas9 system. Ran, FA., Hsu, PD., Wright, J., Agarwala, V., Scott, DA., Zhang, F. Nature Protocols Nov;8(l 1):2281-308 (2013-B);

> Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells. Shalem, 0., Sanjana, NE., Hartenian, E., Shi, X., Scott, DA., Mikkelson, T., Heckl, D., Ebert, BE., Root, DE., Doench, JG., Zhang, F. Science Dee 12. (2013). [Epub ahead of print];

> Crystal structure of cas9 in complex with guide RNA and target DNA. Nishimasu, H., Ran, FA., Hsu, PD., Konermann, S., Shehata, SI., Dohmae, N., Ishitani, R., Zhang, F., Nureki, O. Cell Feb 27, 156(5):935-49 (2014);

> Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells. Wu X., Scott DA., Kriz AJ., Chiu AC., Hsu PD., Dadon DB., Cheng AW., Trevino AE., Konermann S.,

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Chen S., Jaenisch R, Zhang F., Shaip PA. Nat Biotechnol. Apr 20. doi: 10.103 8/nbt.2889 (2014);

> CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling. Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, Dahlman JE, Pamas O, Eisenhaure TM, Jovanovic

M, Graham DB, Jhunjhunwala S, Heidenreich M, Xavier RJ, Langer R, Anderson DG, Hacohen

N, Regev A, Feng G, Sharp PA, Zhang F, Cell 159(2): 440-455 DOI:

10.1016/j.cell.2014.09.014(2014);

> Development and Applications of CRISPR-Cas9 for Genome Engineering, Hsu PD, Lander ES, Zhang F., Cell. Jun 5;157(6):1262-78 (2014).

> Genetic screens in human cells using the CRISPR/Cas9 system, Wang T, Wei JJ, Sabatini DM, Lander ES,, Science. January 3; 343(6166): 80-84. doi :10.1126/science, 1246981 (2014);

> Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation, Doench JG, Hartenian E, Graham DB, Tothova Z, Hegde M, Smith I, Sullender M, Ebert BE, Xavier RJ, Root DE., (published online 3 September 2014) Nat Biotechnol. Dec;32(12): 1262-7 (2014);

> In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9, Swiech L, Heidenreich M, Baneqee A, Habib N, Li Y, Trombetta J, Sur M, Zhang F., (published online 19 October 2014) Nat Biotechnol. Jan;33(l): 102-6 (2015);

> Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex, Konermann S, Brigham MD, Trevino AE, Joung J, Abudayyeh OO, Barcena C, Hsu PD, Habib N, Gootenberg JS, Nishimasu H, Nureki O, Zhang F., Nature. Jan 29;517(7536):583-8 (2015).

> A split-Cas9 architecture for inducible genome editing and transcription modulation, Zetsche B, Volz SE, Zhang F., (published online 02 February⁷ 2015) Nat Biotechnol. Feb;33(2): 139-42 (2015);

> Genome-wide CRISPR Screen in a Mouse Model of Tumor Growth and Metastasis, Chen S, Sanjana NE, Zheng K, Shalem O, Lee K, Shi X, Scott DA, Song J, Pan JQ, Weissleder R, Lee H, Zhang F, Sharp PA. Cell 160, 1246-1260, March 12, 2015 (multiplex screen in mouse), and > In vivo genome editing using Staphylococcus aureus Cas9, Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O, Wu X, Makarova KS, Koonin EV, Sharp PA, Zhang F., (published online 01 April 2015), Nature. Apr 9;520(7546): 186-91 (2015).

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PCT/US2016/038181 > Shalem et al., “High-throughput functional genomics using CRISPR-Cas9,” Nature Reviews Genetics 16, 299-311 (May 2015).

> Xu et al., “Sequence determinants of improved CRISPR sgRNA design,” Genome Research 25, 1147-1157 (August 2015).

> Parnas et al., “A Genome-wide CRISPR Screen in Primary' Immune Cells to Dissect Regulatory⁷ Networks,” Cell 162, 675-686 (July 30, 2015).

> Ramanan et al., CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus,” Scientific Reports 5:10833. doi: 10.1038/srepl0833 (June 2, 2015) > Nishimasu et al., Crystal Structure of Staphylococcus aureus Cas9,” Cell 162, 1113-1126 (Aug. 27, 2015) > BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis, Canver et al., Nature 527(7577):192-7 (Nov. 12, 2015) doi: 10.1038/natureI5521. Epub 2015 Sep 16.

Cpfl Is a Single KNA-Guided Endonuclease of a Class 2 CRISPR-Cas System, Zetsche et al., Cell 163, 759-71 (Sep 25, 2015).

> Discovery and Functional Characterization of Diverse Class 2 CRISPR-Cas Systems, Shmakov et ak, Molecular Cell, 60(3), 385-397 doi: 10.1016.-).molcel.2015.10.008 Epub October 22, 2015.

> Rationally engineered Cash nucleases with improved specificity, Slaymaker et ak, Science 2016 Jan 1 351(6268): 84-88 doi: 10.1126/science.aad5227. Epub 2015 Dec I. [Epub ahead of print].

each of which is incorporated herein by reference, may be considered in the practice of the instant invention, and discussed briefly below:

> Cong et al. engineered type II CRISPR-Cas systems for use in eukaryotic cells based on both Streptococcus thermophilus Cas9 and also Streptococcus pyogenes Cas9 and demonstrated that Cas9 nucleases can be directed by short RNAs to induce precise cleavage of DNA in human and mouse cells. Their study further showed that Cas9 as converted into a nicking enzyme can be used to facilitate homology-directed repair in eukaryotic cells with minimal mutagenic activity. Additionally, their study demonstrated that multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several at endogenous genomic loci sites within the mammalian

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PCT/US2016/038181 genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology. This ability to use RNA to program sequence specific DNA cleavage in cells defined a new class of genome engineering tools. These studies further showed that other CRISPR loci are likely to be transplantable into mammalian cells and can also mediate mammalian genome cleavage. Importantly, it can be envisaged that several aspects of the CRISPR-Cas system can be further improved to increase its efficiency and versatility.

> Jiang et al. used the clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated Cas9 endonuclease complexed with dual-RNAs to introduce precise mutati ons in the genomes of Streptococcus pneumoniae and Escherichia coli. The approach relied on dual-RNA: Cas9~directed cleavage at the targeted genomic site to kill unmutated cells and circumvents the need for selectable markers or counter-selection systems. The study reported reprogramming dual-RNA:Cas9 specificity by changing the sequence of short CRISPR RNA (crRNA) to make single- and multinucleotide changes carried on editing templates. The study showed that simultaneous use of two crRNAs enabled multiplex mutagenesis. Furthermore, when the approach was used in combination with recombineering, in 5. pneumoniae, nearly 100% of cells that were recovered using the described approach contained the desired mutation, and in E. coli, 65% that were recovered contained the mutation.

> Wang et al. (2013) used the CRISPR-Cas system for the one-step generation of mice carrying mutations in multiple genes which were traditionally generated in multiple steps by sequential recombination in embryonic stem cells and/or time-consuming intercrossing of mice with a single mutation. The CRISPR-Cas system wall greatly accelerate the in vivo study of functionally redundant genes and of epistatie gene interactions.

> Konermann et al. (2013) addressed the need in the art for versatile and robust technologies that enable optical and chemical modulation of DNA-binding domains based CRISPR Cas9 enzyme and also Transcriptional Activator Like Effectors > Ran et al. (2013-A) described an approach that combined a Cas9 nickase mutant with paired guide RNAs to introduce targeted double-strand breaks. This addresses the issue of the Cas9 nuclease from the microbial CRISPR-Cas system being targeted to specific

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PCT/US2016/038181 genomic loci by a guide sequence, which can tolerate certain mismatches to the DNA target and thereby promote undesired off-target mutagenesis. Because individual nicks in the genome are repaired with high fidelity, simultaneous nicking via appropriately offset guide RNAs is required for double-stranded breaks and extends the number of specifically recognized bases for target cleavage. The authors demonstrated that using paired nicking can reduce off-target activity by 50- to 1,500-fold in cell lines and to facilitate gene knockout in mouse zygotes without sacrificing on-target cleavage efficiency. This versatile strategy enables a wide variety of genome editing applications that require high specificity.

> Hsu ei al. (2013) characterized SpCas9 targeting specificity in human cells to inform the selection of target sites and avoid off-target effects. The study evaluated >700 guide RNA variants and SpCas9-induced indel mutation levels at >100 predicted genomic off-target loci in 293T and 293FT cells. The authors that SpCas9 tolerates mismatches between guide RNA and target DNA at different positions in a sequence-dependent manner, sensitive to the number, position and distribution of mismatches. The authors further showed that SpCas9-mediated cleavage is unaffected by DNA methylation and that the dosage of SpCas9 and gRNA can be titrated to minimize off-target modification. Additionally, to facilitate mammalian genome engineering applications, the authors reported providing a web-based software tool to guide the selection and validation of target sequences as well as off-target analyses, > Ran et al. (2013-B) described a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified ceil lines for downstream functional studies. To minimize off-target cleavage, the authors further described a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. The protocol provided by the authors experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. The studies showed that beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks, > Shalem et al. described a new way to interrogate gene function on a genome-wide scale. Their studies showed that delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO)

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PCT/US2016/038181 library' targeted 18,080 genes with 64,751 unique guide sequences enabled both negative and positive selection screening in human cells. First, the authors showed use of the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, the authors screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic that inhibits mutant protein kinase BRAF. Their studies showed that the highest-ranking candidates included previously validated genes NF1 and MED 12 as well as novel hits NF2, CUL3, TADA2B, and TADA1. The authors observed a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, and thus demonstrated the promise of genome-scale screening with Cas9.

> Nishimasu et al. reported the crystal structure of Streptococcus pyogenes Cas9 in complex with sgRNA and its target DNA at 2.5 A° resolution. The structure revealed a bilobed architecture composed of target recognition and nuclease lobes, accommodating the sgRNA:DNA heteroduplex in a positively charged groove at their interface. Whereas the recognition lobe is essential for binding sgRNA and DNA, the nuclease lobe contains the HNH and RuvC nuclease domains, which are properly positioned for cleavage of the complementary and non-complementary strands of the target DNA, respectively. The nuclease lobe also contains a carboxyl-terminal domain responsible for the interaction with the protospacer adjacent motif (PAM). This high-resolution structure and accompanying functional analyses have revealed the molecular mechanism of RNAguided DNA targeting by Cas9, thus paving the way for the rational design of new, versatile genome-editing technologies.

> Wu et al. mapped genome-wdde binding sites of a catalytically inactive Cas9 (dCas9) from Streptococcus pyogenes loaded with single guide RNAs (sgRNAs) in mouse embryonic stem cells (mESCs). The authors showed that each of the four sgRNAs tested targets dCas9 to between tens and thousands of genomic sites, frequently characterized by a 5-nucleotide seed region in the sgRNA and an NGG protospacer adjacent motif (PAM). Chromatin inaccessibility decreases dCas9 binding to other sites with matching seed sequences; thus 70% of off-target sites are associated with genes. The authors showed that targeted sequencing of 295 dCas9 binding sites in mESCs transfected with catalytically active Cas9 identified only one site mutated above background levels. The

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PCT/US2016/038181 authors proposed a two-state model for Cas9 binding and cleavage, in which a seed match triggers binding but extensive pairing with target DNA is required for cleavage.

> Platt et al. established a Cre-dependent Cas9 knockin mouse. The authors demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells.

> Hsu et al. (2014) is a review article that discusses generally CRISPR-Cas9 history/ from yogurt to genome editing, including genetic screening of cells.

> Wang et al. (2014) relates to a pooled, loss-of-function genetic screening approach suitable for both positive and negative selection that uses a genome-scale lentiviral single guide RNA (sgRNA) library.

> Doench et al. created a pool of sgRNAs, tiling across all possible target sites of a panel of six endogenous mouse and three endogenous human genes and quantitatively assessed their ability to produce null alleles of their target gene by antibody staining and flow cytometry. The authors showed that optimization of the PAM improved activity and also provided an on-line tool for designing sgRNAs.

> Swiech et al. demonstrate that AAV-mediated SpCas9 genome editing can enable reverse genetic studies of gene function in the brain.

> Konermann el al. (2015) discusses the ability to attach multiple effector domains, e.g., transcriptional activator, functional and epigenomlc regulators at appropriate positions on the guide such as stem or tetraloop with and without linkers.

> Zetsche et al. demonstrates that the Cas9 enzyme can be split into two and hence the assembly of Cas9 for activation can be controlled.

> Chen et al. relates to multiplex screening by demonstrating that a genome-wide in vivo CRISPR-Cas9 screen in mice reveals genes regulating lung metastasis.

> Ran et al. (2015) relates to SaCas9 and its ability to edit genomes and demonstrates that one cannot extrapolate from biochemical assays.

> Shalem et al. (2015) described ways in which catalytically inactive Cas9 (dCas9) fusions are used to synthetically repress (CRISPRi) or activate (CRISPRa) expression, showing, advances using Cas9 for genome-scale screens, including arrayed and pooled screens,

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> Xu el al. (2015) assessed the DNA sequence features that contribute to single guide RNA (sgRNA) efficiency in CRISPR-based screens. The authors explored efficiency of CRISPR/Cas9 knockout and nucleotide preference at the cleavage site. The authors also found that the sequence preference for CRISPRi/a is substantially different from that for CRISPR/Cas9 knockout.

> Parnas et al. (2015) introduced genome-wide pooled CRISPR~Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS). Known regulators of Tlr4 signaling and previously unknown candidates were identified and classified into three functional modules with distinct effects on the canonical responses to LPS.

> Ramanan et al (2015) demonstrated cleavage of viral episornal DNA (cccDNA) in infected cells. The HBV genome exists in the nuclei of infected hepatocytes as a 3.2kb double-stranded episornal DNA species called covalently closed circular DNA (cccDNA), which is a key component in the HBV life cycle whose replication is not inhibited by current therapies. The authors showed that sgRNAs specifically targeting highly conserved regions of HBV robustly suppresses viral replication and depleted cccDNA.

> Nishimasu et al. (2015) reported the crystal structures of SaCas9 in complex with a single guide RNA (sgRNA) and its double-stranded DNA targets, containing the 5'-TTGAAT-3^! PAM and the 5'-TTGGGT-3' PAM, A structural comparison of SaCas9 with SpCas9 highlighted both structural conservation and divergence, explaining their distinct PAM specificities and orthologous sgRNA recognition.

> Canver et al. (2015) demonstrated a CRISPR-Cas9-based functional investigation of noncoding genomic elements. The authors we developed pooled CRISPR-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse BCL11A enhancers which revealed critical features of the enhancers.

> Zetsche et al. (2015) reported characterization of Cpfl, a class 2 CRISPR nuclease from Francisella novicida UI12 having features distinct from Cas9. Cpfl is a single RNA471

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PCT/US2016/038181 guided endonuclease lacking tracrRNA, utilizes a T-rich protospacer-adjacent motif, and cleaves DNA via a staggered DNA double-stranded break.

> Shmakov et al. (2015) reported three distinct Class 2 CRISPR-Cas systems. Two system CRISPR enzymes (C2cl and C2c3) contain RuvC-like endonuclease domains distantly related to Cpfl. Unlike Cpfl, C2cl depends on both crRNA and tracrRNA for DNA cleavage. The third enzyme (C2c2) contains two predicted HEPN RNase domains and is tracrRNA independent.

> Slaymaker et al (2016) reported the use of structure-guided protein engineering to improve the specificity of Streptococcus pyogenes Cas9 (SpCas9). The authors developed enhanced specificity SpCas9 (eSpCas9) variants which maintained robust on-target cleavage with reduced off-target effects.

[001355] Also, “Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing”, Shengdar Q. Tsai, Nicolas Wyvekens, Cyd Khayter, Jennifer A. Foden, Vishal Thapar, Deepak Reyon, Mathew J. Goodwin, Martin J. Aryee, J. Keith Joung Nature Biotechnology 32(6): 569-77 (2014), relates to dimeric RNA-guided FokI Nucleases that recognize extended sequences and can edit endogenous genes with high efficiencies in human cells.

[001356] US Patents Nos. 8,697,359, 8,771,945, 8,795,965, 8,865,406, 8,871,445, 8,889,356, 8,889,418, 8,895,308, 8,906,616, 8,932,814, 8,945,839, 8,993,233 and 8,999,641; US Patent Publications US 2014-0310830 (US App. Ser. No. 14/105,031), US 2014-0287938 Al (U.S. App, Ser. No, 14/213,991), US 2014-0273234 Al (U.S. App, Ser. No, 14/293,674), US20140273232 Al (U.S. App. Ser. No. 14/290,575), US 2014-0273231 (U.S. App. Ser. No. 14/259,420), US 2014-0256046 Al (U.S. App. Ser. No. 14/226,274), US 2014-0248702 Al (U.S. App. Ser. No. 14/258,458), US 2014-0242700 Al (U.S. App. Ser. No. 14/222,930), US 2014-0242699 Al (U.S. App. Ser. No. 14/183,512), US 2014-0242664 Al (U.S. App. Ser. No. 14/104,990), US 2014-0234972 Al (U.S. App. Ser. No. 14/183,471), US 2014-0227787 Al (U.S. App. Ser. No. 14/256,912), US 2014-0189896 Al (U.S. App. Ser. No. 14/105,035), US 2014-0186958 (U.S. App. Ser. No. 14/105,017), US 2014-0186919 Al (U.S, App. Ser, No, 14/104,977), US 2014-0186843 Al (U.S. App. Ser. No. 14/104,900), US 2014-0179770 Al (U.S, App. Ser. No. 14/104,837) and US 2014-0179006 Al (U.S, App. Ser. No. 14/183,486), US 2014-0170753 (US App Ser No 14/183,429); US 2015-0184139 (U.S. App. Ser. No. 14/324,960); 14/054,414 European Patent Applications EP 2 771 468 (EP13818570.7), EP 2

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764 103 (EP13824232.6), and EP 2 784 162 (EP 14170383.5); and PCT Patent Publications WO

2014/093661	(PCT/US2013/074743),	WO	2014/093694	(PCT/US2013/074790),	wo
2014/093595	(PCT/US2013/074611),	wo	2014/093718	(PCT/US2013/074825),	wo
2014/093709	(PCT/US2013/074812),	wo	2014/093622	(PCT/US2013/074667),	wo
2014/093635	(PCT/US2013/074691),	wo	2014/093655	(PCT/US2013/07473 6),	wo
2014/093712	(PCT/US2013/074819),	wo	2014/093701	(PCT/US2013/074800),	wo
2014/018423	(PCT/US2013/051418),	wo	2014/204723	(PCT/US2014/041790),	wo
2014/204724	(PCT/US2014/041800),	wo	2014/204725	(PCT/US2014/041803),	wo
2014/204726	(PCT/US2014/041804),	wo	2014/204727	(PCT/US2014/041806),	wo
2014/204728	(PCT/US2014/041808),	wo	2014/204729	(PCT/US2014/041809),	wo
2015/089351	(PCT/US2014/069897),	wo	2015/089354	(PCT/US2014/069902),	wo
2015/089364	(PCT/US2014/069925),	wo	2015/089427	(PCT/US2014/070068),	wo
2015/089462	(PCT/US2014/070127),	wo	2015/089419	(PCT/US2014/070057),	wo

2015/089465 (PCT/US2014/070135), WO 2015/089486 (PCT/US2014/070175),

PCT/US2015/051691, PCT/US2015/051830. Reference is also made to US provisional patent applications 61/758,468; 61/802,174; 61/806,375; 61/814,263; 61/819,803 and 61/828,130, filed on January 30, 2013; March 15, 2013, March 28, 2013; April 20, 2013, May 6, 2013 and May 28, 2013 respectively. Reference is also made to US provisional patent application 61/836,123, filed on June 17, 2013. Reference is additionally made to US provisional patent applications 61/835,931, 61/835,936, 61/835,973, 61/836,080, 61/836,101, and 61/836,127, each filed June 17, 2013. Further reference is made to US provisional patent applications 61/862,468 and 61/862,355 filed on August 5, 2013, 61/871,301 filed on August 28, 2013; 61/960,777 filed on September 25, 2013 and 61/961,980 filed on October 28, 2013. Reference is yet further made to: PCT/US2014/62558 filed October 28, 2014, and US Provisional Patent Applications Serial Nos.: 61/915,148, 61/915,150, 61/915,153, 61/915,203, 61/915,251, 61/915,301, 61/915,267, 61/915,260, and 61/915,397, each filed December 12, 2013; 61/757,972 and 61/768,959, filed on January 29, 2013 and February 25, 2013; 62/010,888 and 62/010,879, both filed June 11, 2014; 62/010,329, 62/010,439 and 62/010,441, each filed June 10, 2014; 61/939,228 and 61/939,242, each filed February 12, 2014; 61/980,012, filed April 15,2014, 62/038,358, filed August 17, 2014; 62/055,484, 62/055,460 and 62/055,487, each filed September 25, 2014; and 62/069,243, filed October 27, 2014. Reference is made to PCT application designating, inter alia, the United

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States, application No. PCT/US 14/41806, filed June 10, 2014. Reference is made to US provisional patent application 61/930,214 filed on January⁷ 22, 2014. Reference is made to PCT application designating, inter alia, the United States, application No. PCT/US 14/41806, filed June 10, 2014.

[001357] Mention is also made of US application 62/180,709, 17-Jun-15, PROTECTED GUIDE RNAS (PGRNAS); US application 62/091,455, filed, 12-Dec-14, PROTECTED GUIDE RNAS (PGRNAS); US application 62/096,708, 24-Dec-14, PROTECTED GUIDE RNAS (PGRNAS); US applications 62/091,462, 12-Dec-14, 62/096,324, 23-Dec-14, 62/180,681, 17Jun-2015, and 62/237,496, 5-Oct-2015, DEAD GUIDES FOR CRISPR TRANSCRIPTION FACTORS, US application 62/091,456, 12-Dec-14 and 62/180,692, 17-Jun-2015, ESCORTED AND FUNCTIONALIZED GUIDES FOR CRISPR-CAS SYSTEMS, US application 62/091,461, 12-Dec-14, DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR GENOME EDITING AS TO HEMATOPOETIC STEM CELLS (HSCs); US application 62/094,903, 19-Dec-14, UNBIASED IDENTIFICATION OF DOUBLE-STRAND BREAKS AND GENOMIC REARRANGEMENT

BY GENOME-WISE INSERT CAPTURE SEQUENCING; US application 62/096,761, 24-Dec14, ENGINEERING OF SYSTEMS, METHODS AND OPTIMIZED ENZYME AND GUIDE SCAFFOLDS FOR SEQUENCE MANIPULATION; US application 62/098,059, 30-Dec-14, 62/181,641, 18-Jun-20I5, and 62/181,667, 18-Jun-2015, RNA-TARGETING SYSTEM; US application 62/096,656, 24-Dec-14 and 62/181,151, 17-Jun-20I5, CRISPR HAVING OR ASSOCIATED WITH DESTABILIZATION DOMAINS; US application 62/096,697, 24-Dec14, CRISPR HAVING OR ASSOCIATED WITH AAV; US application 62/098,158, 30-Dec-14,

ENGINEERED CRISPR COMPLEX INSERTIONAL TARGETING SYSTEMS; US application 62/151,052, 22-Apr-15, CELLULAR TARGETING FOR EXTRACELLULAR EXOSOMAL REPORTING; US application 62/054,490, 24-Sep-14, DELIVERY, USE AND

THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR TARGETING DISORDERS AND DISEASES USING PARTICLE DELIVERY COMPONENTS; US application 61/939,154, 12-F EB-14, SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPLTLATION WITH OPTIMIZED FUNCTIONAL CRISPR-CAS SYSTEMS; US application 62/055,484, 25-Sep-14, SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION WITH OPTIMIZED

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FUNCTIONAL CRISPR-CAS SYSTEMS; US application 62/087,537, 4-Dec-14, SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION WITH OPTIMIZED

FUNCTIONLAL CRISPR-CAS SYSTEMS; US application 62/054,651, 24-Sep-14, DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR MODELING COMPETITION OF MULTIPLE CANCER MUTATIONS IN VIVO, US application 62/067,886, 23-Oct-14, DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR MODELING COMPETITION OF MULTIPLE CANCER MUTATIONS IN VIVO; US applications 62/054,675, 24-Sep-14 and 62/181,002, 17-Jun-2015, DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS

IN NEURONAL CELL S/TIS SUES; US application 62/054,528, 24-Sep-14, DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS IN IMMUNE DISEASES OR DISORDERS, US application 62/055,454, 25Sep-14, DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR TARGETING DISORDERS AND DISEASES USING CELL PENETRATION PEPTIDES (CPP); US application 62/055,460, 25-Sep-L-L MULTIFUNCTIONAL-CRISPR COMPLEXES AND/OR OPTIMIZED ENZYME LINKED FUNCTIONAL-CRISPR COMPLEXES; US application 62/087,475, 4-Dec-14 and 62/181,690, 18-Jun-20I5, FUNCTIONAL SCREENING WITH OPTIMIZED FUNCTIONAL CRISPR-CAS SYSTEMS, US application 62/055,487, 25-Sep-14, FUNCTIONAL SCREENING WITH OPTIMIZED FUNCTIONAL. CRISPR-CAS SYSTEMS; US application 62/087,546, 4-Dec-14 and 62/181,687, 18-Jun-2015, MULTIFUNCTIONAL CRISPR COMPLEXES AND/OR OPTIMIZED ENZYME LINKED FUNCTIONAL-CRISPR COMPLEXES; and US application 62/098,285, 30-Dec-14, CRISPR MEDIATED IN VIVO MODELING AND GENETIC SCREENING OF TUMOR GROWTH AND METASTASIS.

[001358] Mention is made of US applications 62/181,659, 18-Jun-2015 and 62/207,318, 19Aug-2015, ENGINEERING AND OPTIMIZATION OF SYSTEMS, METHODS, ENZYME AND GUIDE SCAFFOLDS OF CAS9 ORTHOLOGS AND VARIANTS FOR SEQUENCE MANIPULATION. Mention is made of US applications 62/181,663, 18-Jun-20I5 and 62/245,264, 22-Oct-2015, NOVEL CRISPR ENZYMES AND SYSTEMS, US applications 62/181,675, 18-Jun-2015, 62/285,349, 22-Oct-2015, 62/296,522, 17-Feb-2016, and 62/320,231,

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8-Apr-2016, NOVEL CRISPR ENZYMES AND SYSTEMS, US application 62/232,067, 24Sep-2015, US Application 14/975,085, 18-Dec-2015, European application No. 16150428.7, US application 62/205,733, I6-Aug-2015, US application 62/201,542, 5-Aug-2015, US application 62/193,507, 16-Jul-2015, and US application 62/181,739, 18-Jun-2015, each entitled NOVEL CRISPR ENZ YMES AND SYSTEMS and of US application 62/245,270, 22-Oct-2015, NOVEL CRISPR ENZYMES AND SYSTEMS, Mention is also made of US application 61/939,256, 12Feb-2014, and WO 2015/089473 (PCT/US2014/070152), 12-Dec-2014, each entitled

ENGINEERING OF SYSTEMS, METHODS AND OPTIMIZED GUIDE COMPOSITIONS WITH NEW ARCHITECTURE.S FOR SEQUENCE MANIPLRATION. Mention is also made of PCT/US2015/045504, 15-Aug-2015, US application 62/180,699, 17-Jun-2015, and US application 62/038,358, 17-Aug-2014, each entitled GENOME EDITING USING CAS9 NICKASES.

[001359] Each of these patents, patent publications, and applications, and all documents cited therein or during their prosecution (“appln cited documents”) and all documents cited or referenced in the appln cited documents, together with any instructions, descriptions, product specifications, and product sheets for any products mentioned therein or in any document therein and incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. All documents (e.g., these patents, patent publications and applications and the appln cited documents) are incorporated herein by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[001360] The effectiveness of the present invention has since been demonstrated. Preassembled recombinant CRISPR-Cpfl complexes comprising Cpfl and erRNA may be transfected, for example by electroporation, resulting in high mutation rates and absence of detectable off-target mutations. Hur, J.K. et al, Targeted mutagenesis in mice by electroporation of Cpfl ribonucleoproteins, Nat Biotechnol. 2016 Jun 6. doi: 10.1038/nbt.3596. [Epub ahead of print]. Genome-wide analyses show's that Cpfl is highly specific. By one measure, in vitro cleavage sites determined for SpCas9 in human HEK293T cells were significantly fewer that for SpCas9. Kim, D, et al., Genome-wide analysis reveals specificities of Cpfl endonucleases in human cells, Nat Biotechnol. 2016 Jun 6. doi: 10.1038/nbt.3609. [Epub ahead of print]. An efficient multiplexed system employing Cpfl has been demonstrated in Drosophila employing

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PCT/US2016/038181 gRNAs processed from an array containing inventing tRNAs. Port, F. et al, Expansion of the CRISPR toolbox in an animal with tRNA-flanked Cas9 and Cpfl gRNAs. doi: http :/7dx. doi. org/10.1101/046417.

[001361] The present invention will be further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the invention in any way.

Example 1: Origin and evolution of adaptive immunity systems [001362] Classification and annotation of CRISPR-Cas systems in archaea! and bacterial genomes. The CRISPR-Cas loci has more than 50 gene families and there is no strictly universal genes, fast evolution, extreme diversity of loci architecture. Therefore, no single tree feasible and a multi-pronged approach is needed. So far, there is comprehensive cas gene identification of 395 profiles for 93 Cas proteins. Classification includes signature gene profiles plus signatures of locus architecture [001363] A new classification of CRISPR-Cas systems is proposed in FIG. 1. Class 2 includes multisubunit crRNA-effector complexes (Cascade) and Class 2 includes Single-subunit crRNAeffector complexes (Cas9-like). FIG. 2 provides a molecular organization of CRISPR-Cas. FIG. 3 provides structures of Type I and III effector complexes: common architecture/common ancestry despite extensive sequence divergence. FIG. 4 shows CRISPR-Cas as a RNA recognition motif (RRM)-centered system. FIG. 5 shows Cast phylogeny where recombination of adaptation and crRNA-effector modules show a major aspect of CRISPR-Cas evolution. FIG. F show’s a CRISPR-Cas census, specifically a distribution of CRISPR-Cas types/subtypes among archaea and bacteria.

[001364] Casl is not always linked to CRISPR-Cas systems, therefore it may be possible that there are two branches of “solo” Casl which suggests there may be differences in function and origin and possible novel mobile elements (see Makarova, Krupovic, Koonin, Frontiers Genet 2014). The genome organization of three easposon families may provide some clues. In addition to Casl and PolB, casposons incorporate diverse genes including various nucleases (Krupovic et al. BMC Biology 2014). One family has protein-primed polymerase, another family has RNAprimed polymerase. In addition to diverse Euryarchaeota and Thaumarchaeota, casposons found in several bacteria which suggests horizontal mobility. Casposon Casl (transposase/integrase) suggests a basal clade in the Casl phylogeny.

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PCT/US2016/038181 [001365] Bacteria and archae utilize CRISPR for adaptive immunity in procaryotes and eukaryotes via genome manipulation. Cas 1 provides a ready made tool for genome manipulation. There are similar mechanisms of integration in casposons and CRISPR, specifically replication-dependent acquisition by copy/paste not cut-and-paste (Krupovic et al, BMC Biology 2014). Cast is a bona fide integrase (Nunez JK, Lee AS, Engelman A, Doudna JA. Integrase-mediated spacer acquisition during CRISPR-Cas adaptive immunity. Nature. 2015 Feb 18). There is similarity between terminal inverted repeats of casposons and CRISPR (Krupovic et al. BMC Biology 2014). CRISPR-Cas may have originated from a casposon and an innate immunity locus (Koonin, Krupovic, Nature Rev Genet, 2015). The evolution of adaptive immunity systems in prokaryotes and animals may have been along parallel courses with transposon integration at innate immunity loci (Koonin, Krupovic, Nature Rev Genet, 2015). RAG1 transposase (the key enzyme of V(D)J recombination in vertebrates) may have originated from Transib transposons (Kapitonov VV, Jurka J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol. 2005 Jun;3(6):el81), however, none of the Transibs encodes RAG2. RAG1 and RAG2 encoding transposons are described in Kapitonov, Koonin, Biol Direct 2015 and Transib transposase phylogeny is presented in Kapitonov, Koonin, Biol Direct 2015. Defensive DNA elimination in ciliates evolved from a PiggyMAc transposon and RNAi, an innate immune system (Swart EC, Nowacki M. The eukaryotic w^zay to defend and edit genomes by sRNA-targeted DNA deletion. Ann N Y Acad Sci. 2015), [001366] The relative stability of the classification implies that the most prevalent variants of CRISPR-Cas systems are already known. However, the existence of rare, currently unclassifiable variants implies that additional types and subtypes remain to be characterized (Makarova et al. 2015. Evolutionary classification of CRISPR-Cas systems and cas genes).

[001367] Transposons play a key contribution to the evolution of adaptive immunity and other systems involved in DNA manipulation. Class I CRISPR-Cas originate from transposons but only for an adaptation module. Class 2 CRISPR-Cas have both both adaptation and effector functions where modules may have evolved from different transposons.

Example 2: New predicted Class 2 CRISPR-Cas systems and evidence of their independent origins from transposable elements

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PCT/US2016/038181 [001368] The CRISPR-Cas systems of bacterial and archaeal adaptive immunity show extreme diversity of protein composition and genomic loci architecture. These systems are broadly divided into two classes, Class 1 with multisubunit effector complexes and Class 2 with singlesubunit effector modules exemplified by the Cas9 protein. Applicants developed a simple computational pipeline for prediction of putative new Class 2 CRISPR-Cas systems. Analysis of the database of complete bacterial genomes using this pipeline resulted in the identification of two new⁷ variants, each represented in diverse bacteria and containing casl and cas2 genes along with a third gene encoding a large protein predicted to function as the effector module. In the first of these loci, the putative effector protein (C2clp) contains a RuvC-like nuclease domain and resembles the previously described Cpfl protein, the predicted effector of Type V CRISPRCas systems; accordingly, the new putative system is classified as subtype V-B, In depth comparison of protein sequences suggests that the RuvC-containing effector proteins, Cas9, Cpfl and C2CIp independently evolved from different groups of transposon-encoded TnpB proteins. The second group of new putative CRISPR-Cas loci encompasses a large protein containing two highly diverged HEPN domains with predicted RNAse activity. Given the novelty of the predicted effector protein, these loci are classified as new Type VI CRISPR-Cas that is likely to target mRNA. Together, the results of this analysis show that Class2 CRISPR-Cas systems evolved on multiple, independent occasions, by combination of diverse Casl-Cas2-encoding adaptation modules with effector proteins derived from different mobile elements. This route of evolution most likely produced multiple variants of Class 2 systems that remain to be discovered. [001369] The CRISPR-Cas adaptive immunity systems are present in -45% bacterial and -90% archaeal genomes and show extreme diversity of Cas protein composition and sequence, and genomic loci architecture. Based on the structural organization of their crRNA-effector complexes, these systems are divided into two classes, namely class 1, with multisubunit effector complexes, and class 2, with single subunit effector complexes (Makarova, 2015). Class 1 systems are much more common and diverse than Class 2 systems. Class 1 currently is represented by 12 distinct subtypes encoded by numerous archaeal and bacterial genomes, whereas class 2 systems include three subtypes of Type II system and the putative Type V that collectively are found in about 10% of sequenced bacterial genomes (with a single archaeal genome encompassing a putative Type system). Class 2 systems typically contain only three or four genes in the cas operon, namely the casl-cas2 pair of genes that are involved in adaptation

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PCT/US2016/038181 but not in interference, a single multidomain effector protein that is responsible for interference but also contributes to the pre-crRNA processing and adaptation, and often a fourth gene with uncharacterized functions that is dispensable in at least some Type II systems. In most cases, a CRISPR array and a gene for a distinct RNA species known as tracrRNA (trans-encoded small CRISPR RNA) are adjacent to Class 2 cas operons (Chylinski, 2014). The tracrRNA is partially homologous to the repeats within the respective CRISPR array and is essential for the processing of pre-crRNA that is catalyzed by RNAse III, a ubiquitous bacterial enzyme that is not associated with the CRISPR-eas loci (Deltcheva, 201 l)(Chylinski, 2014;Chylinski, 2013). [001370] The Type II multidomain effector protein Cas9 has been functionally and structurally characterized in exquisite detail. In different bacteria, Cas9 proteins encompass between about 950 and 1,400 amino acids and contain two nuclease domains, namely a RuvC-like (RNase H fold) and HNH (McrA-like) nucleases (Makarova, 2011). The crystal structure of Cas9 reveals a bilobed organization of the protein, with distinct target recognition and nuclease lobes, with the latter accommodating both the RuvC and the HNH domains (Nishimasu, 2014)(Jinek, 2014). Each of the nuclease domains of Cas9 is required for the cleavage of one of the target DNA strands (Jinek, 2012; Sapranauskas, 2011). Recently, Cas9 has been shown to contribute to all three stages of the CRISPR response, that is not only target DNA cleavage (interference) but also adaptation and pre-crRNA processing (Jinek, 2012). More specifically, a distinct domain in the nuclease lobe of Cas9 has been shown to recognize and bind the Protospacer-Associated Motif (PAM) in viral DNA during the adaptation stage (Nishimasu, 2014)(Jinek, 2014)(Heler, 2015; Wei, 2015). At this stage of the CRISPR response, Cas9 forms a complex with Cast and Cas2, the two proteins that are involved in spacer acquisition in all CRISPR-Cas systems (Heler, 2015; Wei, 2015).

[001371] The Cas9 protein, combined with tracrRNA, has recently become the key tool for the new⁷ generation of genome editing and engineering methods (Gasiunas, 2013; Mali, 2013; Sampson, 2014; Cong, 2015). This utility of Cas9 in genome editing hinges on the fact that in Type II CRISPR-Cas systems, unlike other types of CRISPR-Cas systems, all the activities required for the target DNA recognition and cleavage are assembled within a single, albeit large, multidomain protein. This feature of Type 11 systems greatly facilitates the design of efficient tools for genome manipulation. Importantly, not all variants of Cas9 are equal. Most of the work so far has been done with Cas9 from Streptococcus pyogenes but other Cas9 species could offer

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PCT/US2016/038181 substantial advantages. As a case in point, recent experiments with Cas9 from Staphylococcus aureus that is about 300 amino acids shorter than the X. pyogenes protein have allowed Cas9 packaging into the adeno-associated virus vector, resulting in a major enhancement of CRISPRCas utility for genome editing in vivo (Ran, 2015).

[001372] Type II CRISPR-Cas systems currently are classified into 3 subtypes (II-A, II-B and Π-C) (Makarova, 201 l)(Fonfara, 2014; Chylinski, 2013; Chylinski, 2014). In addition to the casl, cas2 and cas9 genes that are shared by all Type II loci, subtype II-A is characterized by an extra gene, csn2, that encodes an inactivated ATPase (Nam, 2011, Koo, 2012, Lee, 2012) that plays a still poorly characterized role in spacer acquisition (Barrangou, 2007; Arslan, 2013)(Heler, 2015). Subtype II-B systems lack csn'2 but instead contains the cas4 gene that is otherwise typical of Type I systems and encodes a recB family 5’-3’ exonuclease that contributes to spacer acquisition by generating recombinogeneci DNA ends (Zhang, 2012)(Lemak, 2013; Lemak, 2014). The casl and cas2 genes of subtype II-B are most closely related to the respective proteins of Type I CRISPR-Cas systems which implies a recombinant origin of this Type II subtype (Chylinski, 2014).

[001373] Subtype II-C CRISPR-Cas systems are the minimal variety that consists only of the casl, cas2 and cas9 genes (Chylinski, 2013; Koonin, 2013; Chylinski, 2014). Notably, however, it has been shown that in Campylobacter jejuni spacer acquisition by the Type II-C systems requires the participation of Cas4 encoded by a bacteriophage (Hooton, 2014). Another distinct feature of subtype II-C is the formation of some of the crRNAs by transcription involves transcription from internal alternative promoters as opposed to processing observed in all other experimentally characterized CRISPR-Cas systems (Zhang, 2013).

[001374] Recently, the existence of Type V CRISPR-Cas systems has been predicted by comparative analysis of bacterial genomes. These putative novel CRISPR-Cas systems are represented in several bacterial genomes, in particular those from the genus Francisella and one archaeon, Melhanomethylophilus alvus (Vestergaard, 2014). All putative Type V loci encompass casl, cas2, a distinct gene denoted cpfl and a CRISPR array (Schunder, 2013)(Makarova, 2015), Cpfl is a large protein (about 1300 amino acids) that contains a RuvC-like nuclease domain homologous to the corresponding domain of Cas9 along with a counterpart to the characteristic arginine-rich cluster of Cas9. However, Cpfl lacks the HNH nuclease domain that is present in all Cas9 proteins, and the RuvC-like domain is contiguous in the Cpfl sequence, in contrast to

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Cas9 where it contains long inserts including the HNH domain (Chylinski, 2014; Makarova, 2015 ). These major differences in the domain architectures of Cas9 and Cpfl suggest that the Cpfl-contaning systems should be classified as a new type. The composition of the putative Type V systems implies that Cpfl is a single-subunit effector complex, and accordingly, these systems are assigned to Class 2 CRISPR-Cas. Some of the putative Type V loci encode Cas4 and accordingly resemble subtype 11-B loci, whereas others lack Cas4 and thus are analogous to subtype II-C.

[001375] It has been shown that the closest homologs of Cas9 and Cpfl proteins are TnpB proteins that are encoded in IS605 family transposons and contain the RuvC-like nuclease domain as well as a Zn-finger that has a counterpart in Cpfl. In addition, homologs of TnpB have been identified that contain a HNH domain inserted into the RuvC-like domain and show high sequence similarity to Cas9. The role of TnpB in transposons remains uncertain as it has been shown that this protein is not required for transposition.

[001376] Given the homology of Cas9 and Cpfl to transposon-encoded proteins, Applicants hypothesized that Class 2 CRISPR-Cas systems could have evolved on multiple occasions as a result of recombination between a transposon and a casl-cas2 locus. Accordingly, Applicants devised a simple computational strategy to identify genomic loci that could be candidates for novel variants of Class 2. Here Applicants describe the first application of this approach that resulted in the identification of two groups of such candidates one of which appears to be a distinct subtype of Type V whereas the second one seems to qualify at Type VI. The new variants of Class2 CRISPR-Cas systems are of obvious interest as potential tools for genome editing and expression regulation, [001377] Database search strategy for detection of candidate novel Class 2 CRISPR-Cas loci. Applicants implemented a straightforward computational approach to identify candidate novel Class 2 CRISPR-Cas systems (FIG. 7. Pipeline). Because the vast majority of the CRISPR-Cas loci encompass a casl gene (Makarova, 2011; Makarova, 2015) and the Casl sequence is the most highly conserved one among all Cas proteins (Takeuchi, 2012), Applicants reasoned that casl is the best possible anchor to identify candidate new loci using translating PSI-BLAST search with Casl profiles. After detecting all contigs encoding Casl, the protein-coding genes were predicted using GenemarkS within the 20 KB regions upstream and downstream of the casl gene. These predicted genes were annotated using the NCBI CDD and Cas protein-specific

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PCT/US2016/038181 profiles, and CRISPR arrays were predicted using the PILER-CR program. This procedure provided for assignment of the detected CRISPR-Cas loci to the known subtypes. Unclassified candidate CRISPR-Cas loci containing large (>500 aa) proteins were selected as candidates for novel Class 2 systems given the characteristic presence of such proteins in Types II and V (Cas9 and Cpfl, respectively). All 34 candidate loci detected using this criteria were analyzed on a case by case basis using PSI-BLAST and HHpred. The protein sequences encoded in the candidate loci were farther used as queries to search metagenomic databases for additional homologs, and long configs detected in these searches were analyzed as indicated above. This analysis pipeline yielded two groups of loci strong links to CRISPR-Cas systems.

[001378] Putative type V-B system. The first group of candidate loci, provisionally denoted named C2cl (Class 2 candidate 1), is represented in bacterial genomes from four major phyla, including Bacilli, Verrucomicrobia, alpha-proteobacteria and delta-proteobacteria (FIG. 8 “Organization of complete loci of Class 2 systems”). All C2cl loci encode a Cas1-Cas4 fusion, Cas2, and the large protein that Applicants denote C2clp, and typically, are adjacent to a CRISPR array (FIG. 9, C2cl neighborhoods). In the phylogenetic tree of Cast, the respective Casl proteins cluster with Type I-U system (FIG. 10, Casl tree), the only one in which the CaslCas4 fusion is found. The C2clp proteins consists of approximately 1200 amino acids, and HHpred search detected significant similarity between the C-terminal portion of this protein and a subset of TnpB proteins encoded in transposons of the IS605 family. In contrast, no significant similarity was detected between C2clp and Cas9 or Cpfl that are similar to other groups of TnpB proteins (Chylinski, 2014)(Makarova, 2015; Makarova, 2015). Thus, the domain architecture of C2clp is similar to that of Cpfl and distinct from that of Cas9 although all three Cas proteins seem to have evolved from the TnpB family (FIG. 11 “Domain organization of class 2 families”). The N-terminal region of C2clp shows no significant similarity to other proteins. Secondary structure prediction indicates that this region adopts mostly alpha-helical conformation. The two segments of similarity with TnpB encompass the three catalytic motifs of the RuvC-like nuclease, with the D..E..D signature (FIG. 12, “TnpB homology regions in Class 2 proteins”); the region corresponding to the bridge helix (also known as arginine-rich cluster) that in Cas9 protein is involved in crRNA-binding; and a small region that appears to be the counterpart to the Zn finger of TnpB (however, the Zn-binding cysteine residues are replaced in C2Clp indicating that this protein does not bind zinc). The similarity of the domain architectures

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PCT/US2016/038181 of C2clp and Cpfl suggests that the C2el loci are best classified as Subtype V-B in which case the Cpfl-encoding loci become Subtype V-A.

[001379] Despite similarity of casl genes associated with this system, the CRISPR repeats in the respective arrays are highly heterogeneous although all of them are 36-37 bp long and can be classified as unstructured (folding energy, AG, is -0.5-4.5 kcal/mole whereas highly palindromic CRISPR have AG below -7). According to the CRISPRmap (Lange, 2013) classification scheme, several of the Subtype V-B repeats share some sequence or structural similarity with Type II repeats ..

[001380] Considering the possibility that the putative Subtype V-B CRISPR-Cas systems are mechanistically analogous to Type II systems, Applicants attempted to identify the tracrRNA in the respective genomic loci [001381] Comparison of the spacers from the Type V-B CRISPR arrays to the non-redundant nucleotide sequence database identified several matches to various bacterial genomes. The relevance of these matches is difficult to assess, considering that no phages are known for the bacteria that harbor putative Type V-B CRISPR-Cas systems.

[001382] Putative type VI systems. The second group of candidate CRISPR-Cas loci, denoted C2c2, was identified in genomes from 5 major bacterial phyla, alpha-proteobacteria, Bacilli, Clostridia, Fusobacteria and Bacteroidetes (FIG. 8 “Organization of complete loci of Class 2 systems”). Similar to c2cl, the C2c2 loci encompass casl and cas2 genes along with a large protein (C2c2p) and a CRISPR array; however, unlike C2cl, C2c2p is often encoded next to a CRISPR array but not casl-cas2 (FIG. 13, C2c2 neighborhoods). In the phylogenetic tree of Casl, the Cast proteins from the C2c2 loci are distributed among two clades. The first clade includes Casl from Clostridia and is located within the Type II subtree along with a small Type III-A branch (FIG. 10, Casl tree). The second clade consists of Casl proteins from C2c2 loci of Leptotrichia and is lodged inside a mixed branch that mostly contains Casl proteins from Type III-A CRISPR-Cas systems. Database searches using HHpred and PSI-BLAST detected no sequence similarity between C2c2p and other proteins. However, inspection of multiple alignments of C2c2p protein sequences led to the identification of two strictly conserved RxxxxH motifs that are characteristic of HEPN domains (Anantharaman, 2013), Secondary structure predictions indicates that these motifs are located within structural contexts compatible with the HEPN domain structure as is the overall secondary structure prediction for the

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PCT/US2016/038181 respective portions of C2c2p. The HEPN domains are small (-150 aa) alpha helical domains that have been shown or predicted to possess RNAse activity and are often associated with various defense systems (Anantharaman, 2013) (FIG. 14, HEPN RxxxxH motif in C2c2 family). The sequences of HEPN domains show little conservation except for the catalytic RxxxxH motif Thus, it appears likely that C2c2p contains two active HEPN domains. The HEPN domain is not new to CRISPR-Cas systems as it is often associated with the CARF (CRISPR-Associated Rossmann Fold) domain in Csm6 and Csxl proteins that are present in many Type III CRISPRCas systems (Makarova, 2014). These proteins do not belong to either the adaptation modules or effector complexes hut rather appear to be components of the associated immunity module that is present in the majority of CRISPR-Cas systems and is implicated in programmed cell death as well as regulatory functions during the CRISPR. response (Koonin, 2013; Makarova, 2012; Makarova, 2013). However, C2c2p differs from Csm6 and Csxl in that this much larger protein is the only one encoded in the C2c2 loci, except for Casl and Cas2, Thus, it appears likely that C2c2p is the effector of these putative novel CRISPR-Cas systems and the HEPN domains are the catalytic moieties thereof. Outside of the predicted HEPN domains, the C2clp sequence showed no detectable similarity to other proteins and is predicted to adopt a mixed alpha/beta secondary structure.

[001383] The CRISPR arrays in the C2c2 loci are highly heterogeneous, with the length of 35 to 39 bp, and unstructured (folding energy of -0.9 to 4.7 kcal/mole). According to CRISPRmap (Lange, 2013), these CRISPR do not belong to any of the established structural classes and are assigned to 3 of the 6 superclasses. Only the CRISPR from Listeria seeligeri was assigned to the sequence family 24 that is usually associated with Type II-C systems.

[001384] Spacer analysis of the C2c2 loci identified one 30 nucleotide region identical to a genomic sequence from Listeria weihenstephanensis and two imperfect hits to bacteriophage genomes.

[001385] Given the unique predicted effector complex of C2c2, these systems seem to qualify as a putative Type VI CRISPR-Cas. Furthermore, taking into account that all experimentally characterized and enzymatically active HEPN domains are RNAses, Type VI systems are likely to act at the level of mRNA.

[001386] Applicants applied a simple, straightforward computational strategy to predict new⁷ Class 2 CRISPR-cas systems. The previously described class 2 systems, namely Type II and the

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PCT/US2016/038181 putative Type V, consisted of the easl and cas2 genes (and in some cases also cas4) comprising the adaptation module and a single large protein that comprises the effector module. Therefore, Applicants surmised that any genomic locus containing casl and a large protein could be a potential candidate for a novel Class 2 system that merits detailed investigation. Such analysis using sensitive methods for protein sequence comparison led to the identification of two strong candidates one of which is a subtype of the previously described putative Type V whereas the other one qualifies as a new putative Type VI, on the strength of the presence of a presence of a novel predicted effector protein. Many of these new systems occur in bacterial genomes that encompass no other CRISPR-Cas loci suggesting that Type V and Type VI systems can function autonomously.

[001387] Combined with the results of previous analyses, (Chylinski, 2014; Makarova, 2011), the identification of the putative Type V-B reveals the dominant theme in the evolution of Class 2 CRISPR-Cas systems. The effector proteins of all currently known systems of this class appear to have evolved from the pool of transposable elements that encode TnpB proteins containing the RuvC-like domain. The sequences of the RuvC-like domains of TnpB and the homologous domains of the Class 2 effector proteins are too diverged for reliable phylogenetic analysis. Nevertheless, for Cas9, the effector protein of Type II systems, the specific ancestor seems to be readily identifiable, namely a family of TnpB-like proteins, particularly abundant in Cyanobacteria, that show a relatively high sequence similarity to Cas9 and share with it the entire domain architecture, namely the RuvC-like and HNH nuclease domains and the argininerich bridge helix (Chylinski, 2014) (FIG. 11, “Domain organization of class 2 families”; FIG. 12, “TnpB homology regions in Class 2 proteins”). Unlike Cas9, it was impossible to trace Cpfl and C2cl to a specific TnpB family; despite the conservation of all motifs centered at the catalytic residues of the RuvC-like nucleases, these proteins show only a limited similarity to generic profiles of the TnpB. However, given that C2clp show's no detectable sequence similarity with Cpfl, contains distinct insertions between the RuvC-motifs and clearly unrelated N-terminal regions, it appears most likely that Cpfl and C2cl originated independently from different families within the pool of TnpB-encoding elements.

[001388] It is intriguing that the TnpB proteins seem to be “predesigned” for utilization in Class 2 CRISPR-Cas effector complexes such that they apparently have been recruited on multiple different occasions. Conceivably, such utility of TnpB proteins has to do with their

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PCT/US2016/038181 predicted ability to cut a single-stranded DNA while bound to a RNA molecule via the R-rich bridge helix that in Cas9 has been shown to bind crRNA (Jinek, 2014; Nishimasu, 2014). The functions of TnpB are poorly understood. This protein is not required for transposition, and in one case, has been shown to down-regulate transposition (Pasternak, 2013) but their mechanism of action remains unknown. Experimental study of TnpB is likely to shed light on the mechanistic aspects of the Class 2 CRISPR-Cas systems. It should be noted that the mechanisms of Cpfl and C2cl could be similar to each other but are bound to substantially differ from that of Cas9 because the former two proteins lack the HNH domain that in Cas9 is responsible for nicking one of the target DNA strands (Gasiunas, 2012)(Jinek, 2012)(Chen, 2014). Accordingly, exploitation of Cpfl and C2cl might bring additional genome editing possibilities.

[001389] In evolutionary terms, it is striking that Class 2 CRISPR-Cas appear to be completely derived from different transposable elements given the recent evidence on the likely origin of casl genes from a distinct transposon family (Koonin, 2015, Krupovic, 2014). Furthermore, the likely independent origin of the effector proteins from different families of TnpB, along with the different phylogenetic affinities of the respective casl proteins, strongly suggest that Class 2 systems have evolved on multiple occasions through the combination of various adaptation modules and transposon-derived nucleases giving rise to effector proteins. This mode of evolution appears to be the ultimate manifestation of the modularity that is characteristic of CRISPR-Cas evolution (Makarova, 2015), with the implication that additional combinations of adaptation and effector module are likely to exist in nature.

[001390] The putative Type VI CRISPR-Cas systems encompass a predicted novel effector protein that contains two predicted HEPN domain that are likely to possess RNAse activity. The HEPN domains are not parts of the effector complexes in other CRISPR-Cas systems but are involved in a variety of defense functions including a predicted ancillary' role in various CRISPR-Cas systems (Anantharaman, 2013)(Makarova, 2015). The presence of the HEPN domains as the catalytic moiety of the predicted effector module implies that the Type VI systems target and cleave mRNA. Previously, mRNA targeting has been reported for certain Type III CRISPR-Cas systems (Hale, 2014; Hale, 2009)(Peng, 2015). Although HEPN domains so far have not been detected in bona fide transposable elements, they are characterized by high horizontal mobility and are integral to mobile elements such as toxin-antitoxin units (Anantharaman, 2013). Thus, the putative Type VI systems seem to fit the general paradigm of

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PCT/US2016/038181 the modular evolution of Class 2 CRISPR-Cas from mobile components, and additional variants and new types are expected to be discovered by analysis of genomic and metagenomics data. [001391] Modular evolution is a key feature of CRISPR-Cas systems. This mode of evolution appears to be most pronounced in Class 2 systems that evolve through the combination of adaptation modules from various other CRISPR-Cas systems with effector proteins that seem to be recruited from mobile elements on multiple independent occasions. Given the extreme diversity of mobile elements in bacteria, it appears likely that effector modules of Class 2 CRISPR-Cas systems are highly diverse as well. Here Applicants employed a simple computational approach to delineate two new variants of CRISPR-Cas systems but many more are likely to exist bacterial genomes that have not yet been sequenced. Although most if not all of these new CRISPR-Cas systems are expected to be rare, they could employ novel strategies and molecular mechanisms and would provide a major resource for new applications in genome engineering and biotechnology.

[001392] TBLASTN program was used to search with Cast profile as a query against NCBI WGS database. Sequences of configs or complete genome partitions where Cast hit has been identified where retrieved from the same database. The region around the Cast gene was cut out and translated using GENMARK. Predicted proteins for each were searched against a collection of profiles from CDD database (March! er-Bauer, 2009)and specific Cas profiles available at FTP, with hit priority to Cas proteins. Procedure to identify completeness of CRISPR loci developed previously has been applied to each locus.

[001393] CRISPRmap (Lange, 2013) was used for repeat classification.

[001394] Iterative profile searches with the PSI-BLAST (Altschul, 1997) and composition based-statistics and low complexity filtering turned off, were used to search for distantly similar sequences both NCBI’s non-redundant (NR) database. Each identified non-redundant protein was searched against WGS using TBLAST program. HHpred was used with default parameters was used to identify remote sequence similarity (Soding, 2005). Multiple sequence alignments were constructed using MUSCLE (Edgar, 2004). Protein secondary/ structure was predicted using Jpred 4 (Drozdetskiy, 2015).

[001395] Chosen Gene Candidates [001396] Gene ID: A; Gene Type: C2C1; Organism: 5. Opitutaceae bacterium TAV5; Spacer Length - mode (range): 34 (33 to 37); DR1:

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GCCGCAGCGAAUGCCGUUUCACGAAUCGUCAGGCGG (SEQ ID NO: 27); DR2: none, tracrRNA 1:

GCUGGAGACGUUUUUUGAAACGGCGAGUGCUGCGGAUAGCGAGUUUCUCUUGGG

GAGGCGCUCGCGGCCACUUUU (SEQ ID NO: 28); tracrRNA2: none; Protein Sequence:

MSLNRIYQGRVAAVETGTALAKGNVEWMPAAGGDEVLWQHHELFQAAINYYLVALL

ALADKNNPVLGPLISQMDNPQSPYHVWGSFRRQGRQRTGLSQAVAPYITPGNNAPTLD

EVFRSILAGNPTDRATLDAALMQLLKACDGAGAIQQEGRSYWPKFCDPDSTANFAGDP

AMLRREQHRLLLPQVLHDPAITHDSPALGSFDTYSIATPDIRTPQLTGPKARARLEQAIT

LWRVRLPES AADFDRLAS SLKKIPDDD SRENLQGYVGS S AKGEVQ ARLF ALLLFRHLER

SSFTLGLLRSATPPPKNAETPPPAGVPLPAASAADPVRIARGKRSFVFRAFTSLPCWHGG

DNIHPTWKSFD1AAFKYALTVINQIEEKTKERQKECAELETDFDYMHGRLAKIPVKYTTG

EAEPPPILANDLRIPLLRELLQNIKVDTALTDGEAVSYGLQRRTIRGFRELRRIWRGHAPA

GTVFSSELKEKLAGELRQFQTDNSTTIGSVQLFNELIQNPKYWPIWQAPDVETARQWAD

AGFADDPLAALVQEAELQEDIDALKAPVKLTPADPEYSRRQYDFNAVSKFGAGSRSAN

RHEPGQTERGHNTFTTEIAARNAADGNRWRATHVRIHYSAPRLLRDGLRRPDTDGNEA

LEAVPWLQPMMEALAPLPTLPQDLTGMPVFLMPDVTLSGERRILLNLPVTLEPAALVEQ

LGNAGRWQNQFFGSREDPFALRWPADGAVKTAKGKTHIPWHQDRDHFTVLGVDLGTR

DAGALALLNVTAQKPAKPVHRIIGEADGRTWYASLADARMIRLPGEDARLFVRGKLVQ

EPYGERGRNASLLEWEDARNIILRLGQNPDELLGADPRRHSYPEINDKLLVALRRAQAR

LARLQNRSWRLRDLAESDKALDEIHAERAGEKPSPLPPLARDDAIKSTDEALLSQRDIIR

RSFVQIANLILPLRGRRWEWRPHVEVPDCHILAQSDPGTDDTKRLVAGQRGISHERIEQIE

ELRRRCQSLNRALRHKPGERPVLGRPAKGEEIADPCPALLEKINRLRDQRVDQTAHAILA

AALGVRLRAPSKDRAERRHRDIHGEYERFRAPADFVVIENLSRYLSSQDRARSENTRLM

QWCHRQIV QKLRQLCET YGIP VLAVP AAYS SRF SSRDGS AGFRAVHLTPDHRHRMPW S

RILARLKAHEEDGKRLEKTVLDEARAVRGLFDRLDRFNAGHVPGKPWRTLLAPLPGGP

VFVPLGDATPMQADLNAAINIALRGIAAPDRHDIHHRLRAENKKRILSLRLGTQREKAR

WPGGAPAVTLSTPNNGASPEDSDALPERVSNLFVDIAGVANFERVTIEGVSQKFATGRG

LWASVKQRAWNRVARLNETVTDNNRNEEEDDIPM (SEQ ID NO: 29) [001397] Gene ID: B; Gene Type: C2C1; Organism: 7. Bacillus thermoamylovorans strain B4166; Spacer Length - mode (range): 37 (35-38); DR1:

GUCCAAGAAAAAAGAAAUGAUACGAGGCAUUAGCAC (SEQ ID NO: 30); DR2: none;

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CUGGACGAUGUCUCUUUUAUUUCUUUUUUCUUGGAUCUGAGUACGAGCACCCAC

AUUGGACAUUUCGCAUGGUGGGUGCUCGUACUAUAGGUAAAACAAACCUUUUU (SEQ ID NO: 31); tracrRNA2: none; Protein Sequence:

MATRSFILKIEPNEEVKKGLWKTHEVLNHGIAYYMNILKLIRQEAIYEHHEQDPKNPKK

VSKAEIQAELWDFVLKMQKCNSFTHEVDKDVVFNILRELYEELVPSSVEKKGEANQLSN

KFLYPLVDPNSQSGKGTASSGRKPRWYNLKIAGDPSWEEEKKKWEEDKKKDPLAKILG

KLAEYGLIPLFIPFTDSNEPIVKEIKWMEKSRNQSVRRLDKDMFIQALERFLSWESWNLK

VKEEYEKVEKEHKTLEERIKEDIQAFKSLEQYEKERQEQLLRDTLNTNEYRLSKRGLRG

WREIIQKWLKMDENEPSEKYLEVFKDYQRKHPREAGDYSVYEFLSKKENHFIWRNHPE

YP YLY ATFCEIDKKKKDAKQQATFTL ADPINHPLW VRFEERSGSNLNK YRILTEQLH TF

KLKKKLTVQLDRLIYPTESGGWEEKGKVDIVLLPSRQFYNQIFLDIEEKGKHAFTYKDES

IKFPLKGTLGGARVQFDRDHLRRYPHKVESGNVGR1YFNMTVN1EPTESPVSKSLKIHRD

DFPKFVNFKPKELTEWIKDSKGKKLKSGIESLEIGLRVMSIDLGQRQAAAASIFEWDQK

PDIEGKLFFPIKGTELYAVHRASFNIKLPGETLVKSREAffiRKAREDNI-XLMNQKLNFLRN

VLHFQQFEDITEREKRVTKWISRQLNSDVPLVYQDELIQIRELMYKPYKDWVAFLKQLH

KRLEVEIGKEVKHWRKSLSDGRKGLYGISLKNIDEIDRTRKFLLRWSLRPTEPGEVRRLE

PGQRFAIDQLNHLNALKEDRLKKMANTIIMHALGYCYDVRKKKWQAKNPACQIILFED

LSNYNPYEERSRFENSKLMKWSRREIPRQVALQGEIYGLQVGEVGAQFSSRFHAKTGSP

GIRCSVVTKEKLQDNRFFKNLQREGRLTLDKiAVLKEGDLYPDKGGEKFISLSKDRKLVT

THADINAAQNLQKRFWTRTHGFYKVYCKAYQVDGQTVYIPESKDQKQKIIEEFGEGYFI

LKDGVYEWGNAGKLKIKKGSSKQSSSELVDSDILKDSFDLASELKGEKLMLYRDPSGN

VFPSDKWMAAGVFFGKLERILISKLTNQYSISTIEDDSSKQSM (SEQ ID NO: 32) [001398] Gene ID: C; Gene Type: C2C1; Organism: 9. Bacillus sp. NSP2.1; Spacer Length mode (range): 36 (35-42); DR1: GUUCGAAAGCUUAGUGGAAAGCUUCGUGGUUAGCAC (SEQ ID NO: 33); DR2: none; tracrRNAl:

CACGGAUAAUCACGACUUUCCACUAAGCUOUCGAAUUUUAUGAOGCGAGCAUCCU CUCAGGUCAAAAAA (SEQ ID NO: 34); tracrRNA2: none; Protein Sequence: MAIRSIKLKLKTHTGPEAQNLRKGIWRTHRLLNEGVAYYMKMLLLFRQESTGERPKEEL QEELICHIREQQQRNQADKNTQALPLDKALEALRQLYELLVPSSVGQSGDAQIISRKFLS PLVDPNSEGGKGTSKAGAKPTWQKKKEANDPTWEQDYEKWKKRREEDPTASVITTLEE

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YGIRPIFPLYTNTVTDIAWLPLQSNQFVRTWDRDMLQQAIERLLSWESWNKRVQEEYAK

LKEKMAQLNEQLEGGQEWISLLEQYEENRERELRENMTAANDKYRITKRQMKGWNEL

YELWSTFPASASHEQYKEALKRVQQRLRGRFGDAHFFQYLMEEKNRLIWKGNPQRIHY

FVARNELTKRLEEAKQSATMTLPNARKHPLWVRFDARGGNLQDYYLTAEADKPRSRRF

VTFSQLIWPSESGWMEKKDVEVELALSRQFYQQVKLLKNDKGKQKIEFKDKGSGSTFN

GHLGGAKLQLERGDLEKEEKNFEDGEIGSVYLNVVIDFEPLQEVKNGRVQAPYGQVLQ

LIRRPNEFPKVTTYKSEQLVEWIKASPQHSAGVESLASGFRVMSIDLGLRAAAATSIFSVE

ESSDKNAADFSYWIEGTPLVAVHQRSYMLRLPGEQVEKQVMEKRDERFQLHQRVKFQI

RVLAQIMRMANKQYGDRWDELDSLKQAVEQKKSPLDQTDRTFWEGIVCDLTKVLPRN

EADWEQAWQIHRKAEEYVGKAVQAWRKRFAADERKGIAGLSMWNIEELEGLRKLLIS

WSRRTRNPQEVNRFERGHTSHQRLLTHIQNVKEDRLKQLSHAIVMTALGYVYDERKQE

WCAEYPACQVKFENLSQYRSNLDRSTKENSTLMKWAHRSIPKYVHMQAEPYGIQIGDV

RAEY S SRF Y AKTGTPGIRCKK VRGQDLQGRRFENLQKRL VNEQF LTEEQ VKQLRPGDIV

PDDSGELFMTLTDGSGSKEWFLQADINAAHNLQKRFWQRYNELFKVSCRVIVRDEEE

YLVPKTKSVQAKLGKGLF\/KKSDTAWKDVY\AVDSQAKLKGKTTFTEESESPEQLEDFQ

EIIEEAEEAKGTYRTLFRDPSGVFFPESVWYPQKDFWGEVKRKLYGKLRERFLTKAR (SEQ ID NO; 35) [001399] Gene ID: D; Gene Type: C2C2; Organism: 4. Lachnospiraceae bacterium NK4A144

G619; Spacer Length - mode (range): 35; DR1:

GUUUUGAGAAUAGCCCGACAUAGAGGGCAAUAGAC (SEQ ID NO: 36), DR2:

GUUAUGAAAACAGCCCGACAUAGAGGGCAAUAGACA (SEQ ID NO: 37); tracrRNAl:

none; tracrRNA2: none; Protein Sequence:

MKISKVDHTRMAVAKGNQHRRDEISGILYKDPTKTGSIDFDERFKKLNCSAKILYHVFN

GIAEGSNKYKNIVDKWNNLDRVLFTGKSYDRKSIIDIDTVLRNVEKINAFDRISTEEREQ

IIDDLLEIQLRKGLRKGKAGLREVLLIGAGVTVRTDKKQEIADFLEILDEDFNKTNQAKNI

KLSIENQGLVVSPVSRGEERIFDVSGAQKGKSSKKAQEKEALSAFLLDYADLDKNVRFE

YLRKIRRLINLYFYVKNDDVMSLTEIPAEVNLEKDFDIWRDHEQRKEENGDFVGCPDILL

ADRDVKKSNSKQVKIAERQLRESIREKNIKRYRFSIKTIEKDDGTYFFANKQISVFWIHRI

ENAVERILGSINDKKLYRLRLGYLGEKVWKDILNFLSIKYIAVGKAVFNFAMDDLQEKD

RDIEPGKISENAVNGLTSFDYEQIKADEMLQREVAVNVAFAANNLARVTVDIPQNGEKE

DILLWNK SDIKKYKKNSKKGRKSILQFFGGA STWNMKMFEIAYHDQPGD YEENYLYDI

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PCT/US2016/038181 iQimi.XNKSFliFKTYDHGDKNWNREiJGKMIEFIDAERVISVEREKFHSNNi Ρ\Π ΥΚΙ)Λ

DLKKILDLLYSDYAGRASQVPAFNTVLVRKNFPEFLRKDMGYKVHFNNPEVENQWHSA

VYYLYKEIYYNLFLRDKEVKNLFYTSLKNIRSEVSDKKQKLASDDFASRCEEIEDRSLPEI

CQIIMTEYNAQNFGNRKVKSQRVIEKNKDIFRHYKMLLIKTLAGAFSLYLKQERFAFIGK

ATPIPYETTDVKNFLPEWKSGMYASFVEEIKNNLDLQEWYIVGRFLNGRMLNQLAGSLR

SYIQYAEDIERRAAENRNKLFSKPDEKIEACKKAVRVLDLCIKISTKISAEFTDYFDSEDD

YADYLEKYLKYQDDAIKELSGSSYAALDHFCNKDDLKFDIYVNAGQKPILQRNIVMAK

LFGPDNILSEVMEKVTESAIREYYDYLKKVSGYRVRGKCSTEKEQEDLLKFQRLKNAVE

FRDVTEYyVEVINELLGQLISWSYLRERDLLYFQLGFHYMCLKNKSFKPAEYVDniRNNG

TIIHNAILYQIVSMYINGLDFYSCDKEGKTLKPIETGKGA/GSKIGQFIKYSQYLYNDPSYK

LEIYNAGLEVFENIDEHDNITDLRKYVDHFKYYAYGNKMSLLDLYSEFFDRFFTYDMKY

QKNVVNVLENiLLRHFViFYPKFGSGKKDVGiRDCKKERAQIEiSEQSLTSEDEMEKLDD

KAGEEAKKFPARDERYLQTFAKLLYYPNEIEDMNRFMKKGETINKKVQFNRKKKITRKQ

KNNSSNEVLSSTMGYLFKNIKL (SEQ ID NO: 38) [001400] Gene ID: E; Gene Type: C2C2; Organism: 8. Listeria seeligeri serovar l/2b sir. SLCC3954; Spacer Length - mode (range): 30; DR1:

GUUUUAGUCCUCUUUCAIJAUAGAGGUAGUCUCUUAC (SEQ ID NO: 39); DR2: none;

tracrRNAl:

AUGAAAAGAGGACUAAAACUGAAAGAGGACUAAAACACCAGAUGUGGAUAACUA

UAUUAGUGGCUAUUAAAAAUUCGUCGAUAUUAGAGAGGAAACUUU (SEQ ID NO:

40); tracrRNAl: none; Protein Sequence:

AIWISIKTLIHHLGVLFFCDYMYNRREKKIIEVKTMRITKVEVDRKKVLISRDKNGGKLV

YENEMQDNTEQIMHHKKSSFYKSVVNKTICRPEQKQMKKLVHGLLQENSQEKIKVSDV

TKLNISNFLNHRFKKSLYYFPENSPDKSEEYRIEINLSQLLEDSLKKQQGTFICWESFSKD

MELYINWAENYTSSKTKLIKKSnENNRIQSTESRSGQLMDRYMKDILNKNKPFDIQSVSE

KYQLEKLTSALKATFKEAKKNDKEINYKLKSTLQNilERQIIEELKENSELNQFNIEIRKHL

ETYFP1KK TNRKVGDIRNLEIGEIQKIVNHRLKNKIVQRILQEGKLASYEIESTVNSNSLQK

IKIEEAFALKFINACLFASNNLRNMVYPVCKKDILMIGEFKNSFKEIKHKKFIRQWSQFFS

QEITVDDlELASWGLRGAIAPlRNEllHEKKHSWKKFFNNPTFKVKKSKnNGKTKDVTSE

FLYKETLFKDYFYSELDSVPELIINKMESSKILDYYSSDQLNQVFTIPNFELSLLTSAVPFA

PSFKRVYLKGFDYQNQDEAQPDYNLKLNIYNEKAFNSEAFQAQYSLFKMVYYQVFLPQ

492

WO 2016/205711

PCT/US2016/038181

FTTNNDLFKSSWFILTLNKERKGYAKAFQDIRKMNKDEKPSEYMSYIQSQLMLYQKKQ

EEKEKINHFEKF1NQVFIKGFNSFIEKNRLTYICHPTKNTVPENDNIEIPFHTDMDDSNIAF

WLMCKLLDAKQLSELRNEMIKFSCSLQSTEEISTFTKAREVIGLALLNGEKGCNDWKEL

FDDKEAWKKNMSLYVSEELLQSLPYTQEDGQTPVINRSIDLVKKYGTETILEKLFSSSDD

YKVSAKDIAKLHEYDVTEKIAQQESLHKQWIEKPGLARDSAWTKKYQNVINDISNYQW

AKTKVELTQVRHLHQLTIDLLSRLAGYMSIADRDFQFSSNYILERENSEYRVTSWILLSE NKNKNKYNDYELYNLKNAS1KVSSKNDPQLKVDLKQLRLTLEYLELFDNRLKEKRNNIS HFNYLNGQLGNSILELFDDARDVLSYDRKLKNAVSKSLKEILSSHGMEVTFKPLYQTNH HLKIDKLQPKKIHHLGEKSTVSSNQVSNEYCQLVRTLLTMK (SEQ ID NO: 41) [001401] Gene ID: F; Gene Type: C2C2; Organism: 12. Leptotrichia wadei F0279; Spacer Length - mode (range): 31; DR1:

GUUUUAGUCCCCUUCGUUUUUGGGGUAGUCUAAAUC (SEQ ID NO: 42); DR2: none; tracrRNA 1:

GAUUUAGAGCACCCCAAAAGUAAUGAAAAUUUGCAAUUAAAUAAGGAAUAUUAA

AAAAAUGUGAUUUUAAAAAAAUUGAAGAAAUUAAA.UGAAAAAUUGUCCAAGUAA

AAAAA (SEQ ID NO: 43); tracrRNA2:

AUUUAGAUUACCCCLnjUAA.ULnjA.UUUUACCAUALnjLnjUCUCAUAAUGCAAACUA

AUAUUCCAAAAUUUUU (SEQ ID NO: 44); Protein Sequence:

MGNLFGHKRWYEVRDKKDFKIKRKVKVKRNYDGNKYILNINENNNKEKIDNNKFIRKY

INYKKNDNILKEFTRKFHAGNILFKLKGKEGIIRIENNDDFLETEEVVLYIEAYGKSEKLK

ALGITKKKIIDEAIRQGITKDDKKIEIKRQENEEEIEIDIRDEYTNKTLNDCSIILRIIENDELE

TKJCSIYEIFKNlNMSLYKIIEKnENETEKVFENRYYEEHLREKLLKDDKIDVILTNFMEIRE

KIKSNLEILGFVKFYLNVGGDKKKSKNKKMLVEKILNINVDLTVEDLADFVIKELEFWNI

TKRJEKVKKVNNEFLEKRRNRTYIKSYVLLDKHEKFKIERENKKDKIVKFFVEN1KNNSI

KEKIEKILAEFKIDELIKKLEKELKKGNCDTEIFGIFKKHYKVNFDSKKFSKKSDEEKELY

KIIYR.YLKGRIEKILVNEQKVRLKKMEKIEIEKILNESILSEKILKRVKQYTLEHIMYLGKL

RHNDIDMTTVNTDDFSRLHAKEELDLELITFFASTNMEUNKIFSRENINNDENIDFFGGDR

EKNYVLDKKILNSKIKIIRDLDFIDNKNNITNNFIRKFTKIGTNERNRILHAISKERDLQGT

QDDYNKVlNIIQNLKISDEEVSKALNLDVVFKDKKNnTKlNDlKISEENNNDIKYLPSFSK

VLPEILNLYRNNPKNEPFDTIETEKIVLNALIYVNKELYKKLILEDDLEENESKNIFLQELK

KTLGNIDEIDENIIENYYK.NAQISASKGNNKAIKKYQKK\YECYIGYLRKNYEELFDFSDF

493

WO 2016/205711

PCT/US2016/038181

KMNIQEIKKQIKDINDNKTYERITVKTSDKTWINDDFEYIISIEALLNSNAVINKIRNRFFA

TSVWLNTSEYQNIIDILDEIMQLNTLRNECITENWNENLEEFIQKMKEIEKDFDDFKIQTK

KEIFNNYYEDIKNNILTEFKDDINGCDVLEKKLEKIVIFDDETKFEIDKKSNILQDEQRKLS

NTNKKDLKKKAOQYIKDKDQEIKSKILCRIIFNSDFLKKYKKEIDNLIEDMESENENKFQE

IYYPKERKNELYIYKKNLFLNIGNPNFDKIYGLISNDIKMADAKFLFNIDGKNIRKNKISEI

DAIEKNLNDKLNGYSKEYKEKYIKKLKENDDFFAKNIQNKNYKSFEKDYNRVSEYKKIR

DLVEFNYLNKIESYEIDINWKLAIQMiARFERDMHYIVNGLRELGIIKLSGYNTGISRAYPK

RNGSDGFYTTTAYYKFFDEESYKKFEKICYGFGIDLSENSEINKPENESIRNYISHFYIVRN

PFADYSIAEQIDRVSNLLSYSTRYNNSTYASVFEVFKKDVNLDYDELKKKFKLIGNNDIL

ERI.MKPKK.VSVLElESYNSDYIKNFIIELLTKIENTNDTL (SEQ ID NO: 45) [001402] Gene ID: G; Gene Type: C2C2; Organism: 14. Leptotrichia shahii DSM 19757 B031; Spacer Length - mode (range): 30 (30-32); DR1:

GUUUUAGUCCCCUUCGAUAUUGGGGUGGUCUAUAUC (SEQ ID NO: 46), DR2: none; tracrRNA!:

AUUGAUGUGGUAUACUAAAAAUGGAAAAUUGUAUUUUUGAUUAGAAAGA.UGUAA AAUUGAUUUAAUUUAAAAAUAUUUUAUUAGAUUAAAGUAGA (SEQ ID NO: 47); tracrRNA2: none; Protein Sequence:

MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKAKQIIDKYHQF

FIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKDSEKFKN

LFNQNLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWTTYFKGF

HENRKNVYSSNDIPTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKDLAEELT

FDIDYKTSEA'NQRVFSLDEA'FEIANFNNYLNQSGITKFNTIIGGKFVNGEN TKRKGINEYI

NLYSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDVVTTMQSFYEQIAAFKT

VEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLTDLSQQVFDDYSVIGTAVLEYITQQI

APKNLDNPSKKEQELIAKKTEKAKYLSLETIKLALEEFNKHRDIDKQCRFEEILANFAAIP

MIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEDDVKAIKDLLDQTNNI.>LHKLKIEHIS

Ο5ί4)ΚΑΝΠ.Ι)ΚϋΙΊ Π ΥΙΑΊ·ΕΕ(ΎΙ·Εί.ΑΝ!\'Ρί.ΥΝΚΪΡ.ΝΥΠΪ)ΚΡΥ5ΟΕΚΙΚΙ.ΝΊ·ΕΝ8Γί.Α

NGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENKGEGYKKIVYKLLPG

ANKMLPKVFFSAKSIKFYNPSEDILRIRNHSTHTKNGSPQKGYEKFEFNIEDCRKFIDFYK

QSISKHPEWKDFGFRFSDTQRYNSIDEFYREVENQGYKLTFENISESYIDSVVNQGKLYL

FQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDWYKLNGEAELFYRKQSIPKKITHP

494

WO 2016/205711

PCT/US2016/038181

AKEAIANKNKDNPKKESVFEYDLIKDKRFTEDKFFFITCPITINFKSSGANKFNDEINLLLK BRAND VHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMKTNYHDKLAAIEKDR DSARKDWKKINNIKEMKEGYLSQWHEIAKLVIEYNAIWFEDLNFGFKRGRFKVEKQV YQKLEKMLIEKLNYLVFKDNEFDKTGGVLRAYQLTAPFETFKKMGKQTGnYYVPAGFT SKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGDKAAKGK WTIASFGSRLINFRNSDKNHNWDTREVYPTKELEKLLKDYSIEYGHGECIKAAICGESDK KFFAKLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPKNMPQDADANGA YHIGLKGLMLLGRIKNNQEGKKLNLVIKNEEYFEFVQNRNN (SEQ ID NO; 48) [001403] Gene ID: H; Gene Type: Cpfl; Organism: Francisella ularensis subsp. novicida U112; Spacer Length - mode (range): 31; DR1:

GUCUAAGAACUUUAAAUAAUUUCUACUGUUGUAGAU (SEQ ID NO: 49);; DR2: none, tracrRNAl:

AUCUACAAAAUUAUAAACUAAAUAAAGAUUCUIJAUAAUAACUUUAUAUAUAAUC

GAAAUGUAGAGAAUUUU (SEQ ID NO: 50); tracrRNA2: none; Protein Sequence:

MSIYQEFVNKYSLSKTLRFELIPQGK TLENIKARGLILDDEKRAKDYKKAKQIIDKYITQF

FTEEILSSVCISEDLLQNYSDVYEKLKKSDDDNLQKDFKSAKDTIKKQISEYIKDSEKFKN

LFNQNLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWTTYFKGF

HENRKNVYSSNDIPTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKDLAEELT

FDIDYKTSEVNQRVFSLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRKGINEYI

NLYSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDVVTTMQSFYEQIAAFKT

VEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLTDLSQQVFDDYSVIGTAVLEYITQQI

APKNLDNPSKKEQELIAKKTEKAKYLSLETIKLALEEFNKHRDIDKQCRFEEILANFAAIP

MIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEDDVKAIKDLLDQTNNLLHKLKIT'HIS

QSEDKANILDKDEHFYLVFEECYFELANIVPLYNKIRNYITQKPYSDEKFKLNFENSTLA

NGVVDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENKGEGYKKIVYKLLPG

ANKMLPKWFSAKSIKFYNPSEDILRIRNHSTHTKNGSPQKGYEKEEFNIEDCRKFIDFYK

QSISKHPEWKDFGFRFSDTQRYNSIDEFYREVENQGYKLTFENISESYIDSVVNQGKLYL

FQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDWYKLNGEAELFYRKQSIPKKITHP

AKEAIANKNKDNPKKESVFEYDLIKDKRFTEDKFPTTICPITrNFKSSGANKFNDEINLLLK

EKANDVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMKTNYHDKLAAIEKDR

DSARKDWKKINNIKEMKEGYLSQA/VIIEIAKLVHiYNAIVWEDLNFGFKRGRFKVEKQV

495

WO 2016/205711

PCT/US2016/038181

YQKLEKMLIEKLNYLWKDNEFDKTGGVLRAYQLTAPFETFKKMGKQTGIIYYVPAGFT

SKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGDKAAKGK

WTIASFGSRLINFRNSDKNHNWDTREVYPTKELEKLLKDYSIEYGHGECIKAAICGESDK

KFFAKLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPKNMPQDADANGA YHEGLKGLMLLGRIKNNQEGKKLNLVIKNEEYFEFVQNRNN (SEQ ID NO: 51) [001404] Genes for synthesis [001405] For genes A through H, optimize for human expression and append the following DNA sequence to the end of each gene. Note this DNA sequence contains a stop codon (underlined), so do not add any stop codon to the codon optimized gene sequence:

AAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGggatccTAC

CCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCA/

ATGATGTCCCCGACTATGCCTAA (SEQ ID NO: 52) [001406] For optimization, avoid the following restriction sites: BamHI, EcoRI Hindlll, BsrnBI, Bsal, Bbsl, Age! Xhol, Ndel, Notl, Kpnl, BsrGI, Spel, Xbal, Nhel [001407] These genes are cloned into a simple mammalian expression vector:

[001408] >A

MSLNRIYQGRVAAVETGTALAKGNVEWMPAAGGDEVLWQHHELFQAAINYYLVALL

ALADKNNPVLGPLISQMDNPQSPYHVWGSFRRQGRQRTGLSQAVAPYITPGNNM’TLD

AMLRREQHRLLLPQVLHDPAITHDSPALGSFDTYSIATPDTRTPQLTGPKARARLEQAIT

LWRVRLPESAADFDRLASSLKKIPDDDSRLNLQGYVGSSAKGEVQARLFALLLFRHLER

SSFTLGLLRSATPPPKNAETPPPAGVPLPAASAADPVRIARGKRSFVFRAFTSLPCWHGG

DNIHPTWKSFDIAAFKYALTVINQIEEKTKERQKECAELETDFDYMHGRL.AKIPVKYTTG

EAEPPPILANDLRIPLLRELLQNIKWTALTDGEAVSYGLQRRTIRGFRELRRIWRGHAPA

GTVFSSELKEKLAGELRQFQTDNSTTIGSVQLFNELIQNPKYWPIWQAPDVETARQWAD

AGFADDPLAALVQEAELQEDEDALKAPVKLTPADPEYSRRQYDFNAVSKFGAGSRSAN

RHEPGQ TERGHNTFTT El AARNA ADGNRWRATIIVR THY S A PRLLRDGLRRPDTDGNE A

LEAVPWLQPMMEALAPLPTLPQDLTGMPVFLMPDVTLSGERRILLNLPVTLEPAALVEQ

LGNAGRWQNQFFGSREDPFALRWPADGAVKTAKGKTHIPWHQDRDHFTVLGVDLGTR

DAGALALLNVTAQKPAKPVHRIIGEADGRTWYASLADARMIRLPGEDARLFVRGKLVQ

EPYGERGRNASLLEWEDARNIILRLGQNPDELLGADPRRHSYPEINDKLLVALRRAQAR

496

WO 2016/205711

PCT/US2016/038181

LARLQNRSWRLRDLAESDKALDE1HAERAGEKPSPLPPLARDDAIKSTDEALLSQRDIIR

RSFVQIANLILPLRGRRWEVVRPHVEVPDCHILAQSDPGTDDTKRLVAGQRGISHERIEQ1E

ELRRRCQSLNRALRHKPGERPVLGRPAKGEEIADPCPALLEKINRLRDQRVDQTAHAILA

AALGVRLRAPSKDRAERRHRDIHGEYERFRAPADFVV1ENLSRYLSSQDRARSENTRLM

QWCHRQIVQKLRQLCETYGIPVLAVPAAYSSRFSSRDGSAGFRAVHLTPDHRHRMPWS

RILARLKAHEEDGKRLEK TVLDEARAVRGLFDRLDRFN AGHVPGKPWRTLLA PLPGGP

VFVPLGDATPMQADLNAAINiALRGIAAPDRHDIHHRLRAENKKRILSLRLGTQREKAR

WPGGAPAVTLSTPNNGASPEDSDALPERVSNLFVDIAGVANFERVTIEGVSQKFATGRG

LWASVKQRAWNRVARLNETVTDNNRNEEEDDIPAI (SEQ ID NO: 53) [001409] >B [001410] MATRSFILKIEPNEEVKKGLWKTHEVLNHGIAYYMNILKLIRQEAIYEHHEQD

PKNPKKVSKAEIQAELWDFVLKMQKCNSFTHEVDKDWFNILRELYEELVPSSVEKKGE

ANQLSNKFLYPLVDPNSQSGKGTASSGRKPRWYNLKIAGDPSWEEEKKKWEEDKKKDP

LAKILGKLAEYGLIPLFIPFTDSNEPIVKEIKWMEKSRNQSVRRLDKDMFIQALERFLSWE

SWNLKVKEEYEKVEKEHKTLEERJKEDIQAFKSLEQYEKERQEQLLRDTLNTNEYRLSK

RGLRGWREIIQKWLKMDENEPSEKYLEVFKDYQRKHPREAGDYSVYEFLSKKENHFIW

RNHPEYPYLYATFCEIDKKKKDAKQQATFTLADPINHPLWVRFEERSGSNLNKYRILTE

QLHTEKLKKKLTVQLDRLIYPTESGGWEEKGKVDIVLLPSRQFYNQIFLDIEEKGKHAFT

YKDESIKFPLKGTLGGARVQFDRDHLRRYPHKVESGNVGRIYFNMTVNIEPTESPVSKSL

KIHRDDFPKFVNFKPKELTEWIKDSKGKKLKSGIESLEIGLRVMSIDLGQRQAAAASIFEV

VDQKPDfEGKLFFPiKGTELYAVHRASFNIKLPGETLVKSREVLRKAREDNLKLMNQKL

NFLRNVLHFQQFEDITEREKRVTKWISRQENSDVPLVYQDELIQ1RELMYKPYKDWVAF

LKQLHKRLEVEIGKEVKHWRKSLSDGRKGLYGISLKNIDEIDRTRKFLLRWSLRPTEPGE

VRRLEPGQRFAIDQLNHLNALKEDRLKKMANTIIMHALGYCYDVRKKKWQAKNPACQI

ILFEDLSNYNPYEERSRF'ENSKLMKWSRREIPRQ VALQGEIYGLQ VGEVGAQF S SRF'HAK

TGSPGIRCSVVTKEKLQDNRFFKNLQREGRLTLDKIAAffiKEGDLYPDKGGEKFISLSKDR

KLVTTHADINAAQNLQKRFWTRTHGFYKVYCKAYQVDGQTVYIPESKDQKQKHEEFG

EGYFILKDGVYEWGNAGKLKIKKGSSKQSSSELVDSDILKDSFDLASELKGEKLMLYRD

PSGNVFPSDKWMAAGVFFGKLERILISKLTNQYSISTIEDDSSKQSM (SEQ ID NO: 54) [001411] >C

497

WO 2016/205711

PCT/US2016/038181 [001412] MAIRSIKLKLKTHTGPE AQNLRKGIWRTHRLLNEGVAYYMKMLLLFRQESTG

ERPKEELQEELICHIREQQQRNQADKNTQ.ALPLDKALEALRQLYELLVPSSVGQSGDAQI

ISRKFLSPLVDPNSEGGKGTSKAGAKPTWQKKKEANDPTWEQDYEKWKKRREEDPTAS

VITTLEEYGIRPIFPLYTNTVTDIAWLPLQSNQFVRTWDRDMLQQAIERLLSWESWNKRV

QEEYAKLKEKMAQLNEQLEGGQEWISLLEQYEENRERELRENMTAANDKYRITKRQM

KGWNELYELWSTFPASASHEQYKEALKRVQQRLRGRFGDAHFFQYLMEEKNRLEVKG

NPQR1HYFVARNELTKRLEEAKQSATMTLPNARKHPLWVRFDARGGNLQDYYLTAEAD

KPRSRRFVTFSQLIWPSESGWMEKKDVEVELALSRQFYQQVKLLKNDKGKQKIEFKDK

GSGSTFNGHLGGAKLQLERGDLEKEEKNFEDGEIGSVYLNVVIDFEPLQEVKNGRVQAP

YGQVLQLIRRPNEFPKVTTYKSEQLVEWIKASPQHSAGVESLASGFRVMSIDLGLRAAA

ATSIFSVEESSDKNAADFSYWIEGTPLVAVHQRSYMLRLPGEQVEKQVMEKRDERFQLH

QRVKFQIRVLAQIMRMANKQYGDRWDELDSLKQAVEQKKSPLDQTDRTFWEGIVCDL

TKVLPRNEADWEQAVVQIHRKAEEYVGKAVQAWRKRFAADERKGIAGLSMWNIEELE

GLRKLLISWSRRTRNPQEVNRFERGHTSHQRLLTHIQNVKEDRLKQLSHAIVMTALGYV

YDERKQEWCAEYPACQVILFENLSQYRSNLDRSTKENSTLMKWAHRSIPKYVHMQAEP

YGIQIGDVRAEYSSRFY.AKTGTPGIRCKKVRGQDLQGRRFENLQKRLVNEQFL TEEQVK

QLRPGDIVPDDSGELFMTLTDGSGSKEVVFLQADINAAHNLQKRFWQRYNELFKVSCR

VIVRDEEEYLVPKTKSVQAKLGKGLFVKKSDTAWKDVYVWDSQAKLKGKTTFTEESES

PEQLEDFQEIIEEAEEAKGTYRTLFRDPSGVFFPESVWYPQKDFWGEVKRKLYGKLRERF

LTKAR (SEQ ID NO: 55) [001413] >D [001414] MK1SKVDHTRMAVAKGNQHRRDEISGILYKDPTKTGS1DFDERFKKLNCSAK1

LYHVFNGIAEGSNKYKNIVDKVNNNLDRVLFTGKSYDRKSIIDIDTVLRNVEKIMAFDRI

STEEREQIIDDLLEIQLRKGLRKGKAGLREVLLIGAGVn/RTDKKQEIADFLEILDEDFNK

TNQAKNIKLSIENQGLVVSPVSRGEERIFDVSGAQKGKSSKKAQEKEALSAFLLDYADL

DKNVRFEYLRKIRRLINLYFYVKNDDVMSLTEIPAEVNLEKDFDIWRDHEQRKEENGDF

VGCPDILLADRDVKKSNSKQVKIAERQLRESIREKNIKRYRFSIKTIEKDDGTYFFANKQI

SVFWIHRIENAVERILGSINDKKLYRLRLGYLGEKVWKDILNFLSIKYIAVGKAVFNFAM

DDLQEKDRDIEPGKISENAVNGLTSFDYEQIKADEMLQREVAVNVAFAANNLARVTVDI

PQNGEKEDILLWNKSDIKKYKKNSKKGILKSILQFFGGASTWNMKMFEIAYHDQPGDYE

ENYLYDIIQOTSIXNKSFHFKTYDHGDKNWNREIJGKMIEHDAERVISVEREKFHSNNLP

498

WO 2016/205711

PCT/US2016/038181

MFYKDADLKKILDLLYSDYAGRASQWAFNTVLVRKNFPEFLRKDMGYKVHFNNPFATi

NQWHSAVYYLYKEIYYNLFLRDKEVKNLFYTSLKNIRSEVSDKKQKLASDDFASRCEEI

EDRSLPEICQIIMIEYNAQNFGNRKVKSQRVIEKNKDIFRHYKMLLIKTLAGAFSLYLKQ

ERFAFIGKATPIPYETTDVKNFLPEWKSGMYASFVEEIKNNLDLQEWYIVGRFLNGRML

NQLAGSLRSYIQYAEDIERRAAENRNKLFSKPDEKIEACKKAVRVLDLCIKISIRISAEFT

DYFDSEDDYADYLEKYLKYQDDAIKELSGSSYAALDHFCNKDDLKFDIYVNAGQKPIL

QRNIVMAKLFGPDNFLSEVMEKVTESAIREYYDYLKKVSGYRVRGKCSTEKEQEDLLKF

QRLKNAVEFRDVTEYAEVINELLGQLISWSYLRERDLLYFQLGFHYMCLKNKSFKPAEY

VDIRRNNGTHHNAILYQIVSMYINGLDFYSCDKEGK TLKPIETGKGVGSKIGQFIKYSQY

LYNDPSYKLEIYNAGLEVFENIDEHDNITDLRKYA/DIiFKYYAYGNKMSLLDLYSEFFDR

FFTYDMKYQKNVVNVLENILLRHFVIFYPKFGSGKKDVGIRDCKKERAQIEISEQSLTSE

DFMFKLDDKAGEEAKKFPARDERYLQTIAKLLYYPNEIEDMNRFMKKGETINKKVQFN

RKKKITRKQKNNSSNEVLSSTMGYLFKNIKL (SEQ ID NO; 56) [001415] >E [001416] MWISIKTLnfflLGVLFFCDYMYNRREKKIIEVKTMRITKVEA/DRKKVLISRDK NGGKLVYENEMQDNTEQIMHHKKS SFYKS WNKTICRPEQKQMKKLVHGLLQENSQE KIKVSDVTKLNISNFLNHRFKKSLYYFPENSPDKSEEYRIEINLSQLLEDSLKKQQGTFIC

WESFSKDMELYINWAENYISSKTKLIKKSIRNNRIQSTESRSGQLMDRYMKDILNKNKPF

DIQSVSEKYQLEKLTSALKATFKEAKKNDKEINYKLKSTLQNHERQIIEELKENSELNQF

NIEIRKHLETYFPIKKTNRKVGDIRNLEIGEIQKIVNHRLKNKIVQRILQEGKLASYEIESTV

NSNSLQKIKIEEAFALKFINACLFASNNLRNMVYPVCKKDILMIGEFKNSFKEIKHKKFIR

QWSQFFSQEITVDDIELASWGLRGAIAPIRNEnHLKKHSWKKFFNNPTFKVKKSKIINGK

TKDVTSEFLYKETLFKDYFYSELDSVPELIINKMES SKIED YYS SDQLNQVFTIPNFELSLL

TSAVPFAPSFKRVYLKGFDYQNQDEAQPDYNLKLNIYNEKAFNSEAFQAQYSLFKMVY

YQVFLPQFTTNNDLFKSSVDFILTLNKERKGYAKAFQDIRKMNKDEKPSEYMSYIQSQL

MLYQKKQEEKEKINHFEKFINQVFIKGFNSFIEKNRLTYICHPTKNTVPENDNIEIPFHTD

MDDSNIAFWLMCKLLDAKQLSELENEMIKFSCSLQSTEinSTFTKAREVIGLAIRNGEKG

CNDWKELFDDKEAWKKNMSLYVSEELLQSLPYTQEDGQTPVINRSIDLVKKYGTETILE

KLFSSSDDYKVSAKDIAKLHEYDVTEKIAQQESLHKQWIEKPGLARDSAWTKKYQNVIN

DISNYQWAKTKVELTQVRHLHQLTIDLLSRLAGYMSIADRDFQFSSNYILERENSEYRVT

SWRLSENKNKNKYNDYELYNLKNASIKVSSKNDPQLKWLKQLRLTLEYLELFDNRLK

499

WO 2016/205711

PCT/US2016/038181

EKRNNISHFNYLNGQLGNSILELFDDARDVLSYDRKLKNAVSKSLKEILSSHGMEVTFKP LYQTNHHLKIDKLQPKKIHHLGEKSTVSSNQVSNEYCQLVRTLLTMK (SEQ ID NO: 57) [001417] >F [001418] MK VIK VDGISHKKYIEEGKIATOTSEENRTSERLSELLSIRLDIYIKNPDN ASE

EENRIRRENLKKFF SNKVLHLKD SVL YLKNRKEKNAVQDKNYSEEDISE YDLKNKNSF S

VLKKILLNEDVNSEELEIFRKDVEAKLNKINSLKYSFEENKANYQKINENNVEKVGGKS

KRNIIYDYYRESAKRNDYINNVQEAFDKLYKKEDIEKLEFLiENSKKHEKYKIREYYHKH

GRKNDKENFAKIIYEEIQNVNNIKELIEKIPDMSELKKSQVFYKYYLDKEELNDKNIKYA

FCHFVEIEMSQLLKNYVYKRLSNISNDKIKRIFEYQNLKKLIENKLLNKLDTYVRNCGKY

NYYLQVGEIATSDFIARNRQNEAFLRNIIGVSSVAYFSLRNILETENENDITGRMRGKTA/K

NNKGEEKYVSGEVDKIYNENKQNEVKENLKMFYSYDFNMDNKNEIEDFFANIDEAISSI

RHGIVHFNLELEGKDIFAFKNIAPSEISKKMFQNEINEKKLKLKIFKQLNSANVFNYYEKD

VIIKYLKNTKFNFVNKN1PFVPSFTKLYNKIEDLRNTLKFFWSVPKDKEEKDAQIYLLKNI

YYGEFLNKFVKNSKVFFKIINEVIKINKQRNQKTGHYKYQKFENIEKTVPVEYLAnQSR

EMINNQDKEEKNTYIDFIQQIFLKGFIDYLNKNNLKYIESNNNNDNNDIFSKIKIKKDNKE

KYDKILKNYEKHNRNKED’HEINEFVREIKLGKILKYTENLNMFYLILKLLNHKELTNLK

GSLEKYQSANKEETFSDELELINLLNLDNNRVTEDFELEANEIGKFLDFNENKIKDRKEL

KKFDTNKIYFDGENUKHRAFYNIKKYGMLNLLEKIADKAKYKISLKELKEYSNKKNEIE

KNYTMQQNLHRKYARPKKDEKFNDEDYKEYEKAIGNIQKYTHLKNKVEFNELNLLQG

LLLKILHRLVGYTSIWERDLRFRLKGEFPENHYIEEIFNFDNSKNVKYKSGQIVEKYINFY

KELYKDNVEKRSIYSDKKVKKLKQEKKDLYIRNYIAHFNYIPHAEISLLEVLENLRKLLS

YDRKLKNAIMKSIVDILKEYGFVATFKIGADKKIEIQTLESEKIVHLKNLKKKKLMTDRN

SEELCELVKVMFEYKALE (SEQ ID NO: 58) [001419] >G [001420] MGNLFGHKRWYEVRDKKDFKIKRKVKVKRNYDGNKYILNiNENNNKEKID NNKFIRKYINYKKNDNILKEFTRKFHAGNILFKLKGKEGIIRIENNDDFLETEEVVLYIEA YGKSEKLKALGITKKKIIDEAIRQGITKDDKKIEIKRQENEEEIEIDIRDEYTNK TLNDCSII

LRIIENDELETKKSIYEIFKNINMSLYKIIEKIIENETEKVFENRYYEEHLREKLLKDDKIDV ILTNFMEIREKIKSNLEILGFVKFYLNVGGDKKKSKNKKMLVEKILN1NVDLTVEDIADF VIKELEFWNFFKRIEK VKKVNNEFEEKRRNRTYIKSY VLLDKHEKFKIERENKKDKIVKF FVENIKNNSIKEKIEKILAEFKIDELIKKLEKELKKGNCDTEIFGIFKKHYKVNFDSKKFSK

500

WO 2016/205711

PCT/US2016/038181

KSDEEKELYKIIYRYLKGRIEKILVNEQKVRLKKMEKIEIEKILNESILSEKrLKRVKQYTL

EHIMYLGKLRHNDIDMTT VNTDDF SRLHAKEELDLELITFF ASTNMELNKIF SRENINND

ENIDFFGGDREKNYVLDKKILNSKIKIIRDLDFIDNKNNITNNFIRKFTKIGTNERNRILHAI

SKERDLQGTQDDYNKVINIIQNLKISDEEVSKALNLDVVFKDKKNHTKINDIKISEENNN

DIKYLPSFSKVLPEILNLYRNNPKNEPFDTIETEKIVLNALIYVNKELYKKLILEDDLEENE

SKNIFLQELKKTLGNIDEIDENHENYYKNAQISASKGNNKAIKKYQKKVIECYIGYLRKN

YEELFDFSDFKMNIQEIKKQIKDINDNKTYERITVKTSDKTIVINDDFEYIISIFALLNSNAV

INKIRNRFFATSVWLNTSEYQNIIDILDEIMQLNTLRNECITENWNLNLEEFIQKMKEIEKD

FDDFKIQTKKEIFNNYYEDIKNNILTEFKDDINGCDVLEKKLEKIVIFDDETKFEIDKKSNI

LQDEQRKLSNINKKDLKKKVDQYIKDKDQEIKSKILCRIIFNSDFLKKYKKEIDNLIEDME

SENENKFQEIYYPKERKNELYIYKKNLFLNIGNPNFDKIYGLISNDIKMADAKFLFNIDGK

NIRKNKISEIDAILKNLNDKLNGYSKEYKEKYIKKLKENDDFFAKNIQNKNYKSFEKDYN

RVSEYKKIRDLVEFNYLNKIESYLIDINWKLAIQMARFERDMHYIVNGLRELGIIKLSGY

NTGISRAYPKRNGSDGFYTTTAYYKFFDEESYKKFEKICYGFGIDLSENSEINKPENESIR

NYiSHFYIVRNPFADYSLAEQIDRVSNLLSYSTRYNNSTYASVFEVFKKDVNLDYDELKK

KFKLIGNNDILERLMKPKKVSVLELESYNSDYIKNLIIELLTKIENTNDTL (SEQ ID NO:

59) [001421] >H [001422] MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKAKQII

DKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKD

SEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWT

TYFKGFHENRKNVYSSND1PTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKD

LAEELTFDIDYKTSEVNQRVFSLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRK

GINEYINLYSQQINDKTLKKYKMSMEKQILSDTESKSFVIDKLEDDSDVVTTMQSFYEQI

AAFKTVEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLTDLSQQVFDDYSVIGTAVLE

YITQQIAPKNLDNPSKKEQELIAKKTEKAKYLSLETIKLALEEFNKHRDIDKQCRFEEILA

NFAAIPMIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEDDVKAIKDLLDQTNNLLHK

LKIFHISQSEDKANILDKDEHFYLVFEECYFELANIVPLYNKIRNYITQKPYSDEKFKLNFE

NSTLANGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENKGEGYKKIVY

KLLPGANKMLPKVFFSAKSIKFYNPSEDILRIRNHSTHTKNGSPQKGYEKFEFNIEDCRKF

IDFYKQSISKHPEWKDFGFRFSDTQR.YNSIDEFYREVF.NQGYKLTFENISESYIDSVVNQG

501

WO 2016/205711

PCT/US2016/038181

KLYLFQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDVVYKLNGEAELFYRKQSIPK

KITHl’AKEAIANKNKDNPKKESVFEYDLIKDKRF'TEDKFFFHCPrnNFKSSGANKFNDEI

NLLLKEKANDVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMKTNYHDKLAAI

EKDRDSARKDWKKINNIKEMKEGYLSQVVHEIAKLVIEYNAIVVFEDLNFGFKRGRFKV

PAGFTSKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGDKA

AKGKWTIASFGSRLINFRNSDKNHNWDTREVYPTKELEKLLKDYS1EYGHGEC1KAAIC

GESDKKFFAKLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPKNMPQDAD

ANGAYFUGLKGLMLLGRIKNNQEGKKLNLVIKNEEYFEFVQNRNN (SEQ ID NO: 60) [001423] For A-locus through G-locus, these genes are cloned and inserted into a low-copy plasmid, A vector that does not contain Amp resistance is used.

[001424] > A-locus [001425] TATCCGGTCGAATCGAGAATGACGACCGCTACGTCTTGGACTACGAAGCC

GTGGCCCTTGCCGATGCTCTCGGTGTGGATGTTGCCGACCTGTTCCGCAAGATCGAT

TGCCCCAAGAACCTGCTGCGCAGGCGGGCAGGGTAGGGGAGCGGTTTCCGGCGGAG

ATITTCGGAGGCGCCGGTAACGTTATGTCGGGGAATTTGCTATACATCGACGAIAAT

TAGTTTTGTTGATTCAGGATCGAAATGCGCTCAAACAAAGAACGTTCCGCGTTTCCC

TCATGCGCTACTACGCCCACACCGCCATCTTTCGGCACGCAAACAAAGCAGATGGGT

TGCCTGTCAATGGGTGATCATTGCCTGAAGTTACCATCCATCAATAATATAAATCAT

CCTTACTCCGAATGTCCCTCAATCGCATCTATCAAGGCCGCGTGGCGGCCGTCGAAA

CAGGAACGGCCTTAGCGAAAGGTAATGTCGAATGGATGCCTGCCGCAGGAGGCGAC

GAAGTTCTCTGGCAGCACCACGAACTTTTCCAAGCTGCCATCAACTACTATCTCGTC

GCCCTGCTCGCACTCGCCGACAAAAACAATCCCGTACTTGGCCCGCTGATCAGCCAG

ATGGATAATCCCCAAAGCCCTTACCATGTCTGGGGAAGTTTCCGCCGCCAAGGACGT

CAGCGCACAGGTCTCAGTCAAGCCGTTGCAC’CTTATATCACGCCGGGCAATAACGCT

CCCACCCTTGACGAAGTTTTCCGCTCCATTCTTGCGGGCAACCCAACCGACCGCGCA

ACTTTGGACGCTGCACTCATGCAATTGCTCAAGGCTTGTGACGGCGCGGGCGCTATC

CAGCAGGAAGGTCGTTCCTACTGGCCCAAATTCTGCGATCCTGACTCCACTGCCAAC

TTCG(/GGGAGATC¹CGGCCATCi(lTCCGG(XFrGAACAACACCGCCTCCTCCTTCCGCAA

GTTCTCCACGATCCGGCGATTACTCACGACAGTCCTGCCCTTGGCTCGTTCGACACTT

ATTCGATTGCTACCCCCGACACCAGAACTCCTCAACTCACCGGCCCCAAGGCACGCG

502

WO 2016/205711

PCT/US2016/038181

CCCGTCTTGAGCAGGCGATCACCCTCTGGCGCGTCCGTCTTCCCGAATCGGCTGCTG

ACTTCGATCGCCTTGCCAGTTCCCTCAAAAAAATTCCGGACGACGATTCTCGCCTTA

ACCTTCAGGGCTACGTCGGCAGCAGTGCGAAAGGCGAAGTTCAGGCCCGTCTTTTCG

CCCTTCTGCTATTCCGTCACCTGGAGCGTTCCTCCTTTACGCTTGGCCTTCTCCGTTCC

GCCACCCCGCCGCCCAAGAACGCTGAAACACCTCCTCCCGCCGGCGTTCCTTTACCT

GCGGCGTCCGCAGCCGATCCGGTGCGGATAGCCCGTGGCAAACGCAGTTTTGTTTTT

CGCGCATTCACCAGTCTCCCCTGCTGGCATGGCGGTGATAACATCCATCCCACCTGG

AAGTCATTCGACATCGCAGCGTTCAAATATGCCCTCACGGTCATCAACCAGATCGAG

GAAAAGACGAAAGAACGCCAAAAAGAATGTGCGGAACTTGAAACTGATTTCGACTA

CATGCACGGACGGCTCGCCAAGATTCCGGTAAAATACACGACCGGCGAAGCCGAAC

CGCCCCCCATTCTCGCAAACGATCTCCGCATCCCCCTCCTCCGCGAACTTCTCCAGA

ATATCAAGGTCGACACCGCACTCACCGATGGCGAAGCCGTCTCCTATGGTCTCCAAC

GCCGCACCATTCGCGGTTTCCGCGAGCTGCGCCGCATCTGGCGCGGCCATGCCCCCG

CTGGCACGGTCTTTTCCAGCGAGTTGAAAGAAAAACTAGCCGGCGAACTCCGCCAG

TTCCAGACCGACAACTCCACCACCATCGGCAGCGTCCAACTCTTCAACGAACTCATC

CAAAACCCGAAATACTGGCCCATCTGGCAGGCTCCTGACGTCGAAACCGCCCGCCA

ATGGGCCGATGCCGGTTTTGCCGACGATCCGCTCGCCGCCCTTGTGCAAGAAGCCGA

ACTCCAGGAAGACATCGACGCCCTCAAGGCTCCAGTCAAACTCACTCCGGCCGATC

CTGAGTATTCAAGAAGGCAATACGATTTCAATGCCGTCAGCAAATTCGGGGCCGGCT

CCCGCTCCGCCAATCGCCACGAACCCGGGCAGACGGAGCGCGGCCACAACACCTTT

ACCACCGAAATCGCCGCCCGTAACGCGGCGGACGGGAACCGCTGGCGGGCAACCCA

CGTCCGCATCCATTACTCCGCTCCCCGCCTTC TTCGTGACGGACTCCGCCGACCTGAC

ACCGACGGCAACGAAGCCCTGGAAGCCGTCCCTTGGCTCCAGCCCATGATGGAAGC

CCTCGCCCCTCTCCCGACGCTTCCGCAAGACCTCACAGGCATGCCGGTCTTCCTCAT

GCCCGACGTCACCCTTTCCGGTGAGCGTCGCATCCTCCTCAATCTTCCTGTCACCCTC

GAACCAGCCGCTCTTGTCGAACAACTGGGCAACGCCGGTCGCTGGCAAAACCAGTT

CTTCGGCTCCCGCGAAGATCCATTCGCTCTCCGATGGCCCGCCGACGGTGCTGTAAA

AACCGCCAAGGGGAAAACCCACATACCTTGGCACCAGGACCGCGATCACTTCACCG

TACTCGGCGTGGATCTCGGCACGCGCGATGCCGGGGCGCTCGCTCTTCTCAACGTCA

CTGCGCAAAAACCGGCCAAGCCGGTCCACCGCATCATTGGTGAGGCCGACGGACGC

ACCTGGTATGCCAGCCTTGCCGACGCTCGCATGATCCGCCTGCCCGGGGAGGATGCC

503

WO 2016/205711

PCT/US2016/038181

CGGCTCTTTGTCCGGGGAAAACTCGTTCAGGAACCCTATGGTGAACGCGGGCGAAA

CGCGTCTCTTCTCGAATGGGAAGACGCCCGCAATATCATCCTTCGCCTTGGCCAAAA

TCCCGACGAACTCCTCGGCGCCGATCCCCGGCGCCATTCGTATCCGGAAATAAACGA

TAAACTTCTCGTCGCCCTTCGCCGCGCTCAGGCCCGTCTTGCCCGTCTCCAGAACCG

GAGCTGGCGGTTGCGCGACCTTGCAGAATCGGACAAGGCCCTTGATGAAATCCATG

CCGAGCGTGCCGGGGAGAAGCCTTCTCCGCTTCCGCCCTTGGCTCGCGACGATGCCA

TCAAAAGCACCGACGAAGCCCTCCTTTCCCAGCGTGACATCATCCGGCGATCCTTCG

TTCAGATCGCCAACTTGATCCTTCCCCTTCGCGGACGCCGATGGGAATGGCGGCCCC

ATGTCGAGGTCCCGGATTGC’CACATCCTTGCGCAGAGCGATCCCGGTACGGATGAC

ACCAAGCGTCTTGTCGCCGGACAACGCGGCATCTCTCACGAGCGTATCGAGCAAAT

CGAAGAACTCCGTCGTCGCTGCCAATCCCTCAACCGTGCCCTGCGTCACAAACCCGG

AGAGCGTCCCGTGCTCGGACGCCCCGCCAAGGGCGAGGAAATCGCCGATCCCTGTC

CCGCGCTCCTCGAAAAGATCAACCGTCTCCGGGACCAGCGCGTTGACCAAACCGCG

CATGCCATCCTCGCCGCCGCTCTCGGTGTTCGACTCCGCGCCCCCTCAAAAGACCGC

GCCGAACGCCGCCATCGCGACATCCATGGCGAATACGAACGCTTTCGTGCGCCCGCT

GATTTTGTCGTCATCGAAAAC’CTCTCCCGTTATCTCAGCTCGCAGGATCGTGCTCGTA

GTGAAAACACCCGTCTCATGCAGTGGTGCCATCGCCAGATCGTGCAAAAACTCCGTC

AGCTCTGCGAGACCTACGGCATCCCCGTCCTCGCCGTCCCGGCGGCCTACTCATCGC

GTTTTTCTTCCCGGGACGGCTCGGCCGGATTCCGGGCCGTCCATCTGACACCGGACC

ACCGTCACCGGATGCCATGGAGCCGCATCCTCGCCCGCCTCAAGGCCCACGAGGAA

GACGGAAAAAGACTCGAAAAGACGGTGCTCGACGAGGCTCGCGCCGTCCGGGGACT

CTTTGACCGGCTCGACCGGTTCAACGCCGGGCATGTCCCGGGAAAACCTTGGCGCAC

GCTCCTCGCGCCGCTCCCCGGCGGCC’CTGTGTTTGTCCCCCTCGGGGACGCCACACC

CATGCAGGCCGATCTGAACGCCGCCATCAACATCGCCCTCCGGGGCATCGCGGCTCC

CGACCGCCACGACATCCATCACCGGCTCCGTGCCGAAAACAAAAAACGCATCCTGA

GCTTGCGTCTCGGCACTCAGCGCGAGAAAGCCCGCTGGCCTGGAGGAGCTCCGGCG

GTGACACTCTCCACTCCGAACAACGGCGCCTCTCCCGAAGATTCCGATGCGTTGCCC

GAACGGGTATCCAACCTGTTTGTGGACATCGCCGGTGTCGCCAACTTCGAGCGAGTC

ACGATCGAAGGAGTCTCGCAAAAATTCGCCACCGGGCGTGGCCTTTGGGCCTCCGTC

AAGCAACGTGCATGGAACCGCGTTGCCAGACTCAACGAGACAGTAACAGATAACAA

CAGGAACGAAGAGGAGGACGACATTCCGATGTAACCATTGCTTCATTACATCTGAG

504

WO 2016/205711

PCT/US2016/038181

TCTCCCCTCAATCCCTCTGCCCCATGCGTGATATAACCTCCACCTCATGTCCCGGATC

GGCGCCGGCAACCTGTAGTTCCCTTCCATCCTCCAACACTCCCGCAGATCGCGATCC

GCTGCCGCCGATGCCGGTGCGCCGCCTTCACAACTATCTCTACTGTCCGCGGCTTTTT

TATCTCCAGTGGGTCGAGAATCTCTTTGAGGAAAATGCCGACACCATTGCCGGCAGC

GCCGTGCATCGTCACGCCGACAAACCTACGCGTTACGATGATGAAAAAGCCGAGGC

ACTTCGCACTGGTCTCCCTGAAGGCGCGCACATACGCAGCCTTCGCCTGGAAAACGC

CCAACTCGGTCTCGTTGGCGTGGTGGATATCGTGGAGGGAGGCCCCGACGGACTCG

AACTCGTCGACTACAAAAAAGGTTCCGCCTTCCGCCTCGACGACGGCACGCTCGCTC

CCAAGGAAAACGACACCGTGCAACTTGCCGCCTACGCTCTTCTCCTGGCTGCCGATG

GTGCGCGCGTTGCGCCCATGGCGACGGTCTATTACGCTGCCGATCGCCGGCGTGTCA

CCTTCCCGCTCGATGACGCCCTCTACGCCCGCACCCGTTCCGCCCTCGAAGAGGCCC

GCGCCGTTGCAACCTCGGGGCGCATACCTCCGCCGCTCGTCTCTGACGTCCGCTGCC

IT:CAT1X}TTCCIX:Ci;ATCK:GCTTTGCCT^rrCCCCGCGAGTCCGCCTGGTGGTGCCGCCA

TCGCAGCACGCCGCGGGGAGCCGGCCACACCCCCATGTTGCCGGGCTTTGAGGATG

ACGCCGCCGCCATTCACCAAATCTCCGAACCTGACACCGAGCCACCACCCGATCTTG

CCAGCCAGCCTCCCCGTCCCCCGCGGCTCGATGGAGAATTGTTGGTTGTCCAGACTC

CGGGAGCGATGATCGGACAAAGCGGCGGTGAGTTTACCGTGTCCGTCAAGGGTGAG

GTTTTGCGCAAGCTTCCGGTTCATCAACTCCGGGCCATTTACGTTTACGGAGCCGTG

CAACTCACGGCGCATGCTGTGCAGACCGCCCTTGAGGAGGATATCGACGTCTCCTAT

TTTGCGCCCAGCGGCCGCTTTCTTGGCCTCCTCCGCGGCCTGCCCGCATCCGGCGTG

GATGCGCGTCTCGGGCAATACACCCTGTTTCGCGAACCCTTTGGCCGTCTCCGTCTC

GCCTGCGAGGCGATTCGGGCCAAGATCCATAACCAGCGCGTCCTCCTCATGCGTAAC

GGCGAGCCCGGGGAGGGCGTCTTGCGCGAACTCGCCCGTCTGCGCGACGCCACCAG

TGAGGCGACTTCGCTCGACGAACTCCTCGGCATCGAGGGCATCGCCGCGCATTTCTA

TTTCCAGTATTTTC’CCAC’CATGCTGAAAGAACGGGCGGCCTGGGCCTTTGATTTTTCC

GGACGCAATCGCCGCCCGCCGCGCGACCCGGTCAACGCCCTGCTTTCGTTCGGTTAC

AGiZGTGTTGTCCAAGGAACTTGCCGGCGTCTGCCACGCTGTTGGCCTAGACCCGTTT

TTCGGCTTCATGCACCAGCCGCGTTACGGGCGCCCCGCACTCGCTCTCGATCTGATG

GAGGAGTTTCGCCCTCTCATCGCCGACAGTGTTGCCCTGAATCTCATCAACCGTGGC

GAACTCGACGAAGGGGACTTTATCCGGTCGGCCAATGGCACCGCGCTCAATGATCG

GGGCCGCCGGCGTTTTTGGGAGGCATGGTTCCGGCGTCTCGACAGCGAAGTCAGCC

505

WO 2016/205711

PCT/US2016/038181

ATCCTGAATTTGGTTACAAGATGAGCTATCGACGGATGCTTGAAGTGCAGGCGCGCC

AGCTATGGCGCTATGTGCGCGGTGACGCCTTCCGCTACCACGGATTCACCACCCGTT

GATTCCGATGTCAGATCCCCGCCGCCGTTATCTTGTGTGTTACGACATCGCCAATCC

GAAGCGATTGCGCCAAGTGGCCAAGCTGCTGGAGAGCTATGGCACGCGTCTGCAAT

ACTCGGTTTTCGAATGTCCTTTGGACGATCTTCGTCTTGAACAGGCGAAGGCTGATTT

GCGCGACACGATTAATGCCGACCAAGACCAGGTGTTATTTGTTTCGCTTGGCCCCGA

AGCCAACGATGCCACGTTGATCATCGCCACGCTTGGGCTCCCTTATACCGTGCGCTC

GCGAGTGACGATTATCTGACCCATAACCCACGTGTTGAAGAGGCTGAAAACAGACG

GACCTCTATGAAGAACAATTGACGTTTTGGCCGAACTCAGCAGACCTTTATGCGGCT

AAGGCCAATGATCATCCATCCTACCGCCATTGGGCTGGAGACGTTTTTTGAAACGGC

GAGTGCTGCGGATAGCGAGTTTCTCTTGGGGAGGCGCTCGCGGCCACTTTTACAGAG

GAGATGTTCGGGCGAACTGGCCGACCTAACAAGGCGTACCCGGCTCAAAATCGAGG

CACGCTCGCACGGGATGATGTAATTCGTTGTTTTTCAGCATACCGTGCGAGCACGGG

CCGCAGCGAATGCCGTTTCACGAATCGTCAGGCGGCGGGGAGAAGTCATTTAATAA

GGCCACTGTTAAAAGCCGCAGCGAATGCCGTTTCACGAATCGTCAGGCGGGCAGTG

GATGTTTTTCCATGAGGCGAAGAATTTCATCGCCGCAGTGAATGCCGTTTCACCATT

GATGAAGAATGCGAGGTGAAAACAGAGAAATTGGGTCAACTCTATCACTCTTATTC

AGCCATCGTTTCAAGAAAGGATACCTCGTATTGGATACAACACAGCTCGTTCGTTCT

CTCTACCTCCCTCGACAATCTCAAGGA (SEQ ID NO: 61) [001426] >B-locus [001427] TAATAAAATTGAAAT ATC ACTATGGATT ATTGTAAT ATTACC AT AAAGAT AGGTGACGTTTTTTTGAAAATTGTAAACCTAATTTGAAGAAAACCAATTAAAAATCG

CTTCGGCTTTTTTTTAAGTGCCAGGTAGCATTGATGCTAACCCATGTGTAATAAAGGT

TTGTTTTCCTTCGGGGCACGAACACATTATAAGGGAAACCTAAAGATTCCCTTTCTT

GTTTAATATTATAACCAGTGAAAATAAGAATAATGCACCTAAAACTAATATACAGA

AAATAAGAATTAAAAGTACTAATATATACATCATATGTTATCCTCCAATGCTTTATTT

TTTAATAATTGATGTTAGTATTAGTTTTATTTTAATTTCTAAACATAAGAATTTGAAA

AGGATGTGTTTATTATGGCGACACGCAGTTTTATTTTAAAAATTGAACCAAATGAAG

AAGTTAAAAAGGGATTATGGAAGACGCATGAGGTATTGAATCATGGAATTGCCTAC

TACATGAATATTCTGAAACTAATTAGACAGGAAGCTATTTATGAACATCATGAACAA

GATCCTAAAAATCCGAAAAAAGTTTCAAAAGCAGAAATACAAGCCGAGTTATGGGA

506

WO 2016/205711

PCT/US2016/038181

TTTTGTTTTAAAAATGCAAAAATGTAATAGTTTTACACATGAAGTTGACAAAGATGT

TGTTTTTAACATCCTGCGTGAACTATATGAAGAGTTGGTCCCTAGTTCAGTCGAGAA

AAAGGGTGAAGCCAATCAATTATCGAATAAGTTTCTGTACCCGCTAGTTGATCCGAA

CAGTCAAAGTGGGAAAGGGACGGCATCATCCGGACGTAAACCTCGGTGGTATAATT

TAAAAATAGCAGGCGACCCATCGTGGGAGGAAGAAAAGAAAAAATGGGAAGAGGA

TAAAAAGAAAGATCCCCTTGCTAAAATCTTAGGTAAGTTAGCAGAATATGGGCTTAT

TCCGCTATTTATTCCATTTACTGACAGCAACGAACCAATTGTAAAAGAAATTAAATG

GATGGAAAAAAGTCGTAATCAAAGTGTCCGGCGACTTGATAAGGATATGTTTATCC

AAGCATTAGAGCGTTTTCTTTCATGGGAAAGCTGGAACCTTAAAGTAAAGGAAGAG

TATGAAAAAGTTGAAAAGGAACACAAAACACTAGAGGAAAGGATAAAAGAGGACA

TTCAAGCATTTAAATCCCTTGAACAATATGAAAAAGAACGGCAGGAGCAACTTCTTA

GAGATACATTGAATACAAATGAATACCGATTAAGCAAAAGAGGATTACGTGGTTGG

CGTGAAATTATCCAAAAATGGCTAAAGATGGATGAAAATGAACCATCAGAAAAATA

TTTAGAAGTATTTAAAGATTATCAACGGAAACATCCACGAGAAGCCGGGGACTATT

CTGTCTATGAATTTTTAAGCAAGAAAGAAAATCATTTTATTTGGCGAAATCATCCTG

AATATCCTTATTTGTATGCTACATTTTGTGAAATTGACAAAAAAAAGAAAGACGCTA

AGCAACAGGCAACTTTTACTTTGGCTGACCCGATTAACCATCCGTTATGGGTACGAT

TTGAAGAAAGAAGCGGTTCGAACTTAAACAAATATCGAATTTTAACAGAGCAATTA

CACACTGAAAAGTTAAAAAAGAAATTAACAGTTCAACTTGATCGTTTAATTTATCCA

AC TGAATCCGGCGGTTGGGAGGAAAAAGGTAAAGTAGATATCGTTTTGTTGCCGTC

AAGACAATTTTATAATCAAATCTTCCTTGATATAGAAGAAAAGGGGAAACATGCTTT

TACTTATAAGGATGAAAGTATTAAATTCCCCCTTAAAGGTACACTTGGTGGTGCAAG

AGTGCAGTTTGACCGTGACCATTTGCGGAGATATCCGCATAAAGTAGAATCAGGAA

ATGTTGGACGGATTTATTTTAACATGACAGTAAATATTGAACCAACTGAGAGCCCTG

TTAGTAAGTCTTTGAAAATACATAGGGACGATTTCCCCAAGTTCGTTAATTTTAAAC

CGAAAGAGCTCACCGAATGGATAAAAGATAGTAAAGGGAAAAAATTAAAAAGTGG

TATAGAATCCCTTGAAATTGGTCTACGGGTGATGAGTATCGACTTAGGTCAACGTCA

AGCGGCTGCTGCATCGATTTTTGAAGTAGTTGATCAGAAACCGGATATTGAAGGGA

AGTTATTTTTTCCAATCAAAGGAACTGAGCTTTATGCTGTTCACCGGGCAAGTTTTAA

CATTAAATTACCGGGTGAAACATTAGTAAAATCACGGGAAGTATTGCGGAAAGCTC

GGGAGGACAACTTAAAATTAATGAATCAAAAGTTAAACTTTCTAAGAAATGTTCTAC

507

WO 2016/205711

PCT/US2016/038181

ATTTCCAACAGTTTGAAGATATCACAGAAAGAGAGAAGCGTGTAACTAAATGGATT

TCTAGACAAGAAAATAGTGATGTTCCTCTTGTATATCAAGATGAGCTAATTCAAATT

CGTGAATTAATGTATAAACCCTATAAAGATTGGGTTGCCTTTTTAAAACAACTCCAT

AAACGGCTAGAAGTCGAGATTGGCAAAGAGGTTAAGCATTGGCGAAAATCATTAAG

TGACGGGAGAAAAGGTCTTTACGGAATCTCCCTAAAAAATATTGATGAAATTGATC

GAACAAGGAAATTCCTTTTAAGATGGAGCTTACGTCCAACAGAACCTGGGGAAGTA

AGACGCTTGGAACCAGGACAGCGTTTTGCGATTGATCAATTAAACCACCTAAATGCA

TTAAAAGAAGATCGATTAAAAAAGATGGCAAATACGATTATCATGCATGCCTTAGG

TIACTGTTAIGATGTAAGAAAGAAAAAGTGGCAGGCAAAAAATCCAGCATGTCAAA

TTATTTTATTTGAAGATTTATCTAACTACAATCCTTACGAGGAAAGGTCCCGTTTTGA

AAACTCAAAACTGATGAAGTGGTCACGGAGAGAAATTCCACGACAAGTCGCCTTAC

AAGGTGAAATTTACGGATTACAAGTTGGGGAAGTAGGTGCCCAATTCAGTTCAAGA

TTCCATGCGAAAACCGGGTCGCCGGGAATTCGTTGCAGTGTTGTAACGAAAGAAAA

ATTGCAGGATAATCGCTTTTTTAAAAATTTACAAAGAGAAGGACGACTTACTCTTGA

TAAAATCGCAGTTTTAAAAGAAGGAGACTTATATCCAGATAAAGGTGGAGAAAAGT

TTATTTCTTTATCAAAGGATCGAAAGTTGGTAACTACGCATGCTGATATTAACGCGG

CCCAAAATTTACAGAAGCGTTTTTGGACAAGAACACATGGATTTTATAAAGTTTACT

GCAAAGCCTATCAGGTTGATGGACAAACTGTTTATATTCCGGAGAGCAAGGACCAA

AAACAAAAAATAATTGAAGAATTTGGGGAAGGCTATTTTATTTTAAAAGATGGTGT

ATATGAATGGGGTAATGCGGGGAAACTAAAAATTAAAAAAGGTTCCTCTAAACAAT

CATCGAGTGAATTAGTAGATTCGGACATACTGAAAGATTCATTTGATTTAGCAAGTG

AACTTAAGGGAGAGAAACTCATGTTATATCGAGATCCGAGTGGAAACGTATTTCCTT

CCGACAAGTGGATGGCAGCAGGAGTATTTTTTGGCAAATTAGAAAGAATATTGATTT

CTAAGTTAACAAATCAATACTCAATATCAACAATAGAAGATGATTCTTCAAAACAAT

CAATGTAAAAGTTTGCCCGTATAAGAACTTAATTAATTAGGATGGTAGGATGTTACT

AAATATGTCTGTAGGCATCATTCCTACTATCCGTTTTGTCCGAATATCAGAGCATTAG

GTGAGGAATGGTAAGAAAGGAAAATTTATATGAACCAACCGATTCCTATTCGAATG

TTAAATGAAATACAATATTGTGAGCGACTTTTTTACTTTATGCATGTCCAAAAGCTAT

TTGATGAGAATGCAGATACAGTTGAAGGAAGTGCACAGCATGAGCGGGCAGAAAG

AAGCAAAAGACCAAGTAAAATGGGACCAAAGGAATTATGGGGTGAGGCGCCAAGA

AGTCTTAAGCTTGGTGATGAGCTGTTAAATATTACCGGTGTTCTTGATGCCATAAGT

508

WO 2016/205711

PCT/US2016/038181

CATGAAGAGAACAGTTGGATCCCGGTTGAATCAAAACACAGTTCCGCACCGGATGG

ATTGAACCCTTTTAAAGTAGATGGCTTTCTACTTGACGGGTCTGCATGGCCAAACGA

TCAAATTCAACTTTGTGCACAAGGCTTGCTCTTGAATGCCAATGGATACCCGTGTGA

TTATGGGTATTTATTTTATCGTGGTAATAAGAAAAAGGTGAAAATTTATTTTACTGA

AGATTTAATCGCTGCCACAAAGTACTATATTAAAAAAGCACACGAGATACTAGTATT

ATCTGGTGATGAATCAGCTATTCCTAAGCCTTTAATTGATTCTAATAAGTGTTTTCGC

TGTTCTTTAAACTATATCTGTCTTCCGGATGAAACGAACTATCTATTAGGGGCAAGTT

CAACAATTCGTAAAATTGTGCCTTCAAGGACAGATGGTGGCGTTTTATATGTATCAG

AGTC I’GGI ACAAAATTAGGAAAATCGGGTGAGGAGTIAATCATTCAGTATAAAGA1

GGCCAAAAGCAGGGTGTTCCTATAAAAGATATTATTCAAGTTTCGTTAATTGGAAAT

GTTCAATGCTCAA.CGCAA.TTACTTCATTTTTTAATGCAATCAA.ATA.TTCCTGTAAGTT

ATTTATCATCCCACGGTCGTTTGATTGGTGTCAGTTCATCTTTAGTTACAAAAAATGT

TTTAACAAGGCAGCAACAGTTCATTAAATTTACAAATCCTGAGTTTGGACTAAATCT

AGCAAAACAAATTGTTTATGCCAAGATTCGAAATCAACGAACTTTACTTAGAAGAA

ATGGGGGGAGTGAGGTAAAGGAGATTTTAACAGATTTAAAATCTTTAAGTGACAGT GC AC IGAACGC AA TATCAATAGAACAATTACGGGGI AT TGAAGGGATTTCTGCAAA ACATTATTTCGCAGGATTTCCGTTTATGTTGAAAAATGAATTACGTGAATTGAATTTA ATGAAAGGGCGTAATAGGAGACCGCCAAAAGATCCTGTAAATGTACTTCTTTCTCTT

GGTTATACTTTATTGACACGTGATATTCATGCTGCGTGTGGTTCAGTCGGATTGGATC

CGATGTTTGGTTGTTACCATCGTCCAGAAGCAGGTCGACCGGCTCTAGTATTAGATG

TTATGGAAACATTTCGACCACTTATTGTAGACAGTATTGTCATCCGAGCTTTGAATA

CGGGTGAAATCTCATTAAAAGATTTTTATATAGGAAAAGATAGTTGTCAATTATTAA

AACATGGCCGCGATTCCTTTTTTGCCATTTATGAAAGAAGAATGCATGAAACTATTA

CCGATCCAATTTTCGGCTATAAGATTAGCTATCGCCGTATGCTCGATTTGCACATTCG

AATGCTTGCAAGGTTTATTGAAGGGGAACTGCCGGAATATAAACCATTAATGACCC

GGTGAGTTTGTTTATTAGGTTAAAAGAAGGTGAAGACATGCAGCAATACGTCCTTGT

TTCTTATGATATTTCGGACCAAAAAAGATGGAGAAAAGTATTTAAACTGATGAAAG

GATACGGAGAACATGTTCAATATTCCGTATTCATATGCCAGTTAACTGAATTACAGA

AGGCAAAATTACAAGCCTCTTTAGAAGACATTATCCATCATAAGAATGACCAAGTA

ATGTTTGTTCACATCGGGCCAGTGAAAGATGGTCAACTATCTAAAAAAATCTCAACA

ATTGGGAAAGAATTTGTTCCATTGGATTTAAAGCGGCTTATATTTTGAAAAGATATA.

509

WO 2016/205711

PCT/US2016/038181

GCAAAGAAATCTTATGAAAAAAATACAAAAATATATTGTTAAAAAATAGGGAATAT

TATATAATGGACTTACGAGGTTCTGTCTTTTGGTCAGGACAACCGTCTAGCTATAAG

TGCTGCAGGGGTGTGAGAAACTCCTATTGCTGGACGATGTCTCTTTTATTTCTTTTTT

CTTGGATCTGAGTACGAGCACCCACATTGGACATTTCGCATGGTGGGTGCTCGTACT

ATAGGTAAAACAAACCTTTTTAAGAAGAATACAAAAATAACCACAATATTTTTTAAA

AGGAATTTTGATGGATTTACATAACCTCTCGCAACATGCTTCTAAAACCCAAGCCCA

CCATAGCCCAAAACCCCCTGCGGTCCAAGAAAAAAGAAATGATACGAGGCATTAGC

ACCGGGGAGAAGTCATTTAATAAGGCCACTGTTAAAAGTCCAAGAAAAAAGAAATG

ATACGAGGCATTAGCACAACAATATAAACGACTACTTTACCGTGTTCAAGAAAAAA

GAAATGATATGAGGCATTAGCACGATGGGATGGGAGAGAGAGGACAGTTCTACTCT

TGCTGTATCCAGCTTCTTTTACTTTATCCGGTATCATTTCTTCACTTCTTTCTGCACAT

AAAAAAGCACCTAACTATTTGGATAAGTTAAGTGCTTTTATTTCCGTTTGAAGTTGTC

TATTGCTTTTTTCTTCATATCTTCAAATTTTTTCTGTTTCTCAGAGTCAACTTTACCAA

CTGTAATCCCTTTTCTTTTTGGCATTGGGGTATCTTTCCACCTTAGTGTGTTCATAAG

GCTTATATTTATCACTCATTGTATTCCTCCAACACAATTATAATTTTTCCGTCATCCTC

AATCCAACCGTCAACTGTGACAAAAGACGAATCTCTCTTAT (SEQ ID NO: 62) [001428] >C-locus [001429] GTTTCATTTGGAAAGGGAGAGCATTGGCTTTTCTCTTTGTAAATAAAGTGC

AAGCTTTGTAATAAGCTTCTAGTGGAGAAGTGATTGTTTGAATCACCCAATGCACAC

GCACTAAAGTTAGACGAACCTATAATTCGTATTAGTAAGTATAGTACATGAAGAAA

AATGCAACAAGCATTTACTCTCTTTTAAATAAAGAATTGATAGCTGTTAATATTGAT

AGTATATTATACCTTATAGATGTTCGATTTTTTTTGAAATTCAAAAATCATACTTAGT

AAAGAAAGGAAATAACGTCATGGACAAGCGAAAGCGTAGAAGIT ACGAGITTAGGT

GGGAAGCGGGAGGCACCAGTCATGGCAATCCGTAGCATAAAACTAAAACTAAAAAC

CCACACAGGCCCGGAAGCGCAAAACCTCCGAAAAGGAATATGGCGGACGCATCGGT

TGTTAAATGAAGGCGTCGCCTATTACATGAAAATGCTCCTGCTCTTTCGTCAGGAAA

GCACTGGTGAACGGCCAAAAGAAGAACTACAGGAAGAACTGATTTGTCACATACGC

GAACAGCAACAACGAAATCAGGCAGATAAAAATACGCAAGCGCTTCCGCTAGATAA

GGCACTGGAAGCTTTGCGCCAACTATATGAACTGCTTGTCCCCTCCTCGGTCGGACA

AAGTGGCGACGCCCAGATCATCAGCCGAAAGTTTCTCAGCCCGCTCGTCGATCCGA

ACAGCGAAGGCGGCAAAGGTACTTCGAAGGCAGGGGCAAAACCCACTTGGCAGAA

510

WO 2016/205711

PCT/US2016/038181

GAAAAAAGAAGCGAACGACCCAACCTGGGAACAGGATTACGAAAAATGGAAAAAA

AGACGCGAGGAAGACCCAACCGCTTCTGTGATTACTACTTTGGAGGAATACGGCATT

AGACCGATCTTTCCCCTGTACACGAACACCGTAACAGATATCGCGTGGTTGCCACTT

CAATCCAATCAGTTTGTGCGAACCTGGGACAGAGACATGCTTCAACAAGCGATTGA

AAGACTGCTCAGTTGGGAGAGCTGGAACAAACGTGTCCAGGAAGAGTATGCCAAGC

TGAAAGAAAAAATGGCTCAACTGAACGAGCAACTCGAAGGCGGTCAGGAATGGATC

A GC T T GC TAG AGC AGT AC GA A GA A A AC C GA GA GC GAG AGC T T AGGGA A A AC AT GA

CCGCTGCCAATGACAAGTATCGGATTACCAAGCGGCAAATGAAAGGCTGGAACGAG

CTGTACGAGCTATGGTCAACCTTTCCCGCCAGTGCCAGTCACGAGCAATACAAAGA

GGCGCTCAAGCGTGTGCAGCAGCGACTGAGAGGGCGGTTTGGGGATGCTCATTTCTT

CCAGTATCTGATGGAAGAGAAGAACCGCCTGATCTGGAAGGGGAATCCGCAGCGTA

TCCATTATTTTGTCGCGCGCAACGAACTGACGAAACGGCTGGAGGAAGCCAAGCAA

AGCGCCACG-ATGACGTTGCCCAATGCCAGGAAGCATCCATTGTGGGTGCGCTTCGAT

GCACGGGGAGGAAATTTGCAAGACTACTACTTGACGGCTGAAGCGGACAAACCGAG

AAGCAGACGTTTTGTAACGTTTAGTCAGTTGATATGGCCAAGCGAATCGGGATGGAT

GGAAAAGAAAGACGTCGAGGTCGAGCTAGCTTTGTCCAGGCAGTTTTACCAGCAGG

TGAAGTTGCTGAAAAATGACAAAGGCAAGCAGAAAATCGAGTTCAAGGATAAAGGT

TCGGGCTCGACGTTTAACGGACACTTGGGGGGAGCAAAGCTACAACTGGAGCGGGG

CGATTTGGAGAAGGAAGAAAAAAACTTCGAGGACGGGGAAATCGGCAGCGTTTACC

TTAACGTTGTCATTGATTTCG-AACCTTTGCAAG-AAGTGAAAAATGGCCGCGTGCAGG

CGCCGTATGGACAAGTACTGCAACTCATTCGTCGCCCCAACGAGTTTCCCAAGGTCA

CTACCTATAAGTCGGAGCAACTTGTTGAATGGATAAAAGCTTCGCCACAACACTCGG

CTGGGGTGGAGTCGCTGGCATCCGGTTTTCGTGTAATGAGCATAGACCTTGGGCTGC

GCGCGGCTGCAGCGACTTCTATTTTTTCTGTAGAAGAGAGTAGCGATAAAAATGCGG

CTGATTTTTCCTACTGGATTGAAGGAACGCCGCTGGTCGCTGTCCATCAGCGGAGCT

ATATGCTCAGGTTGCCTGGTGAACAGGTAGAAAAACAGGTGATGGAAAAACGGGAC

GAGCGGTTCCAGCTACACCAACGTGTGAAGTTTCAAATCAGAGTGCTCGCCCAAATC

ATGCGTATGGCAAATAAGCAGTATGGAGATCGCTGGGATGAACTCGACAGCCTGAA

ACAAGCGGTTGAGCAG-AAAAAGTCGCCGCTCG-ATCAAACAGACCGGACATTTTGGG

AGGGGATTGTCTGCGACTTAACAAAGGTTTTGCCTCGAAACGAAGCGGACTGGGAA

CAAGCGGTAGTGCAAATACACCGAAAAGCAGAGGAATACGTCGGAAAAGCCGTTCA

511

WO 2016/205711

PCT/US2016/038181

GGCATGGCGCAAGCGCTTTGCTGCTGACGAGCGAAAAGGCATCGCAGGTCTGAGCA

TGTGGAACATAGAAGAATTGGAGGGCTTGCGCAAGCTGTTGATTTCCTGGAGCCGC

AGGACGAGGAATCCGCAGGAGGTTAATCGCTTTGAGCGAGGCCATACCAGCCACCA

GCGTCTGTTGACCCATATCCAAAACGTCAAAGAGGATCGCCTGAAGCAGTTAAGTC

ACGCCATTGTCATGACTGCCTTGGGGTATGTTTACGACGAGCGGAAACAAGAGTGGT

GiZGCCGAATACCCGGCTTGCCAGGTCATTCTGTTTGAAAATCTGAGCCAGTACCGTT

CTAACCTGGATCGCTCGACCAAAGAAAACTCCACCTTGATGAAGTGGGCGCATCGC

AGCATTCCGAAATACGTCCACATGCAGGCGGAGCCATACGGGATTCAGATTGGCGA

TGTCCGGGCGGAATATTCCTCTCGTTTTTACGCCAAGACAGGAACGCCAGGCATTCG

TTGTAAAAAGGTGAGAGGCCAAGACCTGCAGGGCAGACGGTTTGAGAACTTGCAGA

AGAGGTTAGTCAACGAGCAATTTTTGACGGAAGAACAAGTGAAACAGCTAAGGCCC

GGCGACATTGTCCCGGATGATAGCGGAGAACTGTTCATGACCTTGACAGACGGAAG

CGGAAGCAAGGAGGTCGTGTTTCTCCAGGCCGATATTAACGCGGCGCACAATCTGC

AAAAACGTTTTTGGCAGCGATACAATGAACTGTTCAAGGTTAGCTGCCGCGTCATCG

TCCGAGACGAGGAAGAGTATCTCGTTCCCAAGACAAAATCGGTGCAGGCAAAGCTG

GGC AAAGGGC IΊ TTTGTGAAAAAA TCGGATAC AGCCTGGAAAGA! GT AT AT GTGTG

GGACAGCCAGGCAAAGCTTAAAGGTAAAACAACCTTTACAGAAGAGTCTGAGTCGC

CCGAAC AACTGGAAGACT IT CAGGAGA TC ATCGAGGAAGC AGAAGAGGCGAAAGG

AACATACCGTACACTGTTCCGCGATCCTAGCGGAGTCTTTTTTCCCGAATCCGTATG

GTATCCCCAAAAAGATTTTTGGGGCGAGGTGAAAAGGAAGCTGTACGGAAAATTGC

GGGAACGGTTTTTGACAAAGGCTCGGTAAGGGTGTGCAAGGAGAGTGAATGGCTTG

TCCTGGATACCTGTCCGCATGCTAAATGAAATTCAGTATTGTGAGCGACTGTACCAT

ATTATGCATGTGCAGGGGCTGTTTGAGGAAAGCGCAGACACGGTCGAAGGAGCAGC

ACAACACAAGCGTGCAGAGACACATCTGCGCAAAAGCAAGGCAGCGCCGGAAGAG

ATGTGGGGGGACGCTCCGTTTAGCTTGCAGCTCGGCGACCCTGTGCTTGGCATTACG

GGAAAGCTGGATGCCGTCTGTCTGGAAGAAGGTAAGCAGTGGATTCCGGTAGAAGG

AAAGCATTCGGCGTCGCCAGAAGGCGGGCAGATGTTCACTGTAGGCGTGTATTCGCT

GGACGGTTCTGCCTGGCCCAACGACCAAATCCAATTGTGTGCGCAAGGCTTGCTGCT

TCGCGCGAATGGATATGAATCCGATTATGGCTACTTATACTACCGTGGCAATAAAAA

GAAGGTTCGCATTCCTTTTTCGCAGGAACTCATAGCGGCTACTCACGCCTGCATTCA

AAAAGCTCATCAGCTTCGGGAAGCCGAAATTCCCCCTCCGTTGCAGGAGTCGAAAA

512

WO 2016/205711

PCT/US2016/038181

AGTGCTTTCGATGCTCGTTAAATTACGTATGCATGCCTGACGAGACGAATTACATGT

TGGGGTTGAGCGCAAACATCAGAAAGATTGTGCCCAGTCGTCCAGATGGCGGGGTA

CTGTATGTTACAGAGCAGGGGGCAAAACTGGGCAGAAGCGGAGAAAGCTTGACCAT

CACCTGCCGGGGCGAAAAGATAGACGAAATCCCGATCAAAGACTTGATTCACGTGA

GCTTGATGGGGCATGTGCAATGCTCTACGCAGCTTCTGCACACCTTGATGAACTGTG

GCGTCCACGTCAGCTACTTGACTACGCATGGCACATTGACAGGAATAATGACTCCCC

CTTTATCGAAAAACATTCGAACAAGAGCCAAGCAGTTTATCAAATTTCAGCACGCGG

AGATCGCCCTTGGAATCGCGAGAAGGGTCGTGTATGCGAAAATTTCCAATCAGCGC

ACGATGCTGCGCCGCAATGGCTCACCAGATAAAGCAGTTTTAAAAGAGTTAAAAGA

GCTTAGAGATCGCGCGTGGGAGGCGCCATCACTGGAAATAGTGAGAGGTATCGAGG

GACGTGCAGCACAGTTGTACATGCAGTTTTTCCCTACCATGTTAAAGCACCCAGTAG

TAGACGGTATGGCGATCATGAACGGTCGCAACCGTCGCCCGCCCAAAGATCCGGTC

AATGCGCTGCTCTCCCTCGGCTATACGCTTCTTTCACGGGATGTTTACTCCGCATGTG

CCAATGTCGGACTCGATCCACTGTTCGGCTTTTTCCATACGATGGAGCCGGGCAGAC

CAGCTTTGGCACTCGATCTGATGGAACCGTTCCGCGCCTTGATTGCCGATAGCGTAG

CGATACGTACCTTGAATACGGAGGAACTCACCCTCGGGGACTTTTATTGGGGAAAA

GACAGTTGTTATTTGAAAAAGGCAGGAAGACAAACGTATTTCGCTGCCTATGAAAG

ACGGATGAACGAGACGCTGACGCATCCGCAATTTGGGTATAAGCTCAGCTATCGCC

GTATGCTGGAGCTGGAAGCAAGGTTTTTGGCCCGGTATCTGGATGGAGAGCTGGTG

GAATATACGCCGCTCATGACAAGGTAGGAAATGACCATGCGACAATTTGTTCTGGTA

AGCTATGATATTGCCGATCAAAAACGTTGGAGAAAAGTATTCAAGCTGATGAAGGG

GCAAGGCGAGCACGTCCAGTACTCGGTGTTTCTGTGCCAACTCACCGAGATTCAGCA

AGCCAAGCTAAAGGTAAGCCTGGCGGAGCTGGTTCACCATGGAGAAGACCAGGTCA

TGTTTGTAAAAATCGGCCCAGTGACGAGAGATCAACTGGACAAGCGGATATCTACT

GTTGGCAGGGAGTTTCTGC’CTCGCGATTTGACCAAATTTATCTATTAAGGAATGAAG

AAAGCTAGTTGTAACAAAAGTGGAAAAAGAGTAAAATAAAGGTGTCAGTCGCACGC

TATAGGCCATAAGTCGACTTACATATCCGI’GCGI’GTGCATTATGGGCCCATCCACAG

GTCTATTCCCACGGATAATCACGACTTTCCACTAAGCTTTCGAATTTTATGATGCGAG

CATCCTCTCAGGTCAAAAAAGCCGGGGGATGCTCGAACTCTTTGTGGGCGTAGGCTT

TCCAGAGTTTTTTAGGGGAAGAGGCAGCCGATGGATAAGAGGAATGGCGATTGAAT

TTTGGCTTGCTCGAAAAACGGGTCTGTAAGGCTTGGGGCTGTAGGGGTTGAGTGGGA

513

WO 2016/205711

PCT/US2016/038181

AGGAGTTCGAAAGCTTAGTGGAAAGCTTCGTGGTTAGCACCGGGGAGAAGTCATTT

AATAAGGCCACTGTTAAAAGTTCGAAAGCTTAGTGGAAAGCTTCGTGGTTAGCACG

CTAAAGTCCGTCTAAACTACTGAGATCTTAAATCGGCGCTCAAATAAAAAACCTCGC TAATGCGAGGTTTCAGC (SEQ ID NO: 63) [001430] >D-locus [001431] G AAGTTATGTTG AT A AA ATGGTTT ATGA A A ACGTGAGTCTGTGGTAGT AT

TATAAACAATGATGGAATAAAGTGTTTTTTGCGCCGCACGGCATGAATTCAGGGGTT

AGCTTGGTTTTGTGTATAAATAAATGTTCTACATATTTATTTTGTTTTTTGCGCCGCA

AAATGCAACTGAAAGCCGCATC TAGAGCACCC TGTAGAAGAC AGGGTTT TGAGAAT

AGCCCGACATAGAGGGCAATAGACACGGGGAGAAGTCATTTAATAAGGCCACTGTT

AAAAGTTTTGAGAATAGCCCGACATAGAGGGCAATAGACTTTTGCTTCGTCACGGAT

GGACTTCACAATGGCAACAACGTTTTGAGAATAGCCCGACATAGTTATAGAGATGT

ATAAATATAACCGATAAACATTGACTAATTTGTTGAAGTCAGTGTTTATCGGTTTTTT

GTGTAAATATAGGAGTTGTTAGAATGATACTTTTTGCCTAATTTTGGAACTTTATGAG

GATATAAGATAGACTTGATAAAAAGGTAAAAGAAAGGTTAAAGAGCATGGCAGGA

ATAGTGACCTGTGATGAAGATGATGGTAGAATTAAAAGTGTTCTTAAAGAAAAACA

ATATTGGATAAGGAAAATAATTCAATAGATAAAAAATTTAGGGGGAAAAATGAAAA

TATCAAAAGTCGATCATACCAGAATGGCGGTTGCTAAAGGTAATCAACACAGGAGA

GATGAGATTAGTGGGATTCTCTATAAGGATCCGACAAAGACAGGAAGTATAGATTT

TGATGAACGATTCAAAAAACTGAATTGTTCGGCGAAGATACTTTATCATGTATTCAA

TGGAATTGCTGAGGGAAGCAATAAATACAAAAATATTGTTGATAAAGTAAATAACA

ATTTAGATAGGGTCTTATTTACAGGTAAGAGCTATGATCGAAAATCTATCATAGACA

TAGATACTGTTCTTAGAAATGTTGAGAAAATTAATGCATTTGATCGAATTTCAACAG

AGGAAAGAGAACAAATAATTGACGATTTGTTAGAAATACAATTGAGGAAGGGGTTA

AGGAAAGGAAA AGCTGGA! TAAGAGAGGTA! T AC TAA IT GGI GC TGGIGTAATAGT

TAGAACCGATAAGAAGCAGGAAATAGCTGATTTTCTGGAGATTTTAGATGAAGATTT

CAATAAGACGAATCAGGCTAAGAACATAAAATTGTCTATTGAGAATCAGGGGTTGG

TGGTCTCGCCTGTATCAAGGGGAGAGGAACGGATTTTTGATGTCAGTGGCGCACAA

AAGGGAAAAAGCAGCAAAAAAGCGCAGGAGAAAGAGGCACTATCTGCATTTCTGTT

AGATTATGCTGATCTTGATAAGAATGTCAGGTTTGAGTATTTACGTAAAATTAGAAG

ACTGATAAATCTATATTTCTATGTCAAAAATGATGATGTTATGTCTTTAACTGAAATT

514

WO 2016/205711

PCT/US2016/038181

CCGGCAGAAGTGAATCTGGAAAAAGATTTTGATATCTGGAGAGATCACGAACAAAG

AAAGGAAGAGAATGGAGATTTTGTTGGATGTCCGGACATACTTTTGGCAGATCGTG

ATGTGAAGAAAAGTAACAGTAAGCAGGTAAAAATTGCAGAGAGGCAATTAAGGGA

GTCAATACGTGAAAAAAATATAAAACGATATAGATTTAGCATAAAAACGATTGAAA

AGGATGATGGAACATACTTTTTTGCAAATAAGCAGATAAGTGTATTTTGGATTCATC

GCATTGAAAATGCTGTAGAACGTATATTAGGATCTATTAATGATAAAAAACTGTATA

GATTACGTTTAGGATATCTAGGAGAAAAAGTATGGAAGGACATACTCAATTTTCTCA

GCATAAAATACATTGCAGTAGGCAAGGCAGTATTCAATTTTGCAATGGATGATCTGC

AGGAGAAGGAI’AGAGATA! AGAACCCGGC AAGATAT C AG AAAA1GC AGTAAATGG

ATTGACTTCGTTTGATTATGAGCAAATAAAGGCAGATGAGATGCTGCAGAGAGAAG

TTGCTGTTAATGTAGCATTCGCAGCAAATAATCTTGCTAGAGTAACTGTAGATATTC

CGCAAAATGGAGAAAAAGAGGATATCCTTCTTTGGAATAAAAGTGACATAAAAAAA

TACAAAAAGAATTCAAAGAAAGGTATTCTGAAATCTATACTTCAGTTTTTTGGTGGT

GCTTCAACTTGGAATATGAAAATGTTTGAGATTGCATATCATGATCAGCCAGGTGAT

TACGAAGAAAACTACCTATATGACATTATTCAGATCATTTACTCGCTCAGAAATAAG

AGCTTTCATTTCAAGACATATGATCATGGGGATAAGAATTGGAATAGAGAACTGAT

AGGAAAGATGATTGAGCATGATGCTGAAAGAGTCATTTCTGTTGAGAGGGAAAAGT

TTCATTCCAATAACCTGCCGATGTTTTATAAAGACGCTGATCTAAAGAAAATATTGG

ATCTCTTGTATAGCGATTATGCAGGACGTGCATCTCAGGTTCCGGCATTTAACACTG

TCTTGGTTCGAAAGAACTTTCCGGAATTTCTTAGGAAAGATATGGGCTACAAGGTTC

ATTTTAACAATCCTGAAGTAGAGAATCAGTGGCACAGTGCGGTGTATTACCTATATA

AAGAGATTTATTACAATCTATTTTTGAGAGATAAAGAGGTAAAGAATCTTTTTTATA

CTTCATTAAAAAATATAAGAAGTGAAGTTTCGGACAAAAAACAAAAGTTAGCTTCA

GATGATTTTGCATCCAGGTGTGAAGAAATAGAGGATAGAAGTCTTCCGGAAATTTGT

CAGATAATAATGACAGAATACAATGCGCAGAACTTTGGTAATAGAAAAGTTAAATC

TCAGCGTGTTATTGAAAAAAATAAGGATATTTTCAGACATTATAAAATGCTTTTGAT

AAAGACTTTAGCAGGTGCTTTTTCTCTTTATTTGAAGCAGGAAAGATTTGCATTTATT

GGTAAGGCAACACCTATACCATACGAAACAACCGATGTTAAGAATTTTTTGCCTGAA

TGGAAATCCGGAATGTATGCATCGTTTGTAGAGGAGATAAAGAATAATCTTGATCTT

CAAGAATGGTATATCGTCGGACGATTCCTTAATGGGAGGATGCTCAATCAATTGGCA

GGAAGCCTGCGGTCATACATACAGTATGCGGAAGATATAGAACGTCGTGCTGCAGA

515

WO 2016/205711

PCT/US2016/038181

AAATAGGAATAAGCTTTTCTCCAAGCCTGATGAAAAGATTGAAGCATGTAAAAAAG

CGGTCAGAGTGCTTGATTTGTGTATAAAAATTTCAACTAGAATATCTGCGGAATTTA

CTGACTATTTTGATAGTGAAGATGATTATGCAGATTATCTTGAAAAATATCTCAAGT

ATCAGGATGATGCCATTAAGGAATTGTCAGGATCTTCGTATGCTGCGTTGGATCATT

TTTGCAACAAGGATGATCTGAAATTTGATATCTATGTAAATGCCGGACAGAAGCCTA

TCTTACAGAGAAATATCGTGATGGCAAAGCTTTTTGGACCAGATAACATTTTGTCTG

AAGTIATGGAAAAGGTAACAGAAAGTGCCATACGAGAATACIATGACTATCTGAAG

AAAGTTTCAGGATATCGGGTAAGGGGAAAATGTAGTACAGAGAAAGAACAGGAAG

ATCTGCTAAAGTTCCAAAGATTGAAAAACGCAGTAGAATTCCGGGATGTTACTGAAT

ATGCTGAGGTTATTAATGAGCTTTTAGGACAGTTGATAAGTTGGTCATATCTTAGGG

AGAGGGATCTATTATATTTCCAGCTGGGATTCCATTACATGTGTCTGAAAAACAAAT

CTTTCAAACCGGCAGAATATGTGGATATTCGTAGAAATAATGGTACGATTATACATA

ATGCGATACTTTACCAGATTGTTTCGATGTATATTAATGGACTGGATTTCTATAGTTG

TGATAAAGAAGGGAAAACGCTCAAACCAATTGAAACAGGAAAGGGCGTAGGAAGT

AAGATAGGACAATTTATAAAGTATTCCCAGTATTTATACAATGATCCGTCATATAAG

CTTGAGATCTATAATGCAGGATTAGAAGTTTTTGAAAACATTGATGAACATGATAAT

ATTACAGATCTTAGAAAGTATGTGGATCATTTTAAGTATTATGCATATGGTAATAAA

ATGAGCCTGCTTGATCTGTATAGTGAATTCTTCGATCGTTTCTTTACATATGATATGA

AGTATCAGAAGAATGTAGTGAATGTGTTGGAGAATATCCTTTTAAGGCATTTTGTAA

TTTTCTATCCGAAGTTTGGATCAGGAAAAAAAGATGTTGGAATTAGGGATTGTAAAA

AAGAAAGAGCTCAGATTGAAATAAGTGAGCAGAGCCTCACATCGGAAGACTTCATG

TTTAAGCTTGACGACAAAGCAGGAGAAGAAGCAAAGAAGTTTCCGGCAAGGGATGA

ACGTTATCTCCAGACAATAGCCAAGTTGCTCTATTATCCTAACGAAATTGAGGATAT

GAACAGATTCATGAAGAAAGGAGAAACGATAAATAAAAAAGTTCAGTTTAATAGAA

AAAAGAAGATAACCAGGAAACAAAAGAATAATTCATCAAACGAGGTATTGTCTTCA

ACTATGGGTTATTTATTTAAGAACATTAAATTGTAAAAAAGATTCGTTGTAGATAAT

TGATAGGTAAAAGCTGACCGGAGCCTTTGGCTCCGGACAGTTGTATATAAGAGGAT

ATTAATGACTGAAAATGATTTTTGTTGGAAGTCAGTTTTTTCTGTGGAAAGCGAAAT

CGAATATGATGAGTATGCATATGGCAGAAGAGCTGTAGAAGGCGAGAATACATATG

ATTACATTACTAAGGAAGAAAGACCGGAACTTAATGACGAATATGTAGCGAGACGT

TGCATTTTCGGTAAAAAAGCAGGAAAAATATCCAGGTCGGATTTTAGTAGGATAAG

516

WO 2016/205711

PCT/US2016/038181

ATCTGCGTTGGATCATGCGATGATAAATAATACACATACAGCATTTGCCAGATTTAT

CACTGAAAATCTGACGAGACTCAATCACAAAGAACATTTTCTGAATGTGACACGTGC

ATATTCTAAACCTGATTCTGAAAAATTGATACAACCGAGATACTGGCAGTCGCCTGT

AGTTCCAAAGGATAAACAAATATATTATAGCAAGAATGCGATTAAAAAATGGTGTG

GTTACGAAGATGATATTCCGCCTCGTTCTGTGATAGTTCAGATGTGTCTATTGTGGG

GGACTGATCATGAAGAGGCAGATCATATCCTTCGCAGTTCAGGATACGCGGCGCTTA

GTCCTGTTGTACTTCGAGATCTTATCTATATGTATTATCTGGATCATCAGGATTTGCA

AAAAAATGAGTTGATATGGGAAGTAAAAAAGCAGTTGGATCACTTCGATTTGACAA

ATAGAAATTATGATACAAATCCTTTTGATGTAGGGGGCAGCGTAAATGATCATATCT

GTGAACTGAGCGAGCATATAGCGAAGGCTCATTATATTTATGAGAGGGCTAAGGAA

GGACCATTGCAAAATGTAATTCGGGATATTTTGGGAGATACACCTGCCCTTTATTCT

GAAATGGCATTTCCTCAGCTAGCATCTATAAACAGGTGTGCTTGCAATTCGCTTTCTT

CATATCAAAAAAATATTTTTGATACTGACATAGCTATATATGCAGATGAAAAGGACA

CAAGAGGTAAATCAGACCGTATCCTTGTTGAGGGCGCATCTTCGAAATGGTATGAAT

TGAAGAAACXjCGATGCTAATAATGTCAAAATTTCTGAAAAGCTGAGTATACTCAAT

ACTATTCTTAAATTTAATAGTGTTTTTTGGGAAGAATGTTACCTTGATGGAAATATAA aacaatcgagcggaaagcgatctgaggcaggaaaaattctttatggtcgcgacaac

GGAAAAGAAAATOTCGGAGT TTCAAAATTGGAATTG&TGC&GTAl ATGATAGC TGC aggtcaggaacaaaatctgggaaattacctggtgagttcaggattttggagaaaaa

ATCATATGCTGTCATTTATACAAGGCAATGATATAGCGCTTGATGAGATGGATGAAT

TGGATCTCTTAGACTATATTCTGATATATGCATGGGGATTTAGGGAAAATATCATTA

AAAAGAACAGTAATGTGAATTCTTTGGATGAAAAGACTAGAAAAGTGCAGTTTCCG

TTTATAAAGTTACTCATGGCAATTGCAAGAGATATCCAGATACTTATATGTTCAGCA

CATGAAAAAACAGTCGATGAGTCATCTCGAAATGCAGCAAAGAAGATAGATATATT

GGGAAATTATATTCCTTTTCAGATTCATCTTCAGAGAACTAAAAAAGATGGTGGAAG

AGTGGTAATGGATACATTGTGTGCTGATTGGATTGCGGATTATGAATGGTACATTGA

TCTTGAGAAAGGAACACTTGGATGAGCAGTGATGAAAGGATATTTAAAAAATTTTT

GGAAAAAGGATCGATTTCTGAGCAGAAAAAGATGCTTTTAGAAGAAAAGAAATGTT

CGGATAAACTAACTGCACTGCTTGGGAATTACTGCATACCGATAGACAATATTTCAG

AGTCAGACGGAAAAATATATGCGGTCTATAAGCTTCCAAAAAATGTTAAACCTTTGT

CCGAAATCATTAATGATGTATCCTTTTCTGATTGTACGATGAGAGTACGTTTGCTTCT

517

WO 2016/205711

PCT/US2016/038181

CATAAAGAGAATTCTGGAACTCGTGTGTGCTTTTCACGAAAAAAAATGGTATTGTCT

CAGTATTTCACCGGGAATGCTCATGGTTGAAGATTTTGATATACCGATGGGAAATGT

CGGAAAAGTATTGATATATGATTTCAGAAATCCTGTTCCGTTCGAGTCAGTAAATGA

AAGACATAATTTTAACGTTTCAAATAAATACACTTCACCGGAGCTGCTCATCCATTC

AAGATATGACGAGTCGAAATCTGTGAGTGAAAAATCAGATTTGTATTCTGTTGCAAA

AATTGCGGAAACAATAATAGGAGATTTTAACAGTATTATTGCAAATGGAAATTTGAT

ACTACTTGCAATGCTTAGAGTTTTTATCAGTACAGGGAAAAGTCCGGAACCTGAGTA

TCGGTTTGAATCGTCGGAAAATATGCTTTCAGTATTTGAAAATTTGATCAAAGAAAA

TTGTTTTTTTGAAAAAAACGATTATACATCTATGTTTCATCAGGCGTATGACAATTTT

TTTGAATGGCAGGAATGTTTGATATCACCGGATCACTTGGATAAAAATATGTTCGAG

GCAGCTTTATCAAATCTTGAGGATCAGCTGCTTAGGGTTGATATTGATAAGTATAGA

GCAGAGTACTTCTATAAGCTTCTCCGAGAGTTGTCTAATAAATATAAAAATACAATT

ACTGATGAACAAAAGGTAAGGTTGGCAATACTTGGAATCAGAGCGAAAAATAATCT

GGGAAAAAGTTTTGATGCATTGGAAATATATGAGTCAGTACGTGATTTAGAAACTAT

GTTGGAGGAGATGGCAGAGCTTAGTCCTGTCATTGCTTCGACATATATGGATTGCTA

CCGAIATGCAGATGCGCAGAAAGTGGCGGAAGAAAAC ΑΊ TAI CAGGCTTCAIΑΑΊ A

GTAATATTCGTATGGAGAAAAAAAGAATACTGCTTGGAAGGTCATATAGTTCAAAA

GGGTGCAGCATGGGGTTTCAGCATATTCTTGGTGCGGATGAGTCATTTGAACAGGCT

TTATATTTCTTTAACGAAAAGGACAATTTTTGGAAAGAAATATTTGAGAGCAGAAAT

TTAGAGGACAGCGATAGACTTATAAAGTCTTTACGAAGCAATACGCATATTACGCTG

TTTCATTACATGCAATATGCATGTGAAACAAGGAGAAAGGAATTATATGGAGCACTT

TCAGACAAATATTTTATAGGTAAAGAATGGACAGAAAGACTCAAAGCATATATAAG

CAACAAGGATATATGGAAAAACTATTATGAGATATATATTCTGCTAAAGGGTATTTA

TTGCTTCTATCCAGAAGTCATGTGTTCGTCTGCGTTTTATGATGAAATCCAAAAAATG

TACGATCTTGAATTTGAAAAGGAAAAAATGTTTTACCCATTGAGTCTGATAGAACTG

TATCTTGCTCTGATAGAGATAAAAGTTAATGGGAGTCTGACGGAGAATGCCGAGAA

GTTGTTTAAACAGGCATTGACACATGACAATGAAGTCAAAAAAGGAAATATGAATA

TTCAGACCGCCATTTGGTATCGAATATATGCACTGTATAACGATGTAAAAGATGAAA

CTGATAAGAATAAAAGGCTTTTAAAACGGCTTATGATTCTTTGCCGACGATTTGGTT

GGGCGGATATGTATAGTGCTTTGGAGAAGGATGGGAAGTTAATTGATTTTTTGAGAT

TTGAGGTATGTTAAATGATAACACTTGCATTAGATGAAAATGGCAAATTTGAAGATG

518

WO 2016/205711

PCT/US2016/038181

CTTTTTCTAAAAAAAATGAAAAACCXjATAATGATTGCXjGGGATAATCTATGATGACA

AGGGGAAAGAGTATGATGCIGAGAATGAACGCTACAGGAIATCCAGTTATCTGCGA

GCAGTATGTGACAGTTTGGGTGCGAAATACCCTCAGGATCTACATTCAAATAGTAAT

GGAAATAAGGCGACTGTTGGGAAAGTAAAATGTAAAATTGGTGAAACACTAAAGGA

ATTCTTGAGAGAAGGAACCTATGAAAAAAAGGAATTGCCGACAAAGAACGGTTATT

TAAATAAGAGATCTGGAAAATATGTAATGTTTGCAGAACTCAGGAGTAGTCAGGGA

GTTAAAAAGCGTGTTAGTGGTTGGAATGACAATGATCTGACTCAGGATGAAAAGGT

CAGCAATCTGTACCTTCATATGGCAGAAAATGCCGTTGTCAGAATGCTCTTCCATAA

TCCTATATATGAAGATGTAACAGATGTAAATCTCTATTTTCCCACGCGAAAAGTTGT

TCTGAAAGATAGAGATAGAGAATACGATAAACAAGATTTCAAAATATATGGTGATA

AGGACAAGTGCGAAGCAGAAAGCGGGAGATTGGTGCATTATGATATCGTGTCATCG

GATTTTTACCGTACGATAATGGAGAACGAATGTACAAGAATTAATAAAAAGCAATT

AAATGTTCATTATATGAACACAAGCCCAATTTCGTACTGGGAGAAAAATGAAAAAT

ATAATACATTTTTATATTTGGCTGACATAGTTTGTTCTATGCTGGATTATTACAAAAA

GGGTTCGAGTCCGGCAGAGTGGATGGATTCTTTTGCCGAATGGGGAAACAAATATTT

TGGTGATGATCAGATAATCTTATTTGGGTATGATGATATAGATGACAAATACATGGA

GGCTGTAGATGCAGTAGGACAGGGAGAGTATTTTCATGCGCTGGATATTATATATGA

TGCGGAATGTAGTGGAAGTGAATTTGAGAAGCACTACAAAGATTATTGGTTTCCAA

AGCTTATAAAAAAGATACGAATAACAGCAACTGTGGATAATTTATGCAGATCGATC

TCAGATCTGGAGAGTTTTACATATCGAAGTAATCTTGATCAGCAGAAACTTTTGTGG

ATTTTTGAGGAAATCAAAGCTATCGTCGATAAGGGAGATTTTGGAAAGAAATATCAT

ACAGATCAGGTTATGTTTGATATGTGTAATGCCGGTATTGCTGTGTACAATCATATC

GGAGATTTTGGGACTGCAAAGGAATACTATGATGAGTGCATGAAACACACTGGGGA

TGTGGATCTGGTAAAGATACTTCGTGCATCAAATAAAATGGTGGTCTTTCTTGACGA

TGCTTTTAGGTATGGTGACGCGACAGAACGTGCCAGGAAGAATGTTGAATACCAAA

AAGCTTTGCACGATATAAAGAGTGAGATTTGTCCGGAAAAGAAAGATGAAGACTTG

AACTATGCCATATCGCTCAGTCAATTTGGACAGGCGCTTGCGTGTGAAAAAAATTCT

GATGCAGAGAGTGTTTTCCTAGAGTCGTTGCGGCATATGAGGAAAGGGACTGCCAA

TTATCAGATTACTCTTTCATATTTACTCCATTTTTATCTGGATATGGGAATGACAGAT

TCTTATCGAGAAAAAACAAAGGACTATTTTGGAAGTGAAAAACCAAAGGAACAGCT

GAAAGAATTGCTGAAGTTATCGGGAAAGGATGATAGTATAGTTACTTTCAAATTTGC

519

WO 2016/205711

PCT/US2016/038181

AATGTATGTCTATTTACGTGCACTTTGGGTATTACAGGAACCGCTTACTGATTTTATC

AGAACAAGATTAGAGGACATACGTGAGACTCTTGTAAAGAAGAAAATGAGTGAACA

TATGGTTGGACATCCGTGGGAGTTGATTTATAAATATCTGGCATTTCTTTTTTATCGT

GATGGAAATTGTGAAGCTGCTGAAAAATATATTCATAAAAGTGAAGAGTGCTTGGA

AACACAAGGACTGACTATAGATGCGATTATTCATAATGGTAAGTATGAATATGCAG

AATTGTCAGGTGACGAGGAGATGATGGCAAGAGAGAAAGCGTACTTTGATGAAAAA

GGGATAGATAGAAAAAATGTTTGTACTTTTATGTATCATTGATGTTTAATAAGATTT

GACCGAGGAGTGACAGGTAATCGCCGGTATATCTGGTATTACCTGTCATTTTTTGAT

GAAATAAGCTACTTTTTGCCTAAAAAACGAAACTGTTGGTGTTTTATGATGATTGTG

TCAACAAAAGAGAGCAAAAGAAGAGGAGAAAAGTAATGTCAATGATTTCATGTCCG

AATTGTGGTGGAGAGATATCTGAAAGGTCAAAGAAATGTGTTCATTGTGGATATGTG

TTAGTCGAAGAAGCTAAAGTAGTGTGCACAGAATGTGGAACTGAGGTAGAGAGTGG

CGCTGCTGTATGTCCGAAGTGCGGCTGTCCTGTAAATGATAGTGAGACGCCTCAGAA

AGTTGAAGTGACTAGGGTAAATGTATCTTCCGTAATCAGCAAAAAAGTCGTTGTAAG

CATACTGATCGCAGTGATTACAATTGCAGGTTTTTTCTATGGAGTGAAGTATTCGCA

GGA A A AGAAAGC AATTGA AGAG TC AG Γ AA AGC AGAAGGAAGACT ΑΊ CAAAG! AC G

CTAGAGCTTGCTTCGCTAATGATGCTTCAAGGAGCTTCGGATGCAGAAACTTGTGGG

AA IT 1 GGTTAGGAAAGI GI’GGAGC AACTGCAT IT ATAAGGAGAGGGAT GAAGAAAC

CGACAAGTATACGTGTGATAGCAGGGGTGCAGGATGGTTTTATGATGATTTTAATGA

TGCATTAATGGCTCTTTACAGTGACAGCAGTTTTGGCAAGAAGATAAATGAAATCAA

AAACGGTCAGGAAACCGTTGCGGCGATGATGAAAGATCTGAAAAATCCGCCGGATG

AGATGGCAGATGCCTATGAGGATATTCAAAATTTTTATGTGTCCTATCTAACGCTGA

CAGAAATGGTTGTGAATCCAACTGGAAGTTTGAGTTCTTTTTCATCTGATTTTTCCGA

TGCGGATACGGAGGTGTCCAATGCCTATAGCCGGATGAAGTTGTATTTAGATTAAAC

TATTGAGGAAAAAATGGAG&rGCTTTAArGCGGGGGAGAAACl GTGGAGGGTCATC

AGGCGACGGACTGCTGGTACTTCTCGTACTGCTTGTCCTTTTTTATAAAATCATGCCA

TTCATAGGTTTATGGATTTTAATTTTTGGTGATGCTGAACGTAAAGATCTGGGTATGG

GTATGATTATTGTCGGGATAGTTCTATATGTATTATTAGAGGTTTTTTAATGTGAGTT

TCTGTGGTAAACTATAAAAGTACAAGCTTTTGCGCCGCACCGCATAAATAGCGGATT

TATGACCATTATTTGGTGAAAAAAATGGTGTACACCTGTGTTTTTTTGTTTTGCGCCG

CAAAATGCGCCACGGAACCGCATGCAGAGCACCCTGCAAGAGACAGGGTTATGAAA

520

WO 2016/205711

PCT/US2016/038181

ACAGCCCGACATAGAGGGCAATAGACACGGGGAGAAGTCATTTAATAAGGCCACTG

TTAAAAGTTATGAAAACAGCCCGACATAGAGGGCAATAGACATAAAGACCAAAAAC

AGGTCATCTGCATACTGTGTTATGAAAACAGCCCGATATAGAGGGTGTGAGAGATA TAGTTCTCGTCACAGTGCAGAAAATGACCTATTATGTGCCGAAAAACAAAATGAAA AAAGAATGGAAAGGCGTATTTAATGAAATGCTGATCTGTTGATTTGAATTAACAAA AAAAGGTCGCCCCACGGATGACAAAAACATCCGGGGGCGACCCTTTT (SEQ ID NO; 64) [001432] >E-locus [001433] TACTGTGTGCATAAGTCTTCCTTAGATCCATAGGTACAGCAGTTTTATTTA TTAGCCTTAGAAAATGGAAAATAGAGCTTATAAATGATATGATATTTATGAATAAAA

TGATTGCATTCTCGTGCAAACTTTAAATATATTGATTATATCCTTTACATTGGTTGTT

TTAATTACTATTATTAAGTAGGAATACGATATACCTCTAAATGAAAGAGGACTAAAA

CCCGCCAAAAGTATCAGAAAATGTTATTGCAGTAAGAGACTACCTCTATATGAAAG

AGGACTAAAACTTTTAACAGTGGCCTTATTAAATGACTTCTGTAAGAGACTACCTCT

ATATGAAAGAGGACTAAAACGTCTAATGTGGATAAGTATAAAAACGCTTATCCATC

ATTTAGGTGTTTTATTTTTTTGTGATTATATGTACAATAGAAGAGAGAAAAAAATCA

TTGAGGTGAAAACTATGAGAATTACTAAAGTAGAGGTTGATAGAAAAAAAGTACTA

ATTTCTAGGGATAAAAACGGGGGCAAGTTAGTITAIGAAAATGAAATGCAAGAT A A

TACAGAACAAATCATGCATCACAAAAAAAGTTCTTTTTACAAAAGTGTGGTAAACA

AAACTATTTGTCGTCCTGAACAAAAACAAATGAAAAAATTAGTTCATGGATTATTAC

AAGAAAATAGTCAAGAAAAAATAAAAGTTTCAGATGTCACTAAACTTAATATCTCA

AATTTCTTAAATCATCGTTTCAAAAAAAGTTTATATTATTTTCCTGAAAATAGTCCTG

ACAAAAGCGAAGAATACAGAATAGAAATAAATCTCTCCCAATTGTTAGAAGATAGC

TTAAAAAAACAGCAAGGGACATTTATATGTTGGGAATCTTTTAGCAAAGACATGGA

ATTATACATTAATTGGGCGGAAAATTATATTTCATCAAAAACGAAGCTAATAAAAA

AATCCATTCGAAACAATAGAATTCAATCTACTGAATCAAGAAGTGGACAACTAATG

GATAGATATATGAAAGACATTTTAAATAAAAACAAACCTTTCGATATCCAATCAGTT

AGCGAAAAGTACCAACTTGAAAAATTGACTAGTGCTTTAAAAGCTACTTTTAAAGA

AGCGAAGAAAAACGACAAAGAGATTAACTATAAGCTTAAGTCCACTCTCCAAAACC

ATGAAAGACAAATAATAGAAGAATTGAAGGAAAATTCCGAACTGAACCAATTTAAT

ATAGAAATAAGAAAACATCTTGAAACTTATTTTCCTATTAAGAAAACAAACAGAAA

591

WO 2016/205711

PCT/US2016/038181

AGTTGGAGATATAAGGAATTTAGAAATAGGAGAAATCCAAAAAATAGTAAATCATC

GGTTGAAAAATAAAATAGTTCAACGCATTCTCCAAGAAGGGAAATTAGCTTCTTATG

AGATTGAATCAACAGTTAACTCTAATTCCTTACAAAAAATTAAAATTGAAGAAGCAT

TTGCCTTAAAGTTTATCAATGCTTGTTTATTTGCTTCTAACAATTTAAGGAATATGGT

ATATCCTGTTTGCAAAAAGGATATATTAATGATAGGTGAATTTAAAAATAGTTTTAA

AGAAATAAAACACAAAAAATTCATTCGTCAATGGTCGCAATTCTTCTCTCAAGAAAT

AACTGTTGATGACATTGAATTAGCTTCATGGGGGCTGAGAGGAGCCATTGCACCAAT

AAGAAATGAAATAATTCATTTAAAGAAGCATAGCTGGAAAAAATTTTTTAATAACC

CTACTTTCAAAGTGAAAAAAAGTAAAATAATAAATGGGAAAACGAAAGATGTTACA

TCTGAATTCCTTTATAAAGAAACTTTATTTAAGGATTATTTCTATAGTGAGTTAGATT

CTGTTCCAGAATTGATTATTAATAAAATGGAAAGTAGCAAAATTTTAGATTATTATT

CCAGTGACCAGCTTAACCAAGTTTTTACAATTCCGAATTTCGAATTATCTTTACTGAC

TTCGGCCGTTCCCTTTGCACCTAGCTTTAAACGAGTTTATTTGAAAGGCTTTGATTAT

CAGAATCAAGATGAAGCACAACCGGATTATAATCTTAAATTAAATATCTATAACGA

AAAAGCCTTTAATTCGGAGGCATTTCAGGCGCAATATTCATTATTTAAAATGGTTTA

TTATCAAGTCTTTTTACCGCAATTCACTACAAATAACGATTTATTTAAGTCAAGTGTG

GATTTTATTTTAACATTAAACAAAGAACGGAAAGGTTACGCCAAAGCATTTCAAGAT

ATTCGAAAGATGAATAAAGATGAAAAGCCCTCAGAATATATGAGTTACATTCAGAG

TCAATTAATGCTCTATCAAAAAAAGCAAGAAGAAAAAGAGAAAATTAATCATTTTG

AAAAATTTATAAATCAAGTGTTTATTAAAGGTTTCAATTCTTTTATAGAAAAGAATA

GATTAACCTATATTTGCCATCCAACCAAAAACACAGTGCCAGAAAATGATAATATA

GAAATACCTTTCCACACGGATATGGATGATTCCAATATTGCATTTTGGCTTATGTGTA

AATTATTAGATGCTAAACAACTTAGCGAATTACGTAATGAAATGATAAAATTCAGTT

GTTCCTTACAATCAACTGAAGAAATAAGCACATTTACCAAGGCGCGAGAAGTGATT

GGTTTAGCTCTTTTAAATGGCGAAAAAGGATGTAATGATTGGAAAGAACTTTTTGAT

GATAAAGAAGCTTGGAAAAAGAACATGTCCTTATATGTTTCCXjAGGAATTGCTTCAA

TCATTGCCGTACACACAAGAAGATGGTCAAACACCTGTAATTAATCGAAGTATCGAT

TTAGTAAAAAAATACGGTACAGAAACAATACTAGAGAAATTATTTTCCTCCTCAGAT

GATTATAAAGTTTCAGCTAAAGATATCGCAAAATTACATGAATATGATGTAACGGA

GAAAATAGCACAGCAAGAGAGTCTACATAAGCAATGGATAGAAAAGCCCGGTTTAG

CCCGTGACTCAGCATGGACAAAAAAATACCAAAATGTGATTAATGATATTAGTAATT

522

WO 2016/205711

PCT/US2016/038181

ACCAATGGGCTAAGACAAAGGTCGAATTAACACAAGTAAGGCATCTTCATCAATTA

ACTATTGATTTGCTTTCAAGGTTAGCAGGATATATGTCTATCGCTGAfjCGTGATTTCC

AGTTTTCTAGTAATTATATTTTAGAAAGAGAGAACTCTGAGTATAGAGTTACAAGTT

GGATATTATTAAGTGAAAATAAAAATAAAAATAAATATAACGACTACGAATTGTAT

AATCTAAAAAATGCCTCTATAAAAGTATCATCAAAAAATGATCCCCAGTTAAAAGTT

GATCTTAAGCAATTACGATTAACCTTAGAGTACTTAGAACTTTTTGATAACCGATTG

AAAGAAAAACGAAATAACATTTCACATTTTAATTACCTTAACGGACAGTTAGGGAA

CTCTATTTTAGAATTATTTGACGATGCTCXJAGATGTACTTTCCTATGATCGTAAACTA

AAGAATGCGGTGTCTAAATCTTTGAAAGAAATTTTAAGCTCTCATGGAATGGAAGTG

ACATTTAAACCACTATATCAAACCAATCATCATTTAAAAATTGATAAACTCCAACCT

AAAAAAATACACCACTTAGGTGAAAAAAGTACTGTTTCTTCAAATCAAGTTTCTAAT

GAATACTGTCAACTAGTAAGAACGCTATTAACGATGAAGTAATTCTTTTAAAGCACA

TTAATTACCTCTAAATGAAAAGAGGACTAAAACTGAAAGAGGACTAAAACACCAGA

TGTGGATAACTATATTAGTGGCTATTAAAAATTCGTCGATATTAGAGAGGAAACTTT

AGATGAAGATGAAATGGAAATTAAAAGAAAATGACGTTCGCAAAGGGGTGGTGGTC

ATTGAGTAAAATTGACATCGGAGAAGTAACCCACTTTTTACAAGGTCTAAAGAAAA

GTAACGAAAACGCCCGAAAAATGATAGAAGACATTCAATCGGCTGTCAAAGCCTAC

GCTGATGATACAACTTTAAAAGGAAAAGCAGTGGATTCTTCACAAAGATACTTTGAT

GAAACGTATACTGTTATTTGTAAAAGTATCATAGAAGCATTAGATGAAAGCGAAGA

GAGATTACAACAATATATTCATGATTTTGGAGATCAAGTGGATTCTTCACCTAACGC

ACGAATTGATGCGGAATTACTACAAGAAGCAATGAGTAGGTTAGCTGACATAAAGC

GGAAGCAAGAAGCACTTATGCAATCCTTATCTTCTTCTACAGCAACGCTTTACGAAG

GCAAGCAACAAGCGTTACACACTCAATTCACGGATGCGCTGGAGCAAGAAAAAATA

TTGGAACGCTATATTACTTTTGAACAAACTCACGGGAATTTTTTTGACTCATTTGGAG

AACTTGTCTATCGAACGGGACAAGCAGTGCGTGAATTAGCTAATAACGTCACATTCG

AGAGCCAAACAGGAAGCTATCATTTTGATAAAATAGATGCTTCTAGATTCCAAACTT

TGCAAGAAATGTTGCCAAAGGCAAAGAAAAAAGCATTTAATTTTAATGACTACCAA

ATAACATGGAATGGCACCACGCACCTTTTATGGAAAAATGGTAAAGTGGATGCAGA

AGCAACCAAAGCTTATAACGAGGCGAAACTGAATGGAAAGCTACCAAAGGAAGGT

AATGTAGCAACACAAGATGCAGAACTATTAAAAGGCATTTTGGCTTCACTGAAAAA

CAAGAAAGATCCTATCACTGGAGCAGATATAAGCAGTGTGCATGTATTATCTATCCT

523

WO 2016/205711

PCT/US2016/038181

TAGCGGGCTCGCATTCTCCTATACAGCTGGGAATTATAAGGGAAGAAAACTTACTGT

TCCAAAAAGTTTCTTAGACAAATTAAAGAAAAACCGAAAATCTAAAGTACCTAAAC tatctagtttatcagaaaaacaacaactaaaactcgcaaataaatacaagaaaaaa

TCACCTATTCCAATTCCAGATGATGCTAAAATCAAAGCTCAGACGAAAAAGGC TGGT

TATGAACAAATATCTTATAAATGGAAAGAGAATGGGATAACCTTTGAAGTTAGATG

GCATACTAGGACACCAGGTGCACCAAAGGAACAAGGAAATACGTTTGTTATAGAAA

GAA AA ATTCAGGGT AC AGC AGAAGGGA AAAC AAAAGTTC AAC A AA ΓΑΤ TGGII GGA

GATAATAAGTGGGTGAGTAAAAGTGAGTGGCAAAAGGCTATAACTGATAAGAAAA

ATGGTGTAAGTACCTCGGAGCAAAATAAAATGTTGTCTGATGGACATTGGAAAGAA

TAGAAAGGAGCAAAATGATGGAAGATTATTATAAAGGTTTTGAGGGATATCCAGAG

ATAGATTTTTATACGTATATAGATGATATGAAATTGGGTATAGCAATGTGGGAAGGA

TACTTTGACAACATTATGAAAGAAATTAATCCAAGTAACGGAAGATGGACTTCATTA

GCGTATTATTATCATTTAGATGAGGGGTGGTATGATGAAAGTCCTTGGGAAATACCA

AGTAATACAGAAGCATTAGAATTATTGGAAACAATCCATATATCTAATCTAGATACT

ATCACACAAGAGATATTACTTAAATTAATAAATTTATTAAAGAAGAATATAAATAG

ACAAGTTTATATTGAATACTCATAAAAAAGATGATTATGATATATTATAGAACAAAC

GAACAAGCCCCAAATACGAGGTTTGTTCGTTTGTTTTCAATATAATTATTTGCCACCA

AGTGAGATATTACGGTTTTAAATAGCTTATTTGACGATACCAAACCCTGATAAGAGA

AAGAAGAAAGAGAAAGCTGGTGTAGTTGTTTTAAGTGAACTAGATAAAAAATTAAT

AGCAAAACTTGAAAAAGATGGTGTGAAAATATCAAAAGAAGATGTTATAGGAATAA

AATAATTGCCAGATGATGAGAAATCGTTTGGCTGGAAAAAGGAAATCCATCCGCTG

GATTTGAGCATATTCTTATTGAACATGGTGAACAATTTGCTAAATAGGGAATTTCAA

AAGCTGAGTTACCTGATTTTTTGATGACTGCTTTAGAAAAGGAAA (SEQ ID NO: 65) [001434] >F-locus [001435] ATTCTTTAAAAATATCTAATAATTTATTTACTATATACTCTAATACATCTTT TAACCTATCTAAAACATCATCACCTACAACATCCCAAAAATCATCTAAAAAGTTAAA

AAAATCCATCTTTATCAACTCCTATATCTATTTTTTATTGTGTAATTCCTGAGTTACA

AAACCATTATAACACGTATTACACACGTAGTCAATACTTCAAAAAAATTTTTTGTAT

ATTTTTTTGAATAAGTAAATAAAAAGAGCTGTGTAGCTCTTTATTAAAATCAATATTT

TTATTTTGTTAACAAACTTAGACAACATTAAATTTAGAAACCTATATATATTTCAGTA

CTTTTCATTTTTAGGTAGTCTAAATCAGAAATGGTTTTGTCTAAATGATGTATGTAAG

524

WO 2016/205711

PCT/US2016/038181

TTTTAGTCCCCTTCGTTTTTAGGGTAGTCTAAATCAGAAGTCATTTAATAAGGCCACT

GTTAAAAGTTTTAGTCCCCTTCGTTTTTAGGGTAGTCTAAATCCCATCCAAATTATGG

GATAATATGTTACTTTTTATTTTAATATTTGATTATTTATTGTTTTTTTACTGATTTAG

ATTACCCCTTTAATTTATTTTACCATATTTTTCTCATAATGCAAACTAATATTCCAAA

ATTTTTGTTTCTTTTCTTATGATCTTTTCTCCGATAGTTATTTCTCCAGATAAGATTTT

CATTTTTTTGAATTGATCTTCTGTTAGAATTAATGTTCTTACTGATGAATTTTCTGGA

ACTATCATTGACAACTGATTTTCATAGGAAATTATTTTTTCTTTTGTGCTAGAACTTA

CAATGTATACTGATTTTTGTACCTGATAATATCCTTTTCTTATAATTTCTTTTCTAAAT

TTTGCATATTCTTTTTTTTCTTTTCCTGTTTGCATTGGAAAATCATACATTAGAATCCC

TACATAATTAGTACTCATAATCCTCTATCCTTAACTCAGGAATTTCTACTTCTGACAT

TTCTCCTGTAAAATAATTTCTAATATTATCTAAAAAATAATCAATCACTTGAGCCAAT

TCATATTTTTTATTTTTCCAATAAACTTTTTGTGTTAATACCAATAACAATTTTTGTCT

TAATGATTTATTCAAACTTACTTCTTCCTGTTGATTAAAATATACGATATAATCTACC

ATTGGACGAAATATTTCAATAATATCATCTGCAAAATTATAATTATTAAATTGTGAA

CTGTGATGTATTCCCAAACTTGGATGAAATCCTTTAGCCACAATTTTTGAAGAGATT

AAGCTTCTCAAAACCATATACCCATAATTTAATGCCGAATTTGTC’CCGTCTTCACCA

AATCTCTTAAATTTTTTCCCAAAAAGTTCACCAAAATACATTCTTGCAGCAATTGCTT

CCTGATGTTCCGCTTCTTTTCCTTTTAATCTAATATTATTTTCATATGCTTCCAACTTA

TATGATACTTCCTGAGATTTTTTCAAAAACTGCAATAAATTTCTTTGATTTTCTATTTT

TCTCATTACAATTTTTCTCCAGATTTCTTCTTTTTTATCGTCAATCCAGCTCACTTGCT

CATTAATTCTTGTTGTTACTTGAAAATGATTATACAGTCCTAATGAATGTAAAACTG

GCTGATGTTTTTCATTACAAATTATCAGTGGAATATTATGTTCTGATAATCTTAACTG

TAATATTCCGCTAATTTTACATCTGCAATTTTCAACTACAATTGCCATGATATCATTT

AAAGATACTTTATCAGCCTTATTTTCATCATCTTCATTTATCATCACAAGCTGGTTAT

TTAAAACTGATAATTCATTGACTCTTGTTACATGGATAATATTAGACATTTTTATTAC

TCCTTTACTCTAAAGCTTTATATTCAAACATAACTTTCACAAGTTCACACAATTCTTC

TGAATTTCTATCAGTCATTAATTTTTTCTTTTTTAAATTTTTCAAATGTACAATTTTTT

CCGATTCTAAAGTCTGAATTTCTATTTTCTTATCTGCTCCTATTTTAAATGTTGCTACA

AAACCATATTCCTTTAATATATCCACTATTGATTTCATAATTGCATTTTTAAGTTTTCT

ATCATAAGAAAGTAATTTTCTTAAATTTTCCAGCACTTCTAAAAGTGAAATTTCAGC

ATGCXJGAATATAGTTAAAATGTGCAATATAGTTTCGTATATACAAATCTTTTTTCTCT

525

WO 2016/205711

PCT/US2016/038181

TGTTTTAATTTTTTTACTTTTTTATCAGAATAGATGCTTCTTTTTTCTACATTATCTTTG

TATAATTCTTTATAAAAATTTATATATTTTTCAACAATTTGCCCACTTTTATATTTTAC

ATTTTTACTGTTATCAAAATTAAATATTTCTTCAATATAATGATTTTCAGGAAATTCA

CCTTTCAATCTAAATCTTAAGTCCCTTTCCCAGATCGAAGTATATCCCACAAGTCTGT

GGAGTATTTTTAATAACAAGCCTTGCAACAAGTTTAATTCATTAAATTCCACTTTATT

TTTCAAATGAGTATATTTTTGTATATTTCCAATTGCTTTTTCATATTCTTTATAATCTT

CATCATTAA/kTTTTTCATCTTTTTTAGGTCTTGCATATTTTCTATGTAAATTTTGCTGC

ATTGTATAATTTTTTTCTATTTCATTTTTTTTATTGCTGTATTCTTTCAATTCTTTTAAA

CTTATTTTATACTTCGCTTTATCAGCTATTTTTTCAAGTAAATTTAACATCCCATATTT

TTTTATATTATAAAAAGCTCTATGCTTTATAATATTTTCTCCATCAAAATATATTTTAT

TTGTGTCAAATTTCTTCAATTCTTTCCTATCTTTTATTTTATTTTCATTAAAATCTAAA

AATTTTCCAATTTCATTCGCTTCTAATTCAAAATCTTCTGTTACTCTATTATTATCTAA

ATTTAAAAGATTTATAAGTTCAAGTTCATCTGAAAAAGTTTCTTCTTTATTTGCACTC

TGATATTTTTCAAGACTTCCCTTCAAATTAGTCAATTCTTTATGATTAAGCAATTTTA

AAATTAAATAAAACATATTCAAATTTTCAGTGTATTTTAATATCTTTCCTAATTTTAT

CTCTCTTACAAATTCATTTATTTCATGTGGAATTTCTTTATTCCTATTATGTTTTTCAT

AATTTTTTAAAATTTTATCATATTTTTCTTTATTATCTTTTTTTATTTTTATTTTAGAAA

ATATATCATTATTATCATTGTTATTATTACTTTCTATATATTTTAAATTATTTTTATTC

AAATAATCTATAAAACCTTTTAAAAATATTTGTTGTATAAAATCAATGTATGTATTTT

TTTCTTCTTTATCTTGATTATTAATCATCTCCCTACTTTGTATAATAGCAAGATA.TTCT

ACTGGTACAGTTTTTTCTATATTTTCAAATTTTTGATATTTATAATGTCCTGTTTTTTG

ATTTCTTTGTTTATTTATTTTTATTACTTCATTAGTTATTTTAAAAAAAACTTTACTAT

TTTTAACAAATTTATTAAGAAATTCACCATAATAAATATTTTTCAAAAGATATATTTG

AGCATCTTTTTCTTCTTTATCCTTAGGAACACTCCAAAAAAATTTTAAAGTATTTCTT

AAATCTTCTATTTTATTATATAATTTCGTAAAAGAAGGAACAAAAGGAATATTCTTA

TTTACAAAATTAAATTTTGTATTTTTTAAATATTTAATTATCACATCCTTTTCATAATA

ATTAAATACATTTGCACTATTTAACTGCTTAAATATCTTCAATTTCAATTTTTTCTCAT

TTATTTCATTTTGAAACATTTTTTTTGAAATTTCAGAAGGAGCTATATTTTTAAATGC

AAATATATCTTTCCCTTCTAATTCCAAATTAAAATGCACAATCCCATGTCTAATACTG

CTAATAGCTTCATCAATATTTGCAAAAAAATCTTCTATCTCATTTTTATTATCCATAT

TAAAATCATAACTATAGAACATTTTTAAATTTTCTTTTACTTCATTTTGCTTGTTTTCA

526

WO 2016/205711

PCT/US2016/038181

TTATATATTTTATCAACTTCTCCAGAAACATATTTTTCTTCGCCCTTATTATTTTTTAC

AGTTTTTCCTCTCATTCTACCTGTAATATCATTCTCATTTTCAGTTTCAAGAATATTTC

TCAATGAAAAATATGCAACCGAAGAAACTCCAATTATATTTCGTAAAAATGCTTCAT

TTTGTCTATTCCTAGCAATAAAATCACTTGTTGCAATCTCTCCAACTTGTAAATAATA

ATTGTATTTCCCACAATTTCTTACATAAGTATCCAATTTATTTAGTAATTTGTTTTCAA

TTAATTTTTTTAAATTTTGATATTCAAATATTCTCTTAATTTTATCGTTACTTATGTTA

CTCAGTCTTTTATACACATAATTTTTCAAAAGCTGACTCATTTCAATTTCCACAAAAT

GACAAAAAGCATATTTTATATTTTTATCATTAAGTTCTTCTTTATCCAAATAATATTT

ATAAAACACTTGTGATTTTTTTAATTCACTCATATCCGGAATTTTTTCAATTAATTCTT

TTATATTATTTACATTTTGTATTTCTTCGTAAATAATTTTAGCAAAATTTTCTTTATCA

TTTTTTCTTCCAATTATTTTGTGATAGTATTCTCTTATTTTATATTTTTCATGTTTTTTT

GAATTTTCTATTAAAAAAAATAACTTCTCAATATCTTCTTTTTTATACAATTTATCAA

ATGCTTCCTGTACATTATTTATATAATCATTACGCTTTGCTGATTCTCTATAATAATC

ATAAATAATATTTCTTTTGCTCTTCCCTCCAACTTTTTCAACATTATTTTCATTAATTT

TCTGATAATTAGCCTTATTTTCTTCAAATGAATATTTTAAAGAATTTATCTTATTCAA

TTTTGCCTCAACATCTTTTCTAAATATTTCTAATTCTTCAGAGTTCACATCTTCATTTA

ACAATATTTTCTTTAAAACTGAAAAACTATTTTTATTTTTTAAATCATATTCTGAAAT

ATCTTCTTCAGAATAATTTTTATCCTGTACTGCATTTTTCTCTTTCCTATTCTTTAAAT

ACAGAACACTATCTTTTAGATGCAATACTTTATTTGAAAAAAACTTTTTTAAATTTTC

TCTTCTTATTCTATTTTCTTCTTCACTTGCATTATCAGGATTTTTTATATATATATCCA

GTCTTATACTTAAAAGCTCTGACAATCTCTCACTAGTCCTATTTTCTTCGCTCGTACT

TTTTACTAATTTTCCCTCTTCAATATATTTTTTATGCGAAATTCCATCAACTTTTGTAA _{CTTTCATATATAAAAACCTCCTAATATCTATATTTTTTACTCAATACCTAATTCTTTTT}

TCAATGCTTTTTGTAAAATTTGTGAAAAATTCAGATTTTTTTCCTGTGCCAATATATC

TAACCAAACAGGAATTGTTAAAGTTTTCTTTTTAAGTGCATTTGTAACTTTTGCCACT

TCATACACTGGATCAACAGATAAAATATACAAATACTGATTTTCTTTCAGTTTCACA

TCCTCCACTTTTGAAGGCTCAGGAAATTTTTTTCTTACATCCAAAAAATCAGCCAAAT

GCAGACCCAATGTCTCTCTCAAATTGGAAACAGCCTCCTCCATGCTATCTCCAAATG

TAGCATAATAATTTATCTCTCCATCTTCAAACTTATCAAAATCAACAATACAACCAT

AATAAGTCCCATCTTCCTTAGTTACCACTGCTGGATAAAATACATCCATTTTAATTAT

CTCCAATCTATACCACGTGTTAAATACGTGTTTAAAAATATTTATAAAATTTTTTAGC

527

WO 2016/205711

PCT/US2016/038181

ATCTCTGCTAAAATAAAACAATTATTTCAAATTTTTCTATTCCTTAATCACTCATTGT

TAGTGATTCTTTTTTTACTTGGACAATTTTTCATTTAATTTCTTCAATTTTTTTAAAAT

CACATTTTTTTAATATTCCTTATTTAATTGCAAATTTTCATTACTTTTGGGGTGCTCTA

AATCCCATCCAAATTATGGGATAATAATTTTTAGTGAAAGCAAGAAGGGACTAGAA

TTTAATCCCAACTTGTTTTTCAATACTTCTTAATGTTCCTACAGGTATATCTTTTGAAT

ATGGTACTGTGACCACACCTTCCACACCTGGGATCATCCATTGATAATGACTACCTC

TTATACGCACAACTTTTCCGCCTAATTTTCTAAATCTTTTTTCGAT (SEQ ID NO: 66) [00143 6] >G-locus [001437] CTTTCTATCTTTTTCAAATAAAATTAGGCTCTAGTTAGCCTAATCGCATAA TTATTTATTATAGTATAATTCTTATTTTTTTTCAACCTAAAAATTTAAAACATCTCCA

AAAATTTTCGTTTCAGAACAACCAAGCAACCATATTCAAAAAACAATAAAAAATGA

GCAAGAATTGAAATTTTATTCTCACTCAGAAGTTATTTTTATTAAATATCACTTTTCG

ATATTGGGGTGGTCTATATCAATTTAAAAGACAGAATAGATAATTCTTTAGAGTTTT

AGTCCCCTTCGATATTGGGGTGGTCTATATCAGAAGTCATTTAATAAGGCCACTGTT

AAAAGTTTTAGTCCCCTTCGATATTGGGGTGGTCTATATCCCATCCTAATTTCTTGCT

GATGAGATATTTATTTCTAATTTTTCTATTTTGTCTTTATTTTCAATACTTTCAATCCT

ATTTTTCTCTTTATTAATAATATAGAACCACCCTATACTATTATACCATATTTTTTGAT

TTTTCAAAATTCCAATATTTTGTTTTGTGAAATTTTTTCTCCCATTGTCACTTCTCCTG

CAAGTACCTTCATTTTTTGAAACTGATCTTCTGTCAGGATAATGGAACGGATTGATG

AATTTTCTGGAGCGAGCATTGATAACTGTTTTTCTGCCAGTTCGATTTTTTCTTTTGTT

TTCGACCTCATTATATATACCGATTTTTGAAGCTGATAATATCCCTTTTCTATCAATT

TTTTCCTAAAAGTCCTATATTCAAATCTCTCAACATCTGTCTGCATAGGAAAATCATA

CATAAGCAGACCAAAATACTCAATACTCATAGTCCATCACGCTCAATGTCGGAATTA

TCACTTCTTCATCTTTTACAAAATAATTTCGTATACTATCCAAATAATAGTCTACCGC

TTGGAAAAAATCATATTTCTTATTGTTAAATAATACCTTCTGCTGTGCTACAAGAAGT

ATTTTTTGCCTTATTTCCTTACTTAATTTCACTTCATTCAAAATATCCTTGTACATATA

AACAAGATAATCCACCATAGGACGAAAAACCTCTATTATATCATCAGAAAAATTAT

AGGCATTAAACTGTGACTTATGATGTAATCCTAAACTTGGATGAAATCCTTTTGCTA

CAATCTTTGATGATATTATAGCTCTTAAAATCATATATCCATAATTAAGTGCAGAATT

CACTCCATCTTCATCAAATCTTTTAAAACTATTACTATACAATTCCTGAAAATATATC

CTTGAAGCTATTGCTTCCTGATGTTCTGCACTCGCATCATCTTTTTTCAAGTTTTCCTT

528

WO 2016/205711

PCT/US2016/038181

ATATGTTTTCAGTCTTTCAATGGAAATATCACTTTTTTCAAGATACTCTAACAATGCT

CTTTGATTTTCAATCTTATTCTCCACTATCCTGCTCCACAATTTTTCCTTTTTCTCTTTT

TCCCACTCAATCTGCTCATTTATTCGTAAAGTCACTTGAAAATGATTAAATAATCCCA

GCGAATGAATTTCAGGCTG-ATGTTTCTCGTTGCAAATAATAATCGGAATGTTATTTTC

CACCAGCCTCAACTGCAAAATCGCACTAATCTTACAATAGCAGTTTTCAATAACTAT

CGCAGATA.TATCATTCAAAGAAATCTTATTTTTCTCATCATTATTGTCTTCATCAACC

ATTATAAGCTGATTATTCGATATTGACAAATCATCAGCCCTTGTTATGTGAATTATAT

TGGGCATTTTAATCATACTCCTTATAAATTTCATTCTTATAACXJTATCATTCGTATTTT

CTATTTTTGTTAAAAGTTCTATTATCAAGTTTTTAATATAATCAGAATTATAACTTTC

TAATTCTAAAACAGAAACTTTTTTAGGTTTCATTAATCTTTCAAGTATATCATTATTA

CCGATAAGTTTAAATTTTTTCTTTAATTCATCATAATCTAAATTCACATCTTTTTTAAA

TACTTCAAATACACTTGCATAAGTTGAATTATTATAACGTGTACTATATGATAATAA

ATTAGAAACTCTATCAATTTGTTCTGCAATACTGTAATCAGCAAACGGATTTCTTAC

AATATAGAAATGTGAAATATAGTTTCTAATACTTTCATTTTCCGGCTTATTAATTTCA

GAATTTTCAGACAAATCAATTCCAAATCCATAACATATTTTCTCAAATTTTTTATAAG

ATTCTTCATCAAAAAATTTATAGTATGCTGTTGTTGTATAAAAGCCATCAGATCCATT

ACGCTTAGGATAAGCTCTACTTATTCCAGTATTGTAGCCACTTAACTTAATAATTCCT

AATTCTCTTAGCCCATTTACAATATAGTGCATATCTCTTTCAAATCTAGCCATTTGAA

TAGCAAGTTTCCAATTTATATCTATCAAATAACTTTCTATTTTATTCAAATAATTAAA

TTCTACCAAATCTCTAATTTTTTTGTATTCAGAAACTCTATTATAATCTTTTTCAAATG

ATTTATAGTTTTTATTTTGTATATTTTTTGCAAAAAAGTCATCATTTTCTTTCAATTTT

TTTATATACTTCTCTTTGTATTCTTTAGAATATCCATTTAGTTTATCATTTAGATTTTT

CAATATTGCATCAATTTCAGATATTTTATTTTTTCTAATATTTTTACCATCAATATTAA

ATAAAAATTTTGCATCAGCCATTTTAATATCATTTGAAATTAATCCATAAATTTTATC

AAAATTTGGATTTCCAATATTTAAAAATAAATI'CTTTTTATAAATATATAATTCATTC

TTACGTTCTTTAGGATAATATATTTCTTGAAATTTATTTTCATTCTCTGATTCCATATC

TTCTATTAAATTATCTATTTCTTTTTTGTATTTTTTTAAAAAATCAGAATTAAATATTA

TTCTACACAATATTTTACTCTTTATTTCCTGATCTTTATCTTTTATATACTGATCAACC

TTTTTTTTCAAATCCTTTTTATTTATGTTTGATAACTTTCTTTGTTCATCTTGTAATATA

TTCGATTTTTTATCTATCTCAAATTTAGTTTCATCATCAAAAATTACAATTTTTTCTAA

TTTTTTCTCTAAAACATCACAACCATTAATATCATCTTTAAATTCAGTTAATATATTA

529

WO 2016/205711

PCT/US2016/038181

TTTTTTATATCCTCATAATAATTATTAAAAATTTCTTTTTTAGTTTGTATTTTAAAATC

ATCAAAGTCTTTTTCTATCTCTTTCATTTTTTGAATAAATTCTTCTAAATTAAGATTCC

AATTTTCAGTTATACATTCATTTCTCAAAGTATTTAATTGCATTATTTCATCTAAAAT

ATCTATAATATTTTGATATTCTGAAGTATTTAACCAAACTGATGTTGCAAAAAATCT

ATTTCTAATTTTATTTATAACCGCATTACTATTTAACAGTGCAAATATTGAAATTATA

TATTCAAAATCATCATTTATTACTATAGTTTTATCACTAGTCTTTACAGTTATTCTTTC

GTAAGTTTTATTATCATTAATGTCTTTTATTTGTTTCTTAATTTCTTGAATATTCATTT

TAAAATCTGAAAAATCAAAAAGTTCCTCATAATTTTTTCTCAAATATCCAATATAAC

ATTCTATTACTTTTTTCTGATATTTTTTAATAGCTTTATTATTACCTTTTGAAGCAGAA

ATCTGAGCATTTTTATAATAATTTTCTATAATATTTTCATCTATTTCATCAATGTTTCC

TAAAGTTTTCTTTAATTCTTGTAAAAATATATTCTTACTTTCATTTTCTTCTAAATCAT

CTTCTAAAATTAATTTCTTATACAATTCTTTATTCACATATATTAAAGCATTTAATAC

TATTTTTTCTGTTTCTATAGTATCAAATGGTTCATTCTTAGGATTATTCCTATATAAAT

TTAATATTTCAGGAAGTACTTTAGAAAAGGATGGTAAATATTTAATATCATTATTAT

TTTCTTCTGAAATTTTAATATCATTTATTTTAGTAATTATATTTTTTTTATCTTTAAAT

ACTACATCTAAATTTAATGCTTTTGACACTTCTTCATCTGATATTTTTAAATTTTGAAT

TATATTTATGACTTTATTATAGTCATCTTGCGTTCCTTGTAAATCTCTTTCCTTGCTAA

TCGCATGTAATATCCTGTTTCTTTCATTTGTTCCTATCTTTGTAAATTTCCTAATAAAA

TTATTTGTAATGTTATTTTTATTATCTATAAAATCTAAGTCTCTTATTATTTTTATTTTT

GAATTTAAAATTTTTTTATCAAGTACGTAATTTTTTTCTCGATCTCCTCCAAAGAAAT

CTATATTTTCATCATTATTTATATTTTCTCTAGAAAAAATCTTATTTAATTCCATATTG

GTAGAAGCAAAAAAAGTAATCAATTCTAAATCCAATTCCTCTTTAGCGTGAAGTCTA

GAAAAATCATCAGTATTTACTGTTGTCATATCTATATCATTATGTCTTAATTTCCCTA

AATACATAATATGCTCTAACGTATATTGCTTAACTCTTTTTAAAATTTTTTCAGATAA

TATACTTTCATTTAAAATTTTTTCTATTTCTATTTTTTCCATTTTCTTTAATCTGACTTT

TTGTTCATTTACCAATATTTTTTCAATTCTTCCTTTCAAATATCGATATATGATTTTAT

ATAGTTCTTTTTCTTCATCAGATTTCTTTGAAAATTTTTTCGAATCAAAATTAACTTTA

TAATGTTTTTTAAATATTCCAAAAATTTCTGTATCACAATTTCCTTTTTTTAGTTCTTT

TTCTAATTTTTTTATTAATTCATCTATTTTAAATTCTGCTAAAATTTTTTCTATTTTTTC

TTTTATACTATTATTTTTTATATTTTCTACAAAAAATTTTACAATTTTATCTTTTTTATT

TTCTCTTTCTATTTTAAATTTTTCGTGCTTATCTAATAGTACATAAGATTTTATATATG

530

WO 2016/205711

PCT/US2016/038181

TTCTATTTCTTCTCTTTTCAAGAAATTCATTATTAACTTTTTTTACTTTTTCAATTCTTT

TAGTAATATTCCAAAATTCTAACTCTTTTATAACAAAATCAGCTATATCTTCTACTGT

TAAATCTACATTTATATTTAAAATTTTTTCAACAAGCATTTTTTTATTTTTAGATTTCT

TTTTATCACCACCAACATTAAGATAAAATTTTACAAAACCCAGAATTTCTAAATTAC

TTTTTATTTTTTCTCTTATTTCCATAAAATTAGTCAAAATAACATCTATTTTATCATCT

TTCAATAATTTTTCTCTTAAATGTTCTTCATAATATCGATTTTCAAATACTTTTTCTGT

TTCATTTTCAATTAT TTTTTCTATAATCTTATATAAACTCATGTTAATAT TTTTAAAAA

TTTCGTAAATTGATTTTTTTGTTTCTAATTCATCATTTTCTATTATTCTTAATATTATTG

AACAATCATTTAGTGTTTTATTAGTATACTCATCTCTGATATCTATCTCTATTTCTTCT

TCATTCTCTTGTCTCTTTATTTCTATTTTTTTATCATCTTTAGTTATTCCTTGCCTAATT

GCTTCATCTATTATTTTCTTTTTTGTAATCCCCAATGCTTTCAATTTCTCAGATTTTCC

ATATGCTTCTATATATAATACAACTTCTTCTGTTTCCAAAAAATCATCATTATTTTCT

ATTCTTATGATTCCTTCTTTACCTTTCAACTTAAATAGAATATTTCCTGCATGAAATTT

TCTTGTAAATTCTTTAAGAATATTATCATTTTTTTTGTAATTAATATATTTTCTAATAA

ATTTATTATTATCAATTTTTTCTTTATTATTATTTTCATTAATATTTAAAATGTATTTG

TTTCCATCATAGTTCCTTTTAACTTTTACTTTCCGTTTTATTTTAAAATCTTTTTTATCA

CGAACTTCATACCATCTCTTATGTCCAAATAAATTTCCCATTCCAATCTCCTCGTTTC

TACTTTAATCTAATAAAATATTTTTAAATTAAATCAATTTTACATCTTTCTAATCAAA

AATACAATTTTCCATTTTTAGTATACCACATCAATATTAAATCTCAAAAAAATAAGG

AGCCGTCAAACATAGCTCCCTACTTCTATTTACTCATAATCCCCATCTATCCTTACTT

TTCGTAAAATCAATCCTTCTTTCGCCTTTAGATCCAACTTAATTTTCCCATTTGAACC

TGTTCTAAATGTTCTGCCTTCTGTTACCAAATCAATAAATCTTTCATCCTGATAATTT

GTTTCAAATTCCACATTTTCCCAGCTGTTAAACGAATTATTTATTACAACAATAATTA

AATGATCCTCGATTACTCTTTCATACACAATTATTT (SEQ ID NO: 67)

Example 3: Further evaluation of Cpfl and associated components [001438] Applicants carried out sequence alignments with Cas-Cpfl orthologs and compared the domain structure and organization (Figure 38A-N). An overview of Cpfl loci alignment in shown in Figure 39.

[001439] The sequences of Cpfl loci in various orthologs are listed below:

[001440] >KKP36646 (modified) hypothetical protein UR27 C0015G0004 [Peregrinibacteria bacterium GW2011 GWA2 33 10]

531

WO 2016/205711

PCT/US2016/038181 [001441 ] MSNFFKNFTNL YELSKTLRFELKP VGDTLTNMKDHLEYDEKLQTFLKDQNED

DAYQALKPQFDE1HEEFITDSLESKKAKEIDFSEYLDLFQEKKELNDSEKKLRNKIGETFN

KAGEKWKKEKYPQYEWKKGSKIANGADILSCQDMLQFIKYKNPEDEKIKNYIDDTLKG

FFTYFGGFNQNRANYYETKKEASTAVATRIVHENLPKFCDNVIQFKHIIKRKKDGTVEKT

ERKTEYLNAYQYLKNNNKITQIKD AETEKMIESTPIAEKIFD VYYF S SCLSQKQIEEYNRII

GHYNLLINLYNQAKRSEGKHLSANEKKYKDLPKFKTLYKQIGCGKKKDLFYTIKCDTEE

EANKSRNEGKESHSVEEirNKAQEAINKYFKSNNDCENINTVPDFINYILTKENYEGVYW

SKAAMNTISDKYFANYHDLQDRLKEAKVFQKADKKSEDDIKIPEAIELSGLFGVLDSLA

DWQTTLFKSSILSNEDKLKHTDSQTPSEALLKMIFNDIEKNMESFLKETNDIITLKKYKGN

KEGTEKIKQWFDYTLAINRMLKYFLVKENKIKGNSLDTNISEALKTLIYSDDAEWFKWY

DALRNYLTQKPQDEAKENKLKLNFDNPSLAGGWDVNKECSNFCVILKDKNEKKYLAIM

KKGENTLFQKEWTEGRGKNLTKKSNPLFEINNCEILSKMEYDFWADVSKMIPKCSTQLK

AVVNHFKQSDNEFIFPIGYKVTSGEKFREECKISKQDFELNNKVFNKNELSVTAMRYDLS

STQEKQYIKAFQKEYWELLFKQEKRDTKLTNNEIFNEWINFCNKKYSELLSWERKYKDA

LTNWINFCKYFLSKYPKTTLFNYSFKESENYNSLDEFYRDVDICSYKLNINTTINKSILDR

LVEEGKLYLFEEKNQDSNDGKSIGHKNNLHTIYWNAIFENFDNRPKLNGEAEIFYRKAIS

KDKLGIVKGKKTKNGTEIIKNYRFSKEKFILHVPITLNFCSNNEYWDIVNTKFYNFSNLH

FLGIDRGEKHLAYYSLVNKNGEIVDQGTLNLPFTDKDGNQRSIKKEKYFYNKQEDKWE

AKEVDCWNYNDLLDAMASNRDMARKNWQRIGTIKEAKNGYVSLVIRKIADLAVNNER

PAFIVLEDLN[TGFKRSRQK1DKSVYQKFELALAKKLNFLVDKN AKRDE1GSPTKALQLTP

PVNNYGDIENKKQAGIMLYTRANYTSQTDPATGWRKTIYLKAGPEETTYKKDGKIKNK

SVKDQIIETFTDIGFDGKDYYFEYDKGEFVDEKTGEIKPKKWRLYSGENGKSLDRFRGER

EKDKYEWKIDKIDIVKILDDLFVNFDKNISLLKQLKEGVELTRNNEHGTGESLRFAiNLIQ

QIRNTGNNERDNDFILSPVRDENGKHFDSREYWDKETKGEKISMPSSGDANGAFNIARK

GIIMNAHILANSDSKDLSLFVSDEEWDLHLNNKTEWKKQLNIFSSRKAMAKRKK (SEQ

ID NO: 68) [001442] >KKR91555_(modified) hypothetical protein UU43_C0004G0003 [Parcubacteria (Falkowbacteria) bacterium GW2011 GWA2 41 14] [001443] MLFFMSTDITNKPREKGVFDNFTNLYEFSKTLTFGLIPLKWDDNKKM1VEDE DFSVLRKYGVIEEDKRIAESIKIAKFYLNILHRELIGKVLGSLKFEKKNLENYDRLLGEIEK

NNKNENISEDKKKEIRKNFKKELS lAQDILLKKVGEVFESNG SGILS SKNCLDELTKRFTR

532

WO 2016/205711

PCT/US2016/038181

QEVDKLRRENKDIGVEYPDVAYREKDGKEETKSFFAMDVGYLDDFHKNRKQLYSVKG

KKNSLGRRILDNFEIFCKNKKLYEKYKNLDIDFSEIERNFNLTLEKVFDFDNYNERLTQE

GLDEYAKILGGESNKQERTANIHGLNQIINLYIQKKQSEQKAEQKETGKKKIKFNKKDYP

TF TCLQKQILSQVFRKEFHESDRDLiRELKFFVEESKEKVDKARGIIEFLLNHEENDIDLAM

VYLPKSKINSFVYKVFKEPQDFLSVFQDGASNLDFVSFDKIKTHLENNKLTYKIFFKTLIK

ENHDFESFLILLQQEIDLLIDGGETVTLGGKKESITSLDEKKNRLKEKLGWFEGKVRENE

KMKDEEEGEFC STVLAYSQ AVLNITKRAEIF VVLNEKQD AK VGEDNKDMIF YKKFDEF A

DDGFAPFFYFDKFGNYLKRRSRNTIKEIKLHFGNDDLLEGWDMNKEPEYWSFILRDRN

QYYLGIGKKDGEII'HKKLGNSVEAVKEAYELENEADFYEKIDYKQLNIDRFEGIAFPKKT

KTEEAFRQVCKKRADEFLGGDTYEFKILLAIKKEYDDFKARRQKEKDWDSKFSKEKMS

KLIEYYITCLGKRDDWKRFNLNFRQPKEYEDRSDFVRHIQRQAYWIDPRKVSKDYVDK

KVAEGEMFLFKVHNKDFYDFERKSEDKKNHTANLFTQYLLELFSCENIKNIKSKDLIESI

FELDGKAEIRFRPKTDDVKLKIYQKKGKDVTYADKRDGNKEKEVIQHRRFAKD ALTER

LKIRLNFGKHVNLFDFNKLVNTELFAKVPVKILGMDRGENNLIYYCFLDEHGEIENGKC

GSLNRVGEQIITLEDDKKATCEPVDYFQLLVDREGQRDWEQKNW'QKMTRIKDLKKAYL

GNVVSWISKEMLSGIKEGVVTIGVLEDLNSNFKRTRFFRERQVYQGFEKALVNKLGYLV

DKKYDNYRNVYQFAPR'DSV/EEMEKNKQIGTLVYV/PASYTSKICPFIPKCGWRERLYMK

NSASKEKIVGLLKSDGKiSYDQKNDRFYFEYQWEQEHKSDGKKKKYSGVDKVFSNVS

RMRWDVEQKKSiDFVDGTDGSiTNKLKSLLKGKGiELDNiNOQlVNQQKELGVEFFQSn

FYFNLIMQIRNYDKEKSGSEADYIQCPSCLFDSRKPEMNGKLSAITNGDANGAYNIARK

GFMQLCRJRENPQEPMKLITNREWDEAVREWDIYSAAQKIPVLSEEN (SEQ ID NO: 69) [001444] >KDN25524_(modified) hypothetical protein MBO_03467 [Moraxella bovoculi 237] [001445] MLFQDFTHLYPLSKTVKFELKPIDRITEHIHAKNFLSQDETMADMHQKVKVl

LDDYHRDFIADMMGEVKLTKLAEFYDVYLKFRKNPKDDELQKQLKDLQAVYRKEIVKP

IGNGGKYKAGYDRLFGAKLFKDGKELGDLAKFVIAQEGESSPKLAHLAHFEKFSTYFTG

FHDNRKNMYSDEDKHTAIAYRLIHENLPRFIDNLQILTTIKQKHSALYDQIINELTASGLD

VSLASHLDGYHKLLTQEGITAYNTLLGGISGEAGSPKIQGINELINSHHNQHCHKSERIAK

LRPLHKQILSDGMSVSFLPSKFADDSEMCQAVNEFYRHYADVFAKVQSLFDGFDDHQK

DGIYVEHKNLNELSKQAFGDFALLGRVLDGYYVDVVNPEFNERFAKAKTDNAKAKLT

KEKDKFIKGVHSLASLEQAIEHYTARHDDESVQAGKLGQYFKHGLAGVDNPIQKIHNNH

STIKGFLERERPAGERALPKIKSGKNPEMTQLRQLKELLDNALNVAHFAKLLTTKTTLDN

533

WO 2016/205711

PCT/US2016/038181

QDGNFYGEFGVLYDELAKIPTLYNKVRDYLSQKPFSTEKYKLNFGNPTLLNGWDLNKE

KDNFGVILQKDGCYYLALLDKAHKKVFDNAPNTGKSIYQKMIYKYLEVRKQFPKVFFS

KEAIAINYHPSKELVEIKDKGRQRSDDERLKLYRFILECLKIHPKYDKKFEGAIGDIQLFK

KDKKGREVPISEKDLFDKINGIFSSKPKLEMEDFFIGEFKRYNPSQDLVDQYNIYKKIDSN

DNRKKENFYNNHPKFKKDLVRYYYESMCKHEEWEESFEFSKKLQDIGCYVDVNELFTE lETRRLNYKISFCNINADYIDELVEQGQLYLFQIYNKDFSPKAHGKPNLHTLYFKALFSED

NLADPIYKLNGEAQIFYRKASLDMNETTIHRAGEVLENKNPDNPKKRQFVYDIIKDKRY

TQDKFMLH\/PITMNFGVQGMTIKEFNKKV'NQSIQQYDEV'NVIGIDRGERHLLYLT\/INS

KGEILEQCSLNDITTASANGTQMTTPYHKILDKREIERLNARVGWGEIET1KELKSGYLSH

VATIQISQLMLKYNAIVVI,EDLNFGFKRGRFKVEKQIYQNFENALIKKLNHLA^rLKDKAD

DEIGSYKNALQLTNNFTDLKSIGKQTGFLFYVPAWNTSKIDPETGFVDLLKPRYENIAQS

QAFFGKFDKICYNADKDYFEFHIDYAKFTDKAKNSRQIWTICSHGDKRYVYDKTANQN

KGAAKG1NVNDELKSLFARHHINEKQPNLA''MDICQNNDKEFHKSLMYLLK TLLALRYS

NASSDEDFILSPVANDEGVFFNSALADDTQPQNADANGAYHLALKGLWLLNELKNSDD

LNKVKLAIDNQTWLNFAQNR (SEQ ID NO: 70) [001446] >KKT48220__(modified) hypothetical protein UW39_C0001G0044 [Parcubacteria bacterium GW2011 GWC2 44 17] [001447] MENIFDQFIGKYSLSKTLRFELKPVGKTEDFLKINKVFEKDQTIDDSYNQAKF

YFDSLHQKFIDAALASDKTSELSFQNFADVLEKQNKIILDKKREMGALRKRDKNAVGID

RLQKEINDAEDIIQKEKEKIYKDVRTLFDNEAESWKTYYQEREVDGKKITFSKADLKQK

GADFLTAAGILKVLKYEFPEEKEKEFQAKNQPSLFVEEKENPGQKRYIFDSFDKFAGYLT

KFQQ TKKN LYA ADGTS T A V ATRIADNF HIT -IQNTK VFRDK YKNNHTDLGFD EENIFEIER

YKNCLLQREIEHIKNENSYNKIIGRINKKIKEYRDQKAKDTKLTKSDFPFFKNLDKQILGE

VEKEKQLIEKTREKTEEDAYTERFKEFIENNEERFTAAKKLMNAFCNGEFESEYEGIYIXN

KAINTISRRWFVSDRDF'ELKLPQQKSKNKSEKNEPKVKKFTSIAEIKNAVEELDGDIFKAV

FYDKKIIAQGGSKLEQFLVIWKYEFEYLFRDIERENGEKLLGYDSCLKIAKQLGIFPQEKE

AREKATAVIKNYADAGLGIFQMMKYFSLDDKDRKNTPGQLSTNFYAEYDGYYKDFEFI

KYYNEFRNFITKKPFDEDKIKLNFENGALLKGWDENKEYDFMGVILKKEGRLYLGIMH

KNHRKLFQSMGNAKGDNANRYQKMIYKQIADASKDVPRLLLTSKKAMEKFKPSQEILR

IKKEKTFKRESKNFSLRDLHALIEYYRNCIPQYSNWSFYDFQFQDTGKYQNIKEFTDDVQ

KY'GYKISFRDIDDEYINQAENEGKMYLFEVVNKDIYNTKNGSKNLHTLYFEHILSAENL

534

WO 2016/205711

PCT/US2016/038181

NDPVFKLSGMAEIFQRQPSVNEREKITTQKNQCILDKGDRAYKYRRYTEKKIMFHMSLV

LNTGKGEIKQ VQFNKIINQRIS S SDNEMR VN VIGIDRGEKNLLYYS VVKQNGEIIEQ ASLN

EINGVNYRDKLIEREKERLKNRQSWKPWKIKDLKKGYISHVIHKICQLIEKYSAIWLED

LNMRFKQIRGGIERSVYQQFEKALIDKLGYLVFKDNRDLRAPGGVLNGYQLSAPFVSFE

KMRKQTGILFYTQAEYTSKTDPITGFRKNVYISNSASLDKIKEAVKKFDAIGWDGKEQS

YFFKYNPYNLADEKYKNSTVSKEWAIFASAPRIRRQKGEDGYWKYDRVKVNEEFEKLL

KVWNFVNPKATDIKQEIIKKEKAGDLQGEKELDGRLRNFWHSFIYLFNLVLELRNSFSLQ

IKIKAGEVIAVDEGVDFIASPVKPFFTTPNPYIPSNLCWLAVENADANGAYNIARKGVMI

LKKIREHAKKDPEFKKLPNLFISNAEWDEAARDWGKYAGTTALNLDH (SEQ ID NO; 71) [001448] >WP 031492824 (modified) hypothetical protein [Succinivibrio dextrinosolvens] [001449] MSSLTKFTNKYSKQLTIKNELIPVGKTLENIKENGLIDGDEQLNENYQKAKIIV

DDFLRDFINKALNNTQIGNWRELADALNKEDEDNIEKLQDKIRGnVSKFETFDLFSSYSI

KKDEKIIDDDNDVEEEELDLGKKTSSFKYIFKKNLFKLVLPSYLKTTNQDKLKnSSFDNF

STYFRGFFENRKNIFTKKPISTSIAYRIVHDNFPKFLDNIRCFNVWQTECPQLIVKADNYL

KSKNVIAKDKSLANYFTVGAYDYFLSQNGIDFYNNIIGGLPAFAGHEKIQGLNEFINQEC

QKDSELKSKLKNRHAFKMAVLFKQILSDREKSFVIDEFESDAQVIDAVKNFYAEQCKDN

NVIFNLLNLIKNIAFLSDDELDGIFIEGKYLSSVSQKLYSDWSKLRNDIEDSANSKQGNKE

LAKKIKTNKGDVEKAISKYEFSLSELNSIVHDNTKFSDLLSCTLHKVASEKLVKVNEGD

WPKHLKNNEEKQKIKEPLDALLEIYNTLLIFNCKSFNKNGNFYVDYDRCINELSSVVYLY

NKTRNYCTKKPYNTD1<F1<LNFNSPQLGEGFSKSKENDCLTLLF1<KDDNYYVGI1RKGAK

INFDDTQAIADNTDNCIFKMNYFLLKDAKKFIPKCSIQLKEVKAHFKKSEDDYILSDKEK

FASPLVIKKSTFLLATAHVKGKKGNIKKFQKEYSKENPTEYRNSLNEWIA'FCKEFLK ΊΎΚ

AATIFDITTLKKAEEYADIVEFYKDVDNLCYKLEFCPIKTSFIENLIDNGDLYLFRINNKDF

SSi<STGTKNLHTLYLQAIFDERNT.>NNPTrMLNGGAELFYRKESIEQKNRITHKAGSILVNK

VCKDGTSLDDKIRNEIYQYENKFIDTLSDEAKKVLPNVIKKEATHDITKDKRFTSDKFFF

HCPLTINYKEGDTKQFNNEVLSFLRGNPDINIIGIDRGERNLIYVTVINQKGEILDSVSFNT

VTNKSSKIEQTVDYEEKLAVREKERIEAKRSWDSISKIATLKEGYLSAIVHEICLLM1KHN

AIWLENLNAGFKRIRGGLSEKSVYQKFEKMLINKLNYFVSKKESDWNKPSGLLNGLQL

SDQFESFEKLGIQSGFIFYVPAAYTSKIDPTTGFANVLNLSKVRNVDAIKSFFSNFNEISYS

KKEALFKFSFDLDSLSKKGFSSFVKFSKSKWNVYTFGERIIKPKNKQGYREDKRINLTFE

MKKLLNEYKVSFDLENNLIPNLTSANLKDTFWKELFFIFKTTLQLRNSVTNGKEDVLISP

535

WO 2016/205711

PCT/US2016/038181

VKNAKGEFFVSGTHNKTLPQDCDANGAYHIALKGLMILERNNLVREEKDTKKIMAISN VDVVFEYVQKRRGVL (SEQ ID NO: 72) [001450] >KKT50231 (modified) hypothetical protein UW40 C0007G0006 [Parcubacteria bacterium GW2011_GWF2_44_17] [001451] MKPVGKTEDFLKINKVFEKDQTIDDSYNQAKFYFDSLHQKFIDAALASDKTS

ELSFQNFADVLEKQNKIILDKKREMGALRKRDKNAVGIDRLQKEINDAIiDIIQKEKEKIY

KD VRTLFDNEAESWKT YYQEREVDGKKIT F SK ADLKQKGADFLT A AGILKVLK YEFPEE

KEKEFQAKNQPSLFVEEKENPGQKRYIFDSFDKFAGYLTKFQQTKKNLYAADGTSTAV

ATRIADNFUFHQNTKVFRDKYKNNHTDLGFDEENIFEIERYKNCLLQREIEHIKNENSYN

KIIGRINKKIKEYRDQKAKDTKLTKSDFPFFKNLDKQILGEVEKEKQLIEKTREKTEEDVL lERFKEFIENNEERFTAAKKLMNAFCNGEFESEYEGIYLKNKAINTlSRRWFVSDRDFELK

LPQQKSKNKSEKNEPKVKKFISIAEIKNAVEELDGDIFKAVFYDKKIIAQGGSKLEQFLVI

WKYEFEYLFRDIERENGEKLLGYDSCLKIAKQLGIFPQISKEAREKATAVIKNYADAGLGI

FQMMKYFSLDDKDRKNTPGQLSTNFYAEYDGYYKDFEFIKYYNEFRNFITKKPFDEDKI

KLNFENGALLKGWDENKEYDFMGVILKKEGRLYLGIMHKNHRKLFQSMGNAKGDNA

NRYQKMIYKQIADASKDVPRLLLTSKKAMEKFKPSQEILRIKKEKTFKRESKNFSLRDLH

ALIEYYRNCIPQYSNWSFYDFQFQDTGKYQNIKEFTDDVQKYGYKISFRDIDDEYINQAE

NEGKMYLFEVVNKDIYNTKNGSKNLHTLYFEHILSAENLNDPVFKLSGMAEIFQRQPSV

NEREKITTQKNQCILDKGDRAYKYRRYTEKKIMFHMSLVLNTGKGEIKQVQFNKIINQRI

S S SDNEM RVNVIGIDRGEKNLLYY S VVK QN GEIIEQ ASLNEINGVN YRDKLIEREKERLK

NRQSWKPWKIKDLKKGYISHVIHKICQLIEKYSAIWLEDLNMRFKQIRGGIERSVYQQ

FEKALIDKLGYLVFKDNRDLRAPGGVLNGYQLSAPFVSFEKMRKQTGILFYTQAEYTSK

TDPITGFRKNVYISNSASLDKIKEAVKKFDAIGWDGKEQSYFFKYNPYNLADEKYKNST

VSKEWAIFASAPRIRRQKGEDGYWKYDRVKVNEEFEKLLKVWNFVNPKATDIKQEIIKK

EKAGDLQGEKELDGRLRNFWHSFIYLFNLVLELRNSFSLQIKIKAGEVIAVDEGVDFIASP

VKPFFTTPNPYIPSNLCWLAA/ENADANGAYNLARKGVMILKKIREHAKKDPEFKKLPNL

FISNAEWDEAARDWGKYAGTTALNLDH (SEQ ID NO: 73) [001452] >WP 004356401 (modified) hypothetical protein [Prevotella disiens] [001453] menyqeftnlfqlnktlrfelkpigktcelleegkifasgsflekdkvradnv S YVKKEIDKKHKIFIEETLS SF SISNDLLKQ YFDCYNELKAFKKDCKSDEEEVKKTALRN kctsiqramreaisqaflkspqkkllaiknlienvfkadenvqhfseftsyfsgfetnren

536

WO 2016/205711

PCT/US2016/038181

FYSDEEKSTSIAYRLVHDNLPIFIKNIYIFEKLKEQFDAKTLSEIFENYKLYVAGSSLDEVF

SLEYFNNTLTQKGIDNYNAVIGKIVKEDKQEIQGLNEHINLYNQKHKDRRLPFFTSLKKQI

LSDREALSWLPDMFKNDSEVIKALKGFYIEDGFENNVLTPLATLLSSLDKYNLNGIFIRN

NEALSSLSQNVYRNFSIDEAIDANAELQTFNNYELIANALRAKIKKETKQGRKSFEKYEE ^VV?SEFNSNSGNMPRKVEDYFSLMRKGDFGSNDLIENI

KTKLSAAEKLLGTKYQETAKDIFKKDENSKLIKELLDATKQFQHFIKPLLGTGEEADRDL

VFYGDFLPLYEKFEELTLLYNKVRNRLTQKPYSKDKIRLCFNKPKLMTGWVDSKTEKSD

NGTQYGGYLFRKKNEIGEYDYFLGISSKAQLFRKNEAVIGDYERLDYYQPKANTIYGSA

YEGENSYKEDKKRLNKVIIAYIEQIKQTNiKKSilESISKYPNiSDDDKVTPSSLLEKIKKVSi

DSYNGILSFKSFQSVNKEVIDNLLKTISPLKNKAEFLDLINKDYQIFTEVQAVIDEICKQKT

FIYFPISNVELEKEMGDKDKPLCLFQ1SN1<DILSFAKTFSANLRK1<RGAENLHTMLF1<ALM

EGNQDNLDLGSGAEFYRAKSLDGNKPTHPANEAIKCRNVANKDKVSLFTYDIYKNRRY

MENKFLFHLSIVQNYKAANDSAQLNSSATEYIRKADDLHIIGIDRGERNLLYYSVIDMKG

AQLMLKYNAIIALEDLGQMFVTRGQKIEKAVYQQFEKSLVDKLSYLVDKKRPYNELGGI LK AYQL AS SITKNN SDKQNGFLF YVPAWNTSKIDP VTGFTDLLRPK AMTIKEAQDFFGA FDNiSYNDKGYFEFETNYDKFKIRMKSAQTRWTICTFGNRIKRKKDKNYWNYEEVELTE

DFVREKPYLK (SEQ ID NO: 74) [001454] >CCB70584 (modified) Protein of unknown function [Flavobacterium branchiophilum FL-15] [001455] MTNKFTNQYSLSKTLRFELIPQGKTLEFIQEKGLLSQDKQRAESYQEMKKTID KFHKYFIDLALSNAKLTHLETYLELYNKSAETKKEQKFKDDLKKVQDNLRKEIVKSFSD GDAKSIFAILDI<KELITVELEKVVFENNEQKDIYFDE1<FI<TFTTYFTGFHQNRKNMYSVEP NSTAIAYRLIHENLPKFLENAKAFEKIKQVESLQVNFRELMGEFGDEGLIFVNELEEMFQI

NYYNDVLSQNGrriYNSHSGFTKNDIKYKGLNEYlNNYNQTKDKKDRLPKLKQLYKQIL

IYLKNDTHLTT1SQQ VFGDFSVFSTALNYWYET1<VNP1<FETEYSKANEKKREILDKAI<A

VFTKQDYFSIAFLQEVLSEYILTLDHTSDIVKKHSSNCIADYFKNHFVAKKENETDKTFD

FIANITAKYQCIQGELENADQYEDELKQDQKLIDNLKFFLDAILELLHFIKPLHLKSESITE

537

WO 2016/205711

PCT/US2016/038181

KDTAFYDVFENYYEALSLLTPLYNMVRNYVTQKPYSTEKIKLNFENAQLLNGWDANKE

GDYLTTILKKDGNYFLAIMDKKHNKAFQKFPEGKENYEKMVYKLLPGVNKAiLPKVFFS

NKNIAYFNPSKELLENYKKETHKKGDTFNLEHCHTLIDFFKDSLNKHEDWKYFDFQFSE

TKSYQDLSGFYREVEHQGYKINFKNIDSEYIDGLVNEGKLFLFQIYSKDFSPFSKGKPNM

HTLYWKALFEEQNLQNVIYKLNGQAEIFFRKASIKPKNIILHKKKIKIAKKHFIDKKTKTS

EIVPVQTIKNLNMYYQGKISEKELTQDDLRYIDNFSIFNEKNKTIDIIKDKRFTVDKFQFH

VPITMNFKATGGSYINQTVLEYLQNNPEVKIIGLDRGERHLVYLTLIDQQGNILKQESLN

TITDSKISTPYHKLLDNKENERDLARKNWGTVENIKELKEGYISQAA'HKIATLMLEENAI

VVMEDLNFGFKRGRF'KVEKQIYQKLEKMLIDKLNYLVLKDKQPQELGGLYNALQLI'NK

FESFQKMGKQSGFLFYVPAWNTSKEDPTTGFVNYFYTKYENVDKAKAFFEKFEAIRFNA

EKKYFEFEVKKYSDFNPKAEGTQQAWTICTYGERIETKRQKDQNNKFVSTPINLTEKIED

FLGKNQIVYGDGNCIKSQIASKDDKAFFETLLYWFKMTLQMRNSETRTDIDYLISPVMN

DNGTFYNSRDYEKLENPTLPKDADANGAYHIAKKGLMLLNKIDQADLTKKVDLSISNR

DWLQFVQKNK (SEQ ID NO: 75) [001456] >WP 005398606 (modified) hypothetical protein [Helcococcus kunzii] [001457] MFEKLSNIVSISKTIRFKLIPVGKTLENIEKLGKLEKDFERSDFYPILKNISDDY

YRQYIKEKLSDLNLDWQKLYDAHELLDSSKKESQKNLEMIQAQYRKkEFNILSGELDKS

GEKNSKDLIKNNKALYGKLFKKQFILEVLPDFVNNNDSYSEEDLEGLNLYSKFTTRLKN

FWETRKNVFTDKDIVTAIPFRAVNENFGFYYDNIKIFNKNIEYLENKIPNLENELKEADIL

DDNRSVKDYFTPNGFNYVITQDGIDVYQAIRGGFTKENGEKVQGINEILNLTQQQLRRK

PETKNVKLGVLTKLRKQILEYSESTSFLIDQIEDDNDLVDRINKFNVSFFESTEVSPSLFEQ

IERLYNALKSIKKEEVYIDARNTQKFSQMLFGQWDVIRR.GYTVKITEGSKEEKKKYKEY

LELDEINKAKKYLNiKEIEELVNLVEGFEEVDVFSVLLEKFKMNNIERSEFEAPIYGSPIKL

EAIKEYLEKHLEEYHKWKLLLIGNDDLDTDETFYPLLNEVISDYYIIPLYNLTRNYLTRK

HSDKDKIKVNFDFPTL.ADGWSESKISDNRSIILRKGGYYYLGILIDNKLLINKKNKSKKIY

EILIYNQ1PEFSKSIPNYPFTKKVKEHFKNNVSDFQLIDGYVSPLIITKEIYDIKKEKKYKKD

FYKDNNTNKNYLYTIYKWIEFCKQFLYKYKGPNKESYKEMYDFSTLKDTSLYVNLNDF

YADVNSCAYRVLFNKIDENTIDNAVEDGKLLLFQIYNKDFSPESKGKKNLHTLYWLSMF

SEENLRTRKLKLNGQAEIFYRK KLEKKPIIHKEGSILLNKIDKEGNTIPEN IYHEC YRYLN

KKIGREDLSDEAIALFNKDVLKYKEARFDIIKDRRYSESQFFFHVPITFNWDIKTNKNVN

QIVQGMIKDGEIKHIIGIDRGERHLLYYSVIDLEGNIkEQGSLNTLEQNRFDNSTVKVDYQ

538

WO 2016/205711

PCT/US2016/038181

NKLRTREEDRDRARKNWTNINKIKELKDGYLSHVVHKLSRLIIKYEAIVIMENLNQGFK

RGRFKVERQVYQKFELALMNKLSALSFKEKYDERKNLEPSGILNPIQACYPVDAYQELQ GQNGIVFYLPAAYTSVIDPVTGFTNLFRLKSINSSKYEEFIKKFKNIYFDNEEEDFKFIFNY KDFAKANLVILNNIKSKDWKISTRGERISYNSKKKEYFYVQPTEFLINKLKELNIDYENID IIPLIDNLEEKAKRKILKALFDTFKYSVQLRNYDFENDYIISPTADDNGNYYNSNEIDIDKT NLPNNGDANGAFNIARKGLLLKDRIWSNESKVDLKlKNEDWiNFIIS (SEQ ID NO: 76) [001458] >WP_021736722_(niodified) CRISPR-associated protein Cpfl, subtype PREFRAN [Acidaminococcus sp. BV3L6] [001459] MTQFEGf TNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPII

DRIYKTYADQCLQLVQLDWENLSAAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRT

DNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYE

NRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSI

EEVFSFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHHASLP

HRFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLT

HIFISHKKLETTSSALCDHWDTLRNALYERRISEI HGKITKSAKEKVQRSLKHEDINLQEII

SAAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDWF

AVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNYATKKPYSVEKFKLNFQMPTLASG

WDVNKEKNNGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPD

AAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEPKKFQTAYAK

KTGDQKGYREALCKW1DFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYYAELNPLLYHI

SFQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKL

NGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTP1PDTLYQELYDYVNHRLSHDL

SDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEH

PETPDGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSV

VGTIKDLKQGYLSQVIHEIVDLMIHYQAVVVLENLNFGFKSKRTGIAEKAVYQQFEKML

IDKLNCLVLKDYPAEKVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTG

FVDPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAW

DIVFEKNETQFDAKGTPFIAGKRTVPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGS

N1LPKLLENDDSHAIDTMVAURSVLQMRNSNAATGEDYINSPVRDLNGVCFDSRFQNPE

WPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRN (SEQ ID

NO: 77)

539

WO 2016/205711

PCT/US2016/038181 [001460] >WP 004339290 (modified) hypothetical protein [Francisella tularensis] [001461] MSIYQEFVNKYSLSKTLRFELffQGKTLENIKARGLILDDEKRAKDYKKAKQII

DKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISKYIND

SEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEnKSFKGWT

LAEELTFDIDYKTSEVNQRVFSLDEVFEIANFNNYLNQSGITKFN TIIGGKFVNGEN TKRK

GINEYINLYSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDVVTTMQSFYEQI

AAFKTATEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLTDLSQQWDDYSVIGTAVLE

YITQQVAPKNLDNP5KKEQDLIAKKTEKAKYLSLETn<LALEEFNKHRDIDKQCRFEEILS

NFAAIPMIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEEDVKAIKDLLDQTNNLLHRL

K1FH1SQSEDKANILDKDEHFYLVFEECYFELANIVPLYNKIRNY1TQKPYSDEKFKLNFE

NSTLASGWDKNKESANTAILFIKDDKYYLGIMDKKHNKIFSDKAIEENKGEGYKKIVYK

QIADASKDIQNLMIIDGKTVCKKGRKDRNGVNRQLLSLKRKHLPENIYRIKETKSYEKNE rNSLVNEGKLYLFQIYSKDFSAYSKGRPNLHTLYWKALFDERNLQDVVYKLNGEAELFY

RKQSffKKITHPAKETIANKNKDNPKKESVFEYDLIKDKRF'TEDKFFFHCPrnNFKSSGAN

KFNDEINLLLKEKANDVHmSIDRGERFttAYYTLVDGKGNHKQDNFNIIGNDRMKTNYH

DKLAAIEKDRDSARKDWKKiNNIKEMKEGYLSQVVHEIAKLVIEYNAIVVFEDLNFGFK

GHYYVPAGFTSKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKN

FGDKAAKGKWTIASFGSRLINFRNSDKNHNWDTREVYPTKELEKLLKDYSIEYGHGECI

KAAICGESDKKFFAKLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPKNM

NO; 78) [001462] >WP_022501477_(modified) hypothetical protein [Eubacterium sp. CAG;76] [001463] MNKAADNYTGGNYDEFIALSKVQKTLRNELKPTPFTAEHIKQRGIISEDEYRA

QQSLELKKIADEYYRNYITHKLNDINNLDFYNLFDAIEEKYKKNDKDNRDKEDLVEKSK

RGEIAKMLSADDNFKSMFEAKLITKLLPDYVERNYTGEDKEKALETLALFKGFTTYFKG

YFKTRKNMFSGEGGASSICHRIVNVNASIFYDNLKTFMRIQEKAGDEIALIEEELTEKLDG

MGISEKAFEIPPMYQNDEEVYASFNEFISRLEEVKLTDRLINILQNINIYNTAKIYINARYY

540

WO 2016/205711

PCT/US2016/038181

TNVSSYVYGGWGVIDSAIERYLYNTIAGKGQSKVKKIIiNAKKDNKFAISWELDSIVAEY

EPDYFNAPYIDDDDNAVKAFGGQGVLGYFNKMSELLADVSLYTIDYNSDDSLENKESA

LRIKKQLDDIMSLYHWLQTFIIDEWEKDNAFYAELEDICCELENVVTLYDRIRNYVTKK

PYSTQKFKLNFASPTLAAGWSRSKEFDNNAIILLRNNKYYIAIFNVNNKPDKQIIKGSEEQ

RLSTDYKKMVYNLLPGPNKMLPKVFIKSDTGKRDYNPSSYILEGYEKNRHIKSSGNFDIN

YCHDLIDYYKACINKHPEWKNYGFKFKETNQYNDIGQFYKDVEKQGYSISWAYISEEDI

NKLDEEGKIYLFEIYNKDLSAHSTGRDNLHTMYLKNIFSEDNLKNICIELNGEAELFYRK

SSMKSNITHKKDTILVNKTYINETGVRVSLSDEDYMKVYNYYNNNYVIDTENDKNLIDII

EKIGHRK SKID IVKDKRYTEDKYFL YEP rnNYGIEDENVNSKIIEYIAKQDNAlNVIGIDRG

ERNLIYISVIDNKGNIIEQKSFNLVNNYDYKNKLKNMEKTRDNARKNWQEIGKIKDVKS

GYLSGVISKIARMVIDYNAIIVMEDLNKGFKRGRFKVERQVYQKFENMLISKLNYLVFK

ERKADENGGILRGYQLTYIPKSIKNVGKQCGCIFYVPAAYTSKIDPATGFINIFDFKKYSG

SGINAKVKDKKEFLMSMNSIRYINECSEEYEKIGHRELFAFSFDYNNFKTYNVSSPVNEW

TAYTYGERIKKLYKDGRWLRSEVLNLTENLIKLMEQYNIEYKDGHDIREDISHMDETRN

ADFICSLFEELKYTVQLRNSKSEAEDENYDRLVSPILNSSNGFYDSSDYMENENNTTHTM

PKDADANGAYCIALKGLYEINKIKQNWSDDKKFKENELYINVTEWLDYIQNRRFE (SEQ

ID NO: 79) [001464] >WP_014550095_(modified) hypothetical protein [Francisella tularensis] [001465] MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKAKQII

DKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKD

SEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWT

TYFKGFHENRKNVYSSND1PTSI1YRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKD

LAEELTFDIDYKTSEVNQRVFSLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRK

GINEYINLYSQQINDKTLKKYKAiSkYFKQILSDTESKSFVIDKLEDDSDVVTTMQSFYEQI

AAFKTVEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLTDLSQQVFDDYSVIGTAVLE

YITQQVAPKNLDNPSKKEQDLIAKKTEKAKYLSLETIKLALEEFNKHRDIDKQCREEEIL

ANFAAIPMIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEDDVKAIKDLEDQTONLLH

RLKIFHISQSEDKANILDKDEHFYLVFEECYFELANIVPLYNKIRNYITQKPYSDEKFKLN

FENSTLANGWDKNKEPDNTAIEFIKDDKYYLGVMNKKNNKIFDDKAIKENKGEGYKKI

VYKLLPGANKMLPKVFFSAKSIKFYNPSEDILRIRNHSTHTKNGNPQKGYEKFEFNIEDC

RKFIDFYKESISKHPEWKDFGFRFSDTQRYNSIDEFYREVENQGYKLTFENISESYIDSVV

541

WO 2016/205711

PCT/US2016/038181

NQGKLYLFQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDVVYKLNGEAELFYRKKS

IPKKITHPAKEAIANKNKDNPKKESFFEYDLIKDKRFTEDKFFFHCPrnNEKSSGANKFND

EINLLLKEKANDVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMKTNYHDKLA

AIEKDRDSARKDWKKINNIKEMKEGYLSQVVHEIAKLVIEHNAIVVFEDLNFGFKRGRF

KVEKQVYQKLEKMLIEKLNYLVFKDNEFDKTGGVLRAYQLTAPFETFKKMGKQTGUY

YVPAGFTSKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGD

KAAKGKWTIASFGSRLINFRNSDKNHNWDTREVYPTKELEKLLKDYSIEYGHGECIKAA

ICGESDKKEFAKLTSILNTILQMRNSKTGTELDYIJSPVADWGNFFDSRQAPKNMPQDA

DANGAYHIGLKGLMLLDRIKNNQEGKKLNI,VIKNEEYFEFVQNRNN (SEQ ID NO: 80) [001466] >WP 003034647 (modified) hypothetical protein [Francisella tularensis] [001467] MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKAKQIIDKYH

QFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKDSEKFKNLFNQ

NLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWTIYFKGFHENRKNVYS

SDDIPTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKDLAEELTFDIDYKTSEVNQRVF

SLDEVFEIANFNNYLNQSGITKFNTTIGGKFVNGENTKRKGINEYINLYSQQINDKTLKKYKMSVL

FKQILSDTESKSFVIDKLEDDSDWITMQSFYEQIAAFKTVEEKSIKETLSLLFDDLKAQKLDLSKI

YFKNDKSLTDLSQQVFDDYSVIGTAVLEYITQQVAPKNLDNPSKKEQDLIAKKTEKAKYLSLETI

KLALEEFNKHRDIDKQCRFEEiLANFAAIPMIFDEiAQNKDNLAQISLKYQNQGKKDLLQASAEE

DVKAIKDLLDQTNNLLHRLKIFHISQSEDKANILDKDEHFYLVFEECYFELANIVPLYNKIRNYIT

QKPYSDEKFKLNFENSTLANGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENK

GEGYKKIVYKLLPGANKMLPKVFFSAKSIKFYNPSEDILRIRNHSIHTKNGNPQKGYEKFEFNIED

CRKFIDFYKESISKHPEWKDFGFRFSDTQRYNSIDEFYREVENQGYKLTFENISESYIDSVVNQGK

LYLFQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDWYKLNGEAELFYRKQSIPKKITHPAK

EAIANKNKDNPKKESVFEYDLIKDKRFTEDKFFFHCPITINFKSSGANKFNDEINLLLKEKANDVH

ILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMKTNYHDKLAAIEKDRDSARKDWKKINNI

KEMKEGYLSQVVHEIAKLVIEHNAIVVFEDLNFGFKRGRFKVEKQVYQKLEKMLIEKLNYLVFK

DNEFDKTGGVLRAYQLTAPFETFKKMGKQTGITYYVPAGFTSKICPVTGFVNQLYPKYESVSKSQ

EFFSKFDKICYNLDKGYFEFSFDYKNFGDKAAKGKWTIASFGSRLINFRNSDKNEINWDTREVYP

TKELEKLLKDYSIEYGHGECIKAAICGESDKKFFAKLTSVLNIILQMRNSKTGTELDYLISPVADV

NGNFFDSRQAPKNMPQDADANGAYHIGLKGLMLLDRIKNNQEGKKLNLVIKNEEYFEFVQNRN

N (SEQ ID NO: 81) [001468] >FnCpfl Francisella tularensis subsp. novicida U112, complete genome

542

WO 2016/205711

PCT/US2016/038181 [001469] MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKAKQII DKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKD

SEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWT

TYFKGFHENRKNVYSSNDIPTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKD

LAEELTFDIDYKTSEVNQRVFSLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRK

GINEYINLYSQQiNDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDVVTTMQSFYEQI

AAFKTVEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLTDLSQQVFDDYSVIGTAVLE

YITQQIAPKNLDNPSKKEQELIAKKTEKAKYLSLETIKLALEEFNKHRDIDKQCRFEEILA

NFAAIPMIFDEIAQNKDNLAQISKYQNQGKKDLLQASAEDDVKAIKDLLDQTNNLLHK

LKIFHISQSEDKANILDKDEHFYLATEECYFELANIVPLYNKIRNYITQKPYSDEKFKLNFE

NSTLANGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENKGEGYKKIVY kllpgankmlpkvffsaksikfynpsedilrirnhsthtkngspqkgyekfefniedcrkf

KLYLFQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDWYKLNGEAELFYRKQSIPK

KITHPAKEAIANKNKDNPKKESVFEYDLIKDKRFTEDKFFFHCPITINFKSSGANKFNDEI

NLLLKEKANDVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNUGNDRMKTNYHDKLAAI

EKDRDSARKDWKKINNIKEMKEGYLSQA/VHEIAKLVIEYNAIVWEDLNFGFKRGRFKV

EKQVYQKLEKMLIEKLNYLVFKDNEFDKTGGVLRAYQLTAPFETFKKMGKQTGIIYYV

PAGFTSKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGDKA

AKGKWUASFGSRLJNFRNSDKNHNWDTREVYPTKELEKLLKDYSffiYGHGECKAAIC

GESDKKFFAKLTSVLNTILQMRNSKTGIELDYLISPVADVNGNFFDSRQAPKNMPQDAD

ANGAYHIGLKGLMLLGR1KNNQEGKKLNLVIKNEEYFEFVQNRNN (SEQ ID NO: 82) [001470] >KKQ38174_(modified) hypothetical protein US54_C0016G0015 [Microgenomates (Roizmanbacteria) bacterium GW2011..GWA2 37 7] [001471] MKSFOSFTNLYSLSKTLKFEMRPVGNTQKMLDNAGVFEKDKLIQKKYGKI'K

PYFDRLHREFIEEALTGVELIGLDENFRTLVDWQKDKKNNVAMKAYENSLQRLRTEIGK ifnlkaedwvknkypilglknkntdilfeeavfgilkarygeekdtfieveeidktgkski

NQISIFDSWKGFTGYFKKFFETRKNFYKNDGTSTAIATRIIDQNLKRFIDNLSIVESVRQK

VDLAETEKSFSISLSQFFSIDFYNKCLLQDGIDYYNKIIGGETLKNGEKLIGLNELINQYRQ

NNKDQKIPFFKLLDKQILSEKILFLDEIKNDTELIEALSQFAKTAEEKTKIVKKLFADFVEN

NSKYDLAQIYISQEAFNTISNKWTSETETFAKYLFEAMKSGKLAKYEKKDNSYKFPDFIA

543

WO 2016/205711

PCT/US2016/038181

LSQMKSALLSISLEGHFWKEKYYKISKFQEKTNWEQFLAIFLYEFNSLFSDKINTKDGET

KQVGYYLFAKDLHNLILSEQIDffKDSKVTIKDFADSVLTIYQMAKYFAVEKKlGkWLAE

YELDSFYTQPDTGYLQFYDNAYEDIVQVYNKLRNYLTKKPYSEEKWKLNFENSTLANG

WDKNKESDNSAVILQKGGKYYLGLITKGHNKIFDDRFQEKFIVGIEGGKYEKIVYKFFPD

QAKMFPKVCFSAKGLEFFRPSEEILRIYNNAEFKKGETYSIDSMQKLIDFYKDCLTKYEG

WACYTFRHLKPTEEYQNNIGEFFRDVAEDGYRIDFQGISDQYIHEKNEKGELHLFEIHNK

DWNLDKARDGKSKTTQKNLHTLYFESLFSNDNVVQNFPIKLNGQAEIFYRPK TEKDKLE

SKKDKKGNKVIDHKRYSENKIFFHVPLTLNRTKNDSYRFNAQINNFLANNKDINIIGVDR

GEKHLVYYSVITQASDILESGSLNELNGVNYAEKLGKKAENREQARRDWQDVQGIKDL

KKGYISQVVRKLADLAIKHNAIIILEDLNMRFKQVRGGIEKSIYQQLEKALIDKLSFLWK

GEKNPEQAGHLLKAYQLSAPFETFQKMGKQTGnFYTQASYTSKSDPVTGWRPHLYLKY

F S AKKAKDDIAKFTKIEFVNDRFELTYDIKDFQQAKEYPNKT VWKVC SNVERFRWDKN

LNQNKGGYTHYTNrrENIQELFTKYGIDITKDLLTQISTIDEKQNTSFFRDFIFYFNLICQIR

NTDDSEIAKKNGKDDFILSPVEPFFDSRKDNGNKLPENGDDNGAYNIARKGIVILNKISQ

YSEKNENCEKMKWGDLYVSNIDWDNFVTQANARH (SEQ ID NO: 83) [001472] >WP_022097749_(modified) hypothetical protein [Eubacterium eligens CAG:72] [001473 ] MNGNRSIVYREFVGVTPVAKTLRNELRPVGHTQEHIIQNGLIQEDELRQEKST

ELKNIMDDYYREYIDKSLSGLTDLDFTLLFELMNSVQSSLSKDNKKALEKEHNKMREQI

CTHLQSDSDYKNMFNAKLFKEILPDFIKNYNQYDVKDKAGKLETLALFNGFSTYFTDFF

EKRKNVFTKEAVSTSIAYRIVHENSLIFLANMTSYKKISEKALDEIEVIEKNNQDKMGDW

ELNQIFNPDFYNMVLIQSGIDFYNEICGWNAHMNLYCQQTKNNYNLFKMRKLHKQILA ytstsfevpkmfeddmsvynawafidetekgnhgkekdivnkydeldekriyiskdfy

ETLSCFMSGNWNLITGCVENFYDENIHAKGKSKEEKVKKAVKEDKYKSINDVNDLVEK yidekernefknsnakqyireisniitdtetahleydehislieseekadeikkrldmymn

MYHWVKAFIVDEVLDRDEMFYSDIDDIYNILENIVPLYNRVRNYVTQKPYTSKKIKLNF qsptlangwsqskefdnnaiilirdnkyylaifnaknkpdkkiiqgnsdkkndndykkm

VYNLLPGANKMLPKVFLSKKGIETFKPSDYnSGYNAHKHIKTSENFDISFCRDLIDYFKN

SIEKHAEWRKYEFKFSATDSYNDISEFYREVEMQGYRIDWTYISEADINKLDEEGKIYLF qiynkdfaenstgkenlhtmyfknifseenlkniviklngqaelfyrkasvknpvkhkk

DSVLVNKTYKNQLDNGDWRJPIPDDIYNEIYKMYNGYIKESDLSEAAKEYLDKVEVRT

AQKDIVKDYRYTWKYFniTPITINYKVTARNNA/NDMAVKYIAQNDDIHVIGIDRGERN

544

WO 2016/205711

PCT/US2016/038181

LIYISVEDSHGNIVKQKSYNILNNYDYKKKLVEKEKTREYARKNWKSIGNIKELKEGYIS GVVHEIAMLMVEYNAIIAMEDLNYGFKRGRFKVERQVYQKFESMLINKLNYFASKGKS VDEPGGLLKGYQLTYVPDNIKNLGKQCGVIFYVPAAFTSKIDPSTGFISAFNFKSISTNAS RKQFFMQFDEIRYCAEKDMFSFGFDYNNFDTYNITMGKTQWTVYTNGERLQSEFNNAR RTGKTKSINLTETIKLLLEDNEINYADGHDVRIDMEKMYEDKNSEFFAQLLSLYKLTVQ MRNSYTEAEEQEKGISYDKIISPVINDEGEFFDSDNYKESDDKECKMPKDADANGAYCI ALRGLYEVLKIKSEWTEDGFDRNCLKLPHAEVVLDFIQNKRYE (SEQ ID NO: 84) [001474] >WP 012739647 (modified) hypothetical protein [[Eubacterium] eligens] [001475] MNGNRSIVYREFVGVIPVAKTLKNELRPVGHTQEHIIQNGLIQEDELRQEKST

ELKN1MDDYYREYIDKSLSGVTDLDFTLLFELMNLVQSSPSKDNKKALEKEQSKMREQI

CTHLQSDSNYKNIFNAKLLKEILPDFIKNYNQYDVKDKAGKLETLALFNGFSTYFTDFFE

KRKNVFTKEAVSTSIAYRIVHENSLIFLANMTSYKKISEKALDEIEVIEKNNQDKMGDWE

LN QIFNPDFYNM VLIQ SGIDF YNEICGVVN AHMNLYCQQTKNN YNLFKMRKLHKQ ILA

YTSTSFEVPKMFEDDMSVYNAVNAFIDETEKGNIIGKLKDIVNKYDELDEKRIYISKDFY

ETLSCFMSGNWNLITGCATNFYDENIHAKGKSKEEKVKKAVKEDKYKSINDVNDIATiK

YIDEKERNEFKNSNAKQYIREISNIITDTETAHLEYDDHISLIESEEKADEMKKRLDMYM

NMYHWAKAFIVDEVLDRDEMFYSDIDDIYNILENIVPLYNRVRNYVTQKPYNSKKIKLN

FQSPTLANGWSQSKEFDNNAIILIRDNKYYLArFNAKNKPDKKIIQGNSDKKNDNDYKK

MVYNLLPGANKMLPKVFLSKKGIETFKPSDYIISGYNAHKHIKTSENFDISFCRDLIDYFK

NSIEKHAEWRKYEFKFSATDSYSDISEFYREVEMQGYRIDWTYISEADINKLDEEGKIYL

FQIYNKDFAENSTGKENLHTMYFKNIFSEENLKDniKLNGQAELFYRRASVKNPVKHKK

DSVLVNKIYKNQLDNGDVVRIPIPDDIYNEIYKMYNGYIKESDLSEAAKEYLDKVEVRT

AQKDIVKDYRYTVDKYFIHTPrnNYKVTARNNVNDMVVKYIAQNDDIHVIGIDRGERN

LIYISVEDSHGNIVKQKSYNILNNYDYKKKLVEKEKTREYARKNWKSIGNIKELKEGYIS

GVVHEIAMLiVEYNAIIAMEDLNYGFKRGRFKVERQVYQKFESMLINKLNYFASKEKSV

DEPGGLI KGYQITYYPDNiKM GKQCGYiiYYPAAlHSKIDPSTGFISAFNFKSISTNASR

KQFFMQFDEIRYCAEKDMFSFGFDYNNFDTYNITMGKTQWTVYTNGERLQSEFNNARR

TGKTKSINLTETIKLLLEDNEINYADGHDIRIDMEKMDEDKKSEFFAQLLSLYKLTVQMR

NSYTEAEEQENGISYDKIISPVINDEGEFFDSDNYKESDDKECKMPKDADANGAYCIALK

GLYEVLKIKSEWTEDGFDRNCLKLPHAEWLDFIQNKRYE (SEQ ID NO: 85) [001476] >WP 045971446 (modified) hypothetical protein [Flavobacterium sp. 316]

545

WO 2016/205711

PCT/US2016/038181 [001477] MKNFSNLYQVSKTVRFELKPIGNTLENIKNKSLLKNDSIRAESYQKMKKTIDE

FHKYFIDLALNNKKLSYLNEYIALYTQSAEAKKEDKFKADFKKVQDNLRKEIVSSFTEG

EAKAIFSVLDKKELITIELEKWKNENNLAVYLDESFKSFTTYFTGFHQNRKNMYSAEAN

STAIAYRLIHENLPKFIENSKAFEKSSQ1AELQPKIEKLYKEFEAYLNVNS1SELFEIDYFNE

VLTQKGITVYNNnGGRTATEGKQKIQGLNEIINLYNQTKPKNERLPKLKQLYKQILSDRI

SLSFLPDAFTEGKQVLKAVFEFYK1NLLSYKQDGVEESQNLLELIQQVVKNLGNQDVNK1

YLKNDTSLTTIAQQLFGDF S VF SAALQ YR YET V VNPK YTAEYQKANE AKQEKLDKEKIK

FVKQDYFSIAFLQEVVADY\/KTLDEN1.DWKQKYTPSCIADYFTTHFIAKKENEADKTFN

FIANIKAKYQCIQGiLEQADDYEDELKQDQKLIDNIKFFLDAILEVVHFIKPLHLKSESITE

KDNAFYDATENYYEALNVVTPLYNMA/RNYVTQKPYSTEKIKLNFENAQLLNGWDANK

EKDYLTTILKRDGNYFLAIMDKKHNKTFQQFTEDDENYEKIVYKLLPGVNKMILPKVFFS

NKNIAFFNPSKEILDNYKNNTHKKGATFNLKDCHALIDFFKDSLNKHEDWKYFDFQFSE

TKTYQDLSGFYKEVEHQGYKINFKKVSVSQ1DTLIEEGKMYLFQ1YNKDFSPYAKGKPN

MHTLYWKALFETQNLENVIYKLNGQAEIFFRKASIKKKNIITHKAHQPIAAKNPLTPTAK

NTFAYDLIKDKRYTXT)KFQFHVPITMNFKATGNSYINQDVI .AYLKDNPEVNIIGLDRGE

RHLVYLTLIDQKGTILLQESLNVIQDEKTHTPYHTLLDNKELARDKARKNWGSIESIKELK

EGYISQVVHKITKMMIEHNAIVVMEDLNFGFKRGRFKVEKQIYQKLEKMIADKLNYLVL

KDKQPHELGGLYNALQLTNKFESFQKMGKQSGFLFYVPAWNTSKIDPTTGFVNYFY TK

YENVEKAKTFFSKFDSILYNKTKGYFEFWKNYSDFNPKAADTRQEWTICTHGERIETK

RQKEQNNNFVSTTIQLTEQFVNFFEKVGLDLSKELKTQLIAQNEKSFFEELFHLLKLTLQ

MRNSESHTEIDYLISPVANEKGIFYDSRKATASLPIDADANGAYHIAKKGLWIMEQINKT

NSEDDLKKVKLAISNREWLQYVQQVQKK (SEQ ID NO: 86) [001478] >WP_044110123_(modified) hypothetical protein [Prevotella brevis] [001479] MKQFTNLYQLSKTLRFELKPIGKTLEHINANGFIDNDAHRAESYKKVKKLIDD

YHKDYIENVLNNFKLNGEYLQAYFDLYSQDTKDKQFKDIQDKLRKSIASALKGDDRYK

TIDKKELIRQDMKTFLKKDTDKALLDEFYEFTTYFTGYITENRKNMYSDEAKSTAIAYRL

IHDNLPKFIDNIAVFKKIANTSVADNFSTIYKNFEEYLNVNSIDEIFSLDYYNIVLTQTQIEV

YNSDGGRTLEDDTKIQGINEFVNLYNQQLANKKDRLPKLKPLFKQILSDRVQLSWLQEE

FNTGADVLNAVKEYCTSYFDNVEESVKVLLTGISDYDLSKIYITNDLALTDVSQRMFGE

WSIIPNAIEQRLRSDNPKKTNEKEEKYSDRISKLKKLPKSYSLGYINECISELNGIDIADYY

ATI./JAINTESKQEPSIPTSiQVHYNALKPiLDTDYPREKNLSQDKLTVMQLKDLLDDFKA

546

WO 2016/205711

PCT/US2016/038181

LQHFIKPLLGNGDEAEKDEKFYGELMQLWEVIDSITPLYNKVRNYCTRKPFSTEKIKWF

ENAQLLDGWDENKESTNASIILRKNGMYYLGIMKKEYRNILTKPMPSDGDCYDKVVYK

FFKDITTMVPKCTTQMKSVKEHFSNSNDDYIEFEKDKFIAPWITKEIFDLNNVLYNGVK

KFQIGYLNNTGDSFGYNHAVE1WKSFCLKFLKAYKSTS1YDFSSIEKNIGCYNDLNSFYG

AVNLLLYNLTYRKVSVDYfflQLVDEDKMYLFMIYNKDFSTYSKGTPNMHTLYWKMLF

DESNLNDVVYKENGQAEVFYRKKSITYQHPTHPANKPIDNKNVNNPKKQSNFEYDLIK

DKRYTVDKFMFHVPrr'LNFKGMGNGDINMQVREYIKTTDDLHFIGIDRGERHLLYICVIN

GKGEIVEQYSLNEIVNNYKGTEYKTDYHTLLSERDKKRKEERSSWQTIEGIKELKSGYLS

QVIHKITQLMIKYNAIVLLEDLNMGFKRGRQKVESSVYQQFEKALIDKLNYLVDKNKDA

NEIGGLLHAYQLTNDPKLPNKNSKQSGFLFYVPAWNTSKIDPVTGFVNLLDTRYENVAK

AQAFFKKFDSIRYNKEYDRFEFKFDYSNFTAKAEDTRTQWTLCTYGTR1ETFRNAEKNS

NWDSREIDLTTEWKTLFTQHNIPLNANLKEAILLQANKNFYTDILHLMKLTLQMRNSVT

GTDIDYMVSPVANECGEFFDSRKVKEGLPVNADANGAYNIARKGLWLAQQIKNANDLS

DVKLAITNKEWLQFAQKKQYLKD (SEQ ID NO: 87) [001480] >WP 036388671 (modified) hypothetical protein [Moraxella caprae] [001481] MLFQDFTHLYPLSKTMRFELKPIGKTLEHIHAKNFLSQDETALADMIYQKVKAI

LDDYHRDFIADMMGEVKLTKLAEFYDVYLKFRKNPKDDGLQKQLKDLQAVLRKEIVK

PIGNGGKYKAGYDRLFGAKLFKDGKELGDLAKFVIAQEGESSPKLAHLAHFEKFSTYFT

GFHDNRKNMYSDEDKHTAITYRLIHENLPRFIDNLQILATIKQKHSALYDQIINELTASGL

DVSLASHLDGYHKLLTQEG1TAYNTLLGGISGEAGSRKIQGINELINSHHNQHCHKSER1A

KLRPLHKQILSDGMGVSFLPSKFADDSEMCQAVNEFYRHYADVFAKVQSLFDGFDDHQ

KDGIYVEHKNLNELSKQAFGDFALLGRVLDGYYVDVVNPEFNERFAKAKTDNAKAKL

TKEKDKF1KGVHSLASLEQAIEHYTARHDDESVQAGKLGQYFKHGLAGVDNPIQKIHNN

HSTIKGFLERERPAGERALPKIKSGKNPEMTQLRQLKELLDNALNVAHFAKLLTTKTTLD

NQDGNFYGEFGALYDELAKIPTLYNKVRDYLSQKPFSTEKYKLNFGNPTLLNGWDLNK

EKDNFGIILQKDGCYYLALLDKAHKKWDNAPNTGKNVYQKMIYKLLPGPNKMLPKAT

FAKSNLDYYNPSAELLDKYAQGTHKKGNNFNLKDCHALIDFFKAGINKHPEWQHFGFK

FSPTSSYQDLSDFYREVEPQGYQVKFVDINADYINELVEQGQLYLFQIYNKDFSPKAHGK

PNLHTLYFKALFSKDNLANPIYKLNGEAQIFYRKASLDMNETTIHRAGEVLENKNPDNP

KKRQFVYDIIKDKRYTQDKFMLHVPITMNFGVQGMTIKEFNKKVNQSIQQYDEVNVIGI

DRGERHLLYLTVINSKGEILEQRSLNDITTASANGTQMTTPYHKmDKREIERENAR.VGW

547

WO 2016/205711

PCT/US2016/038181

GEIETIKELKSGYLSHVVHQISQLMLKYNAIVVLEDLNFGFKRGRFKVEKQIYQNFENAL rKKLNHLVLKDEADDEIGSYKNALQL TNNF TDLKSIGKQTGFLFYVPAWNTSKIDPETGF

VDLLKPRYENIAQSQAFFGKFDKICYNADKDYFEFHIDYAKFTDKAKNSRQIWKICSHG DKRYVYDKTANQNKGATKGINVNDELKSLFARHHINDKQPNLVMDICQNNDKEFHKSL IYLLKTLLALRYSNASSDEDFILSPVANDEGMFFNSALADDTQPQNADANGAYHIALKG LWVLEQIKNSDDLNKVKLAIDNQTWLNFAQNR (SEQ ID NO: 88) [001482] >WP_020988726_(modified) CRISPR-associated protein Cpfl, subtype PREFRAN [Leptospira inadai] [001483] MEDYSGFVNIYSIQKTLRFELKPVGKTLEHIEKKGFLKKDKIRAEDYKAVKKII

DKYHRAYIEEVFDSVLHQKKKKDKTRFSTQFIKEIKEFSELYYKTEKNIPDKERLEALSE

KLRKMLVGAFKGEFSEEVAEKYKNLFSKELIRNEIEKFCETDEERKQVSNFKSFTTYFTG

FHSNRQNIYSDEKKSTAIGYRIIHQNLPKFLDNLKIIESIQRRFKDFPWSDLKKNLKKIDKN

IKLTEYFSIDGFVNVLNQKGIDAYNTILGGKSEESGEKIQGLNEYINLYRQKNNIDRKNLP

NVKILFKQILGDRETKSFIPEAFPDDQSVLNSITEFAKYLKLDKKKKSIIAELKKFLSSFNR

YELDGIYLANDNSLASISTFLFDDWSFIKKSVSFKYDESVGDPKKKIKSPLKYEKEKEKW

LKQKYYTISFLNDAIESYSKSQDEKRVKIRLEAYFAEFKSKDDAKKQFDLLERIEEAYAIV

EPLLGAEYPRDRNLKADKKEVGKIKDFLDSIKSLQFFLKPLLSAEIFDEKDLGFYNQLEG

YYEEIDSIGHLYNKVRNYLTGKIYSKEKFKLNFENSTLLKGWDENREVANLCVff'REDQ

KYYLGVMDKENNTILSDIPKVKPNELFYEKMVYKLIPTPHMQLPRIIFSSDNLSIYNPSKSI

LKIREAKSFKEGKNFKLKDCHKFEDFYKESISKNEDWSRFDFKFSKTSSYENISEFYREVE

RQGYNLDFKKVSKF YIDSLVEDGKLYLFQIYNKDF SIF SKGKPNLHTIYFRSLF SKENLKD

VCLKLNGEAEMFFRKKS1NY DEKKKR EGHI1PELFEKLKY PILKDKRYSEDKFQFHLPISL

NFKSKERLNFNLKVNEFLKRNKDINIIGIDRGERNLLYLVMINQKGEILKQTLLDSMQSG

KGRPEINYKEKLQEKEIERDKARKSWGTVENIKELKEGYLSIVIHQISKLMVENNAIVVL

EDLNIGFKRGRQKVERQVYQKFEKMLIDKLNFLVFKENKPTEPGGVLKAYQLTDEFQSF

EKLSKQTGFLFYVPSWNTSKIDPRTGFIDFLHPAYENIEKAKQWINKFDSIRFNSKAIDWF

EFTADTRKFSENLMLGKNRVWVICTTNVERYFTSKTANSSIQYNSIQITEKLKELFVDIPF

SNGQDLKPEILRKNDAVFFKSLLFYIKTTLSLRQNNGKKGEEEKDFILSPWDSKGRFFNS

LEASDDEPKDADANGAYHIALKGLMNLLVLNETKEENLSRPKWKIKNKDWLEFVWER

NR (SEQ ID NO: 89) [001484] >WP 023936172 (modified) exonuclease SbcC [Porphyromonas crevioricanis]

548

WO 2016/205711

PCT/US2016/038181 [001485] MPWIDLKDFTNLYPVSKTLRFELKPVGKTLENIEKAGILKEDEHRAESYRRVK

KUDTYHKVFIDSSLENMAKMGIENEIKAMLQSFCELYKKDHRTEGEDKALDKIRAVLRG

LIVGAFTGVCGRRENTVQNEKYESLFKEKLIKEILPDFVLSTEAESLPFSVEEATRSLKEF

DSFTSYFAGFYENRKNIYSTKPQSTAIAYRLIHENLPKFIDNILVFQKIKEPIAKELEHIRAD

FSAGGYIKKDERLEDIFSLNYYIHVLSQAGIEKYNALIGKIVTEGDGEMKGLNEHINLYN

QQRGREDRLPLFRPLYKQILSDREQLSYLPESFEKDEELLRALKEFYDHIAEDILGRTQQL

MTSiSEYDLSRIYVRNDSQLTDISKKMLGDWNAiYMARERAYDFlEQAPKRiTAKYERDR

IKALKGEESISLANLNSCIAFLDNVRDCRWTYLSTLGQKEGPHGLSNLVENWASYITEA

EQLLSFPYPEENNLIQDKDNVVL1KNLLDNISDLQRFLKPLWGMGDEPDKDERFYGEYN

YIRGALDQVIPLYNKVRNYIffiRKPYSTRKVKLNFGNSQLLSGWDRNKEKDNSCVILRK gqnfylaimnnrhkrsfenkvlpeykegepyf:ekm:dykf:lpdpnkmlp:kvflskkgiei

YEPSPKLLEQYGHGTHKKGDTFSMDDLHELIDFFKHSIEAHEDWKQFGFKFSDTATYEN

VSSFYREVEDQGYKLSFRKVSESYVYSLIDQGKLYLFQ1YNKDFSPCSKGTPNLHTLYW

RMLFDERNLADVIYKLDGKAEIFFREKSLKNDHPTHPAGKPIKKKSRQKKGEESLFEYD

LVKDRRYTMDKFQFHVPITMNFKCSAGSKWDMA/NAFnREAKDMHVIGIDRGERNLLY

ICVIDSRGTILDQISLNTIND1DYHDLLESRDKDRQQERRNWQTIEGIKELKQGYLSQAVH

RIAELMVAYKAVVALEDLNMGFKRGRQKVESSA/YQQFEKQLIDKLNYLWKKKRPEDI

GGLLRAYQFTAPFKSFKEMGKQNGFLFYIPAWNTSNIDPTTGFVNLFHAQYENVDKAKS

FFQKFDSISYNPKKDWFEFAFDYKNFTKKAEGSRSMWILCTHGSRIKNFRNSQKNGQW

DSEEFALTEAFKSLFVRYEIDYTADLK TAIVDEKQKDFFVDLLKLFKLTVQMRNSWKEK

DLDYLISPVAGADGRFFDTREGNKSLPKDADANGAYNIALKGLWALRQIRQTSEGGKL

KLAISNKEWLQFVQERSYEKD (SEQ ID NO: 90) [001486] >WP_009217842_(modified) hypothetical protein [Bacteroidetes oral taxon 274] [001487] MRKFNEFVGLYPISKTLRFELKPIGKTLEHIQRNKLLEHDAVRADDYVKVKKI

IDKYFIKCLIDEALSGFTFDTEADGRSNNSLSEYYLYYNLKKKNEQEQKTFKTiQNNLRK

QIVNKLTQSEKYKRJDKKELITTDLPDFLTNESEKELVEKFKNFTTYFTEFHKNRKNMYS

KEEKSTAIAFRLINENLPKFVDN1AAFEKVVSSPLAEK1NALYEDFKEYLNVEEISRVFRL

DYYDELLTQKQIDLYNAIVGGRTEEDNKIQIKGLNQYINEYNQQQTDRSNRLPKLKPLY

KQILSDRESVSWLPPKFDSDKNLLIKIKECYDALSEKEKVFDKLESILKSLSTYDLSKIYIS

NDSQLSYISQKMFGRWDnSKAIREDCAKRNPQKSRESLEKFAERIDKKLKTIDSISIGDV

DECLAQLGETYA/KRVEDYFVAMGESEIDDEQTDTTSFKKNIEGAYESWELLNNADNIT

549

WO 2016/205711

PCT/US2016/038181

DNNLMQDKGNVEKIKTLLDAIKDLQRFIKPLLGKGDEADKDGVFYGEFTSLWTKLDQV

TPLYNMVRNYLTSKPYSTKKIKLNFENSTLMDGWDLNKEPDNTTVIFCKDGLYYLGIM

GKKYNRVFVDREDLPHDGECYDKMEYKLLPGANKMLPKVFFSETGIQRFLPSEELLGK

YERGTHKKGAGFDLGDCRALIDFFKKSIERHDDWKKFDFKFSDTSTYQDISEFYREVEQ

QGYKMSFRKVSVDYIKSLVEEGKLYLFQIYNKDFSAHSKGTPNMHTLYWKMLFDEENL

KDVVYKLNGEAEVFFRKSSITVQSPTHPANSPKNKNKDNQKKESKFEYDLIKDRRYTV

DKFLFHVPITMNFKSVGGSNINQLVKRHIRSATDLHIIGIDRGERHLLYLTVIDSRGNIKEQ

FSLNEIVNEYNGNTYRTDYHELLDTREGERTEARRNWQTIQNIRELKEGYLSQVIHKISE

LAIKYNAVIVLEDLNFGFMRSRQKVEKQVYQKFEKML]DKLNYLVDKKKPV.AETGGLL

RAYQLTGEFESFKTLGKQSGn..FYVPA\WTSKIDP\/TGFVNLFDTHYE,NIEKAK\TFDKF

K S [RYNSDKD WFEF V VDD YTRF SPK AEGTRRD WTICTQGKRIQICRNHQRNNEWEGQEI

DLTKAFKEHFEAYGVDISKDLREQINTQNKKEFFEELLRLLRLTLQMRNSMPSSDIDYLIS

PVANDTGCFFDSRKQAELKENAVLPMNADANGAYNIARKGLLAIRKMKQEENDSAKIS

LAISNKEWLKFAQTKPYLED (SEQ ID NO: 91) [001488] >WP 036890108 (modified) hypothetical protein [Porphyromonas crevioricanis] [001489] MDSLKDFTNLYPVSKTLRFELKPVGKTLENIEKAGILKEDEHIGkESYRRVKKI IDTYHKVFIDSSLENMAKMGIENEIKAMLQSFCELYKKDHRTEGEDKALDKIR.AVLRGLI

VGAFTGVCGRRENTVQNEKYESLFKEKLIKEILPDFVLSTEAESLPFSVEEATRSLKEFDS

FTSYFAGFYENRKNIYSTKPQSTAIAYRLIHENLPKFIDNILVFQKIKEPIAKELEHIRADFS

AGGYiKKDERLEDIFSLNYYIHVLSQAGIEKYNALIGKIVTEGDGEMKGLNEHlNLYNQQ

RGREDRLPLFRPLYKQILSDREQLSYLPESFEKDEELLRALKEFYDHIAEDILGRTQQLMT

SISEYDLSR1YVRNDSQLTDISKKMLGDWNAIYMARERAYDHEQAPKRITAKYERDRIK

ALKGEESISLANLNSCIAFLDNVRDCRVDTYLSTLGQKEGPHGLSNLVENVFASYHEAE

QLLSFPYPEENNLIQDKDNVVLIKNLLDNISDLQRFLKPLWGMGDEPDKDERFYGEYNYI

RGALDQVIPLYNKVRNYLTRKPYSTRKVKLNFGNSQLLSGWDRNKEKDNSCVILRKGQ

NFYLAIAINNRHKRSFENKMLPEYKEGEPYFEKMDYKFLPDPNKMLPKVFLSKKGIEIYK

PSPKLLEQYGHGTHKKGDTFSMDDLHELIDFFKHSIEAHEDWKQFGFKFSDTATYENVS

SF YREVEDQGYKLSFRKVSES YVYSLIDQGKLYLFQIYNKDF SPC SKGTPNLHTLYWRM

LFDERNLADVIYKLDGKAEIFFREKSLKNDHPTHPAGKPIKKKSRQKKGEESLFEYDLVK

DRRYTMDKFQFHVPITMNFKCSAGSKVNDMVNAHEREAKDMHVIGIDRGEKNLLYICVI

DSRGTILDQISLNTINDIDYHDLLESRDKDRQQEHRNWQTIEGIKELKQGYLSQAVHRIA

550

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ELMVAYKAWALEDLNMGFKRGRQKVESSVYQQFEKQLIDKLNYLVDKKKRPEDIGG

LLlGkYQFTAPFKSFKEMGKQNGFLFYIPAWNTSNIDPTTGFVNLFHVQYENVDKAKSFF

QKFDSISYNPKKDWFEFAFDYKNFTKKAEGSRSMWILCTHGSRIKNFRNSQKNGQWDS

EEFALTEAFKSLFVRYEIDYTADLKTAIVDEKQKDFFVDLLKLFKLTVQMRNSWKEKDL

DYLISPVAGADGRFFDTREGNKSLPKDADANGAYNIALKGLWALRQIRQTSEGGKLKL

AISNKEWLQFVQERSYEKD (SEQ ID NO; 92) [001490] >WP_036887416_(modified) hypothetical protein [Porphyromonas crevioricanis] [001491] MDSLKDFTNI.WPVSKTLRFELKPVGKTLENIEKAGILKEDEHRAESYRRVKKI

IDTYHKVFIDSSLENMAKMGIENEIKAMLQSFCELYKKDHRTEGEDKALDKDIAVLRGLI

VGAFTGVCGRRENTVQNEKYESLFKEKLIKEILPDFVLSTEAESLPFSVFEATRSLKEFDS

FTSYFAGFYENRKNIYSTKPQSTAIAYRLIHENLPKFIDNILVFQKIKEPIAKELEHIRADFS

AGGYIKKDERLEDIFSLNYYIHVLSQAGIEKYNALIGKIVTEGDGEMKGLNEHINLYNQQ

RGREDRLPLFRPLYKQILSDREQLSYLPESFEKDEELLRALKEFYDHIAEDILGRTQQLMT

SISEYDLSRIYVRNDSQLTDISKKMLGDWNAIYMARERAYDHEQAPKRITAKYERDRIK

ALKGEESISLANI.>NSCIAFLDNVRDCR\/DTYLSTLGQKEGPHGLSNLVENVFASYI-IEAE

QLLSFPYPEENNLIQDKDNVVLIKNLLDNISDLQRF'LKPLWGMGDEPDKDERF'YGEYNYI

RGALDQVIPLYNKVRNYLTRKPYSTRKVKLNFGNSQLLSGWDRNKEKDNSCVILRKGQ

NFYLAIMNNRHKKSFENKVLPEYKEGEPYFEKMDYKFLPDPNKMLPKVFLSKKGIEIYK

PSPKLLEQYGHGTHKKGDTFSMDDLHELIDFFKHSIEAHEDWKQFGFKFSDTATYENVS

SFYREVEDQGYKLSFRKVSESYVYSLIDQGKLYLFQIYNKDFSPCSKGTPNLHTLYWRM

LFDERNLADVIYKLDGKAEIFFREKSLKNDHPTHPAGKPIKKKSRQKKGEESLFEYDLVK

DRHYTMDKFQFHVPITMNFKCSAGSKVNDMVNAHIREAKDMHVIGIDRGERNLLYICVI

DSRGTILDQISLNTINDIDYHDLLESRDKDRQQERRNWQTIEGIKELKQGYLSQAVHRIAE

LMVAYKAVVALEDLNMGFKRGRQKVESSVYQQFEKQLIDKLNYLVDKKKRPEDIGGL

LRAYQFTAPFKSFKEMGKQNGFLFYIPAWNTSNIDPTTGFVNLFHAQYENVDKAKSFFQ

KFDSISYNPKKDWFEFAFDYKNFTKKAEGSRSMWELCTHGSRIKNFRNSQKNGQWDSEE

FALTEAFKSLFVRYEIDYTADLKTAIVDEKQKDFFVDLLKLFKLTVQMRNSWKEKDLDY

LISPVAGADGRFFDTREGNKSLPKDADANGAYNIALKGLWALRQIRQTSEGGKLKLAIS

NKEWLQFVQERSYEKD (SEQ ID NO; 93) [001492] >WP 023941260 (modified) exonuclease SbcC [Porphyromonas cansulci]

551

WO 2016/205711

PCT/US2016/038181 [001493] MDSLKDFTNLYPVSKTLRFELKPVGKTLENIEKAGILKEDEHRAESYRRVKKI

IDTYHKVFIDSSLENMAKMGIENEIKAMLQSFCELYKKDHRTEGEDKALDKIRA VERGE!

VGAFTGVCGRRENTVQNEKYESLFKEKLIKEILPDFVLSTEAESLPFSVEEATRSLKEFDS ftsyfagfyenrkniystkpqstaiayrlihenlpkfidnilvfqkikepiakelehiradfs

AGGYIKKDERLEDIFSLNYYIHVLSQAGIEKYNALIGKIVTEGDGEMKGLNEHINLYNQQ

RGREDRLPLFRPLYKQILSDREQLSYLPESFEKDEELLRALKEFYDl HAEDILGRTQQLMT siseydlsriyvrndsqltdiskkmlgdwnaiymareraydheqapkritakyerdrik

ALKGEESISLANLNSCIAFLDNVRDCRVDTYLSTLGQKEGPHGLSNLVENVFASYHEAE qllsfpypeennliqdkdnvvliknlldnisdlqrflkplwgmgdepdkderfygeynyi

RGALDQVEPLYNKVRNYLTRKPYSTRKVKLNFGNSQLLSGWDRNKEKDNSCVILRKGQ nfylaimnnrhkrsfenkvlpeykegepyfekmdykflpdpnkmlpkvflskkgieiyk

PSPKLLEQYGHGTHKKGDTFSMDDLHELIDFFKHSIEAHEDWKQFGFKFSDTATYENVS

SFYREVEDQGYKLSFRKVSESYVYSLIDQGKLYLFQIYNKDFSPCSKGTPNLHTLYWRM

LFDERNLADVIYKLDGKAEIFFREKSLKNDHPTHPAGKPIKKKSRQKKGEESLFEYDLVK

DRRYTMDKFQFHVPITMNFKCSAGSKVNDMVNAHIREAKDMHVIGIDRGERNLLYICVI

DSRGTILDQISLNTrNDIDYHDLLESRDKDRQQERRNWQTlEGIKELKQGYLSQAVHRLAE

LMVAYKAVVALEDLNMGFKRGRQKVESSVYQQFEKQLIDKLNYI-A''DKKKRPEDIGGL

LRAYQFTAPFKSFKEMGKQNGFLFYIPAWNTSNIDPTTGFVNLFHAQYENVDKAKSFFQ

KFDSISYNPKKDWFEFAFDYKNFTKKAEGSRSMWILCTHGSRIKNFRNSQKNGQWDSEE

FALTEAFKSLFVRYE1DYTADLKTAIVDEKQKDFFVDLLKLFKLTVQMRNSWKEKDLDY

LISPVAGADGRFFDTREGNKSLPKDADANGAYNIALKGLWALRQIRQTSEGGKLKLAIS

NKEWLQFVQERSYEKD (SEQ ID NO: 94) [001494] >WP_037975888_(modified) hypothetical protein [Synergistes jonesii] [001495] MANSLKDFTNIYQLSKTLRFELKPIGKTEEHINRKLIIMHDEKRGEDYKSVTK

LIDDYHRKFIHETLDPAHFDWNPLAEALIQSGSKNNKALPAEQKEMREK1ISMFTSQAVY

KKLFKKELFSELLPEMIKSELVSDLEKQAQLDAVKSFDKFSTYFTGFHENRKNIYSKKDT

STSIAFRIVHQNFPKFLANVRAYTLIKERAPEVIDKAQKELSGILGGKTLDDIFSIESFNNV

LTQDKIDYYNQnGGVSGKAGDKKLRGVNEFSNLYRQQHPEVASLRIKMVPLYKQILSD

RTTLSFVPEALKDDEQAINAVDGLRSELERND1FNR1KRLFGKNNLYSLDKIWIKNSSISA

FSNELFKNWSFIEDALKEFKENEFNGARSAGKKAEKWLKSKYFSFADIDAAVKSYSEQV

SADiSSAPSASYFAKFTNLIETAAENGRKFSYFAAESKAFRGDDGKTEIIKAYLDSLNDIL

552

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HCLKPFETEDISDIDTEFYSAFAEIYDSVKDVIPVYNAVRNYTTQKPFSTEKFKLNFENPA

LAKGWDKNKEQNNTAIILMKDGKYYLGVIDKNNKLRADDLADDGSAYGYMKMNYKF

IPTPHMELPKVFLPKRAPKRYNPSREILLIKENKTFIKDKNFNRTDCHKLIDFFKDSINKHK

DWRTFGFDFSDTDSYEDISDFYMEVQDQGYKLTFTRLSAEKIDKWVEEGRLFLFQIYNK

DFADGAQGSPNLHTLYWKAEFSEENLKDWLKLNGEAELFFRRKSIDKPAVHAKGSMK

VNRRDIDGNPIDEGTYVEICGYANGKRDMASLNAGARGLIESGLVRITEVKHELVKDKR

YTIDKYFFHVPFTINFKAQGQGNINSDVNLFLRNNKDVNIIGIDRGERNLVYVSLIDRDGH

IKLQKDFNIIGGMDYHAKLNQKEKERDTARKSWKTIGTIKELKEGYLSQA/VHEIVRLAV

DNNAVIVMEDLNIGFKRGRFKVEKQVYQKFEKMLIDKLNYLVFKDAGYDAPCGILKGL

QLTEKFESFTKEGKQCXJIIFYIPAGYTSKIDPTTGFVNLFNINDVSSKEKQKDFIGKLDSIR

FDAKRDMFTFEFDYDKFRTYQTSYRKKWAVWTNGKRIVREKDKDGKFRMNDRLLTED

MKNILNKYALAYKAGEDILPDVISRDKSLASEIFYVFKNTLQMRNSKRDTGEDFIISPVL

NAKGRFFDSRKTDAALPiDADANGAYHIALKGSLVLDAIDEKLKEDGRiDYKDMAVSNP

KWFEFMQTRKFDF (SEQ ID NO: 95) [001496] >EFI70750 (modified) conserved hypothetical protein [Prevotella bryantii B14] [001497] MQINNLKIIYMKFTDFTGLYSLSKTLRFELKPIGKTLENIKKAGLLEQDQHRA

DSYKKVKKIIDEYHKAFIEKSLSNFELKYQSEDKLDSLEEYLMYYSMKRIEKTEKDKFAK

IQDNLRKQIADHLKGDESYKTIFSKDLIRKNLPDFVKSDEERTLIKEFKDFTTYFKGFYEN

RENMYSAEDKSTAISHRIIHENLPKFVDNINAFSKIILIPELREKLNQIYQDFEEYLNVESID

EIFHLDYFSMVMTQKQIEVYNAIIGGKSTNDKKIQGLNEYINLYNQKHKDCKLPKLKLLF

KQILSDRIAISWLPDNFKDDQEALDSIDTCYKNLLNDGNVLGEGNLKLLLENIDTYNLKG

IFIRNDLQLTDISQKMYASWNVIQDAVILDLKKQVSRKKKESAEDYNDRLKKLYTSQES

FSIQYLNDCLRAYGKTENIQDYFAKLGAVNNEHEQTINLFAQVRNAYTSVQAILTTPYPE

NANLAQDKETVALIKNLLDSLKRLQRFIKPLLGKGDESDKDERFYGDFTPLWETLNQITP

LYNMVRNYMTRKPYSQEKIKLNFENSTLLGGWDLNKEHDN¹TAIILRKNGLYYLAIMKK

SANKEFDKDKLDNSGDCYEKMVYKLLPGANKMLPKVFFSKSRIDEFKPSENIIENYKKG

THKKGANFNLADCHNLIDFFKSSISKHEDWSKFNFHFSDTSSYEDLSDFYREVEQQGYSI

SFCDVSVEYINKMVEKGDLYLFQIYNKDFSEFSKGTPNMHTLYWNSLFSKENLNNHYKL

NGQAEIFFRKKSLNYKRPTHPAHQAIKNKNKCNEKKESIFDYDLVKDKRYTVDKFQFHV

PITMNFKSTGNTNINQQVIDYLRTEDDTHIIGIDRGERHLLYLVVIDSHGKIVEQFTLNEIV

NEYGGNIYRTNYHDLLDTREQNREKARESWQTIENIKELKEGYISQVIHKITDLMQKYH

553

WO 2016/205711

PCT/US2016/038181

AVVVLEDLNMGFMRGRQKVEKQVYQKFEEMLINKLNYLVNKKADQNSAGGLLHAYQ

LTSKFESFQKLGKQSGFLFYIPAWNTSKIDPVTGFVNLFDTRYESIDKAKAFFGKFDSniY

NADKDWFEFAFDYNNFTTKAEGTRTNWTICTYGSRIRTFRNQAKNSQWDNEEIDLTKA

YKAFFAKHGiNlYDNIK'EAIAMETEKSFFEDELHLLKLTLQMlLNSlTGTTTDYLISPVHDS

KGNFYDSRICDNSLPANADANGAYNIARKGLMLIQQIKDSTSSNRFKFSPITNKDWLIFA

QEKPYLND (SEQ ID NO: 96) [001498] >WP_024988992_(modified) hypothetical protein [Prevotella albensis] [001499] MNIKNFTGLYPLSKTLRFELKPIGKTKENIEKNGILTKDEQRAKDYLIVKGFID

EYHKQFIKDRLWDFKLPLESEGEKNSLEEYQELYELTKRNDAQEADFTEIKDNLRSSITE

QLTKSGSAYDRIFKKEFIREDLVNFLEDEKDKNIVKQFEDFTTYFTGFYENRKNMYSSEE

KSTAIAYRLIHQNLPKFMDNMRSFAKIANSSVSEHFSDIYESWKEYLNVNSIEEIFQLDYF

SETLTQPHIEVYNYnGKKVLEDGTEIKGINEYVNLYNQQQKDKSKRLPFLVPLYKQILSD reklswiaeef:ds:dk:kmlsaitesynhlhnvlmgnenes:lr.nlllnik:dynlekinitnd

LSLTEISQNLFGRYDVFTNGIKNKLRVLTPRKKKETDENFEDRINKIFKTQKSFSIAFLNK lpqpemedgkprniedyfitqgaintksiqkedifaqienayedaqvflqikdtdnklsqn

K lAVEKIKIELDALKELQHFIKIffiLGSGEENEKDELFYGSFLAIWDELDITi'PLYNKVRN wltrkpystekiklnfdnaqllggwdvnkehdcagillrkndsyylgiinkktnhifdt

DITPSDGECYDKIDYKLLPGANKMLPKATFSKSRIKEFEPSEAIINCYKKGTHKKGKNFN

LTDCHRLINFFKTSIEKHEDWSKFGFKFSDTETYEDISGFYREVEQQGYRLTSHPVSASYI

HSLVKEGKLYLFQlWNKDFSQFSKGTPNLHTLYWKMLFDKRNLSDVVYKLNGQAEA^rF

YRKSSIEHQNRUHPAQHPITNKNELNKKHTSTFKYDIIKDRRYTVDKFQFHVPITINFKAT

GQNNINPIVQEVIRQNGITHIIGIDRGIiRHLLYLSLlDLKGNUKQM TLNEIINEYKGVTYKT

NYHNLLEKREKERTEARHSWSSIESIKELKDGYMSQVIHKITDMMVKYNAIVVLEDLNG

GFMRGRQKVEKQVYQKFEKKLIDKLNYIAT)KKI.OANEVGGVLNAYQLTNKFESFKKI

GKQSGFLFYIPAWNTSKIDPITGFVNLFNTRYESIKETKVFWSKFDIIRYNKEKNWFEFVF

DYNTFTTKAEGTRTKWTLCTHGTRIQTFRNPEKNAQWDNKEINLTESFKALFEKYKIDIT

SNLKESIMQETEKKFFQELHNLLHLTLQMRNSVTGTDIDYLISPVADEDGNFYDSRINGK

NFPENADANGAYNIARKGLMLIRQIKQADPQKKFKFETITNKDWLKFAQDKPYLKD (SEQ ID NO: 97) [001500] >WP 039658684 (modified) hypothetical protein [Smithella sp. SC K08D17]

554

WO 2016/205711

PCT/US2016/038181 [001501 ] MQTLFENFTNQYPVSKTLRFELIPQGKTKDFIEQKGLLKKDEDRAEK YKKVK

NIIDEYHKDFIEKSLNGLKLDGLEKYK TLYLKQEKDDKDKKAFDKEKENLRKQIANAIR

NNEKFKTLFAKELIKNDLMSFACEEDKKNVKEFEAFTTYFTGFHQNRANMYVADEKRT

AI.ASRLIHENLPKFIDNIKIFEKMKKEAPELLSPFNQTLKDMKDVIKGTTLEEiFSLDYFNK

TLTQSGIDIYNSVIGGRTPEEGKTKIKGLNEYINTDFNQKQTDKKKRQPKFKQLYKQILSD

RQSLSFIAEAFKNDTEILE.AIEKFYVNELLHFSNEGKSTNVLD.AIKNAVSNLESFNLTKMY

FRSGASLTDVSRKVFGEWSIINRALDNYYATTYPIKPREKSEKYEERKEKWLKQDFNVS

LIQTAIDEYDNETVKGKNSGKVIADYFAKFCDDKETDLIQKVNEGYIAVKDLLNTPCPEN

EKLGSNKDQVKQIKAFMDSIMDIMHFVRPLSLKDTDKEKDETFYSLFTPLYDHLTQTIAL

YNKVRNYLTQKPYSTEKEKLNFENSTLLGGWDLNKETDNTAIILRKDNLYYLGIMDKRH

NRIFRNVPKADKKDFCYEKMVYKLLPGANKMLPKVFFSQSRIQEFTPSAKLLENYANET

HKKGDNFNLNHCHKLIDFFKDSINKHEDWKNFDFRFSATSTYADLSGFYHEVEHQGYKI

SFQSVADSFIDDLVNEGKLYLFQIYNKDFSPFSKGKPNLHTLYWKMLFDENNLKDVVYK

LNGEAEVFYRKKSIAEKNTTIHKANESIINKNPDNPKATSTFNYDIVKDKRYTIDKFQFHI

PITNINFKAEGIFNNINQRWQFLKANPDINIIGIDRGERHLLYYALINQKGKILKQDTLNVI

ANEKQKVDYHNLLDKKEGDRATARQEWGVIETIKELKEGYLSQVIHKLTDLMIENNAII

Y'MEDLNFGFKRGRQKVEKQVYQKFEKMLIDKLNYLAOKNKKANELGGLLNAFQLANK

FESFQKMGKQNGFIFYVPAVVNTSKTDPATGFIDFLKPRYENLNQAKDFFEKFDSIRLNSK adyfefafdfknftekadggrtkwtvcttnedryawnralnnnrgsqekyditaelk

SLFDGKVDYKSGKDLKQQIASQESADFFKALMKNLSITLSLRHNNGEKGDNEQDYILSP vadskgrffdsrkadddmpknadangayhialkglwcleqisktddlkkvklaisnke

WLEFVQTLKG (SEQ ID NO: 98) [001502] >WP_037385181_(modified) hypothetical protein [Smithella sp. SCADC] [001503] MQTLFENFTNQYPVSKTLRFELIPQGKTKDFIEQKGLLKKDEDRAEKYKKW

NIIDEYHKDFIEKSENGLKLDGLEEYKTLVLKQEKDDKDKKAFDKEKENLRKQIANAFR

NNEKFKTLFAKELIKNDLMSFACEEDKKNVKEFEAFTTYFTGFHQNRANMYVADEKRT

AI.ASRiTHENLPKFIDNIKIFEKMKKEAPELLSPFNQTLKDMKDVIKGTTLEEIFSLDYFNK

TLTQSGIDIYNSVIGGRTPEEGKTKIKGLNEYINTDFNQKQTDKKKRQPKFKQLYKQILSD

RQSLSFIAEAFKNDTEILEAIEKFYVNELLHFSNEGKSTOVLDAIKNAVSNLESFNLTKIYF

RSGTSLTDVSRKVFGEWSIINRALDNYYATTYPIKPREKSEKYEERKEKWLKQDFNVSLI

QTAIDEYDNETVKGKNSGKVIYDYFAKFCDDKETDLIQKVNEGYIAA/KDLLNTPYPENE

555

WO 2016/205711

PCT/US2016/038181

KLGSNKDQVKQIKAFMDSIMDIMHFVRPLSLKDTDKEKDETFYSLFTPLYDHLTQTIAL

YNKVRNYLTQKPYSTEKIKLNFENSTLLGGWDLNKETDNTAIILRKENLYYLGIMDKRH NRIFRNVPKADKKDSCYEKMVYKLLPGANKMLPKVFFSQSRIQEFTPSAKLLENYENET HKKGDNFNLNHCHQLIDFFKDSINKHEDWKNFDFRFSATSTYADLSGFYHEVEHQGYKI SFQ SIAD SFIDDLVNEGKL YLFQIYNKDF SPF SKGKPNLHTL YWKMLFDENNLKD WYK LNGEAEVFYRKKSIAEKN TTIHKANESHNKNPDNPKATSTFNYDIVKDKRYTIDKFQIHY PITMNFKAEGIFNMNQRVNQFLKANPDINUGIDRGERHLLYYTLINQKGKILKQDTLNVI ANEKQKVDYFINLLDKKEGDRATARQEWGVIETIKELKEGYLSQVIHKLTDLMIENNAII VMEDLNFGFKRGRQKVEKQVYQKFEKMLIDKLNYLVDKNKKANELGGLLMYFQLANK FESFQKMGKQNGFIFYVPAWNTSK TDPATGFIDFLKPRYENLKQAKDFFEKFDS1RLNSK ADYFEFAFDFKNFTGKADGGRTKWTVC TTNEDRYAWNRALNNNRGSQEKYDITAELK SLFDGKVDYKSGKDLKQQIASQELADFFRTLMKYLSVTLSLRHNNGEKGETEQDYILSP VADSMGKFFDSRKAGDDMPKNADANGAYHIALKGLWCLEQISKTDDLKKVKLAISNK EWLEFMQTLKG (SEQ ID NO: 99) [001504] >WP 039871282 (modified) hypothetical protein [Prevotella bryantii] [001505] MKFTDFTGLYSLSKTLRFELKPIGKTLENIKKAGLLEQDQHRADSYKKVKKII

DEYHKAFIEKSLSNFELKYQSEDKLDSLEEYLMYYSMKRIEKTEKDKFAKIQDNLRKQIA

DHLKGDESYKTIFSKDLIRKNLPDFVKSDEERTLIKEFKDFTTYFKGFYENRENMYSAED

KSTAISHRIIHENLPKFVDNINAFSKIILIPELREKLNQIYQDFEEYLNVESIDEIFHLDYFSM

VMTQKQIEVYNAIIGGKS rNDKKIQGLNEYINLYNQKHKDCK LPKLKLLFKQILSDRIAIS

WLPDNFKDDQEALDSIDTCYKNLLNDGNVLGEGNLKLLLENIDTYNLKGIFIRNDLQLT

DISQKMYASWNVIQDAVILDLKKQVSRKKKESAEDYNDRLKKLYTSQESFSIQYLNDCL

RAYGKTENIQDYFAKLGAVNNEHEQTINLFAQVRNAYTSVQAILTTPYPENANLAQDKE

TVALIKNLLDSLKRLQRFIKPLLGKGDESDKDERFYGDFTPLWETLNQITPLYNMVRNY

MTRKPYSQEKIKLNFENSTLLGGWDLNKEHDNTAilLRKNGLYYLAIMKKSANKIFDKD

KLDNSGDCYEKMVYKLLPGANKMLPKVFFSKSRIDEFKPSENIIENYKKGTHKKGANFN

LADCHNLIDFFKSSISKHEDWSKFNFHFSDTSSYEDLSDFYREVEQQGYSISFCDVSVEYI

NKMVEKGDLYLFQIYNKDFSEFSKGTPNMHTLYWNSLFSKENLNNHYKLNGQAEIFFR i/i/Cf ΧΤΛΖΊΧΌ DTLTD A E-JYN A ΪΊΧ’ΜΊΧ \^TV PVC ΊΧ FE C ΤΓΤλ'\⁷Τλϊ A /'ΊΧΓΑΊΧΈ» A/‘ΤΑ ΤΤΑΐΧ BIWESOA ZDTTA /ΓΚΤΙΖ C ^rT

GNTNINQQViDYLRTEDDTHnGiDRGERHLLYLVVIDSHGKIVEQFTLNEIVNEYGGNlY

RTNYHDLLDTREQNREKARESWQTIENIKELKEGYISQVn-IKITDLMQKYHAVVATEDL

556

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NMGFMRGRQKVEKQVYQKFEEMIJNKLNYLWKKADQNSAGGLLHAYQLTSKFESFQ

KLGKQSGFLFYIPAWNTSKIDPVTGFVNLFDTRYESIDKAKAFFGKFDSIRYNADKDWFE

FAFDYNNFTTKAEGTRTNWTICTYGSRIRTFRNQAKNSQWDNEEIDLTKAYKAFFAKHG INIYDNIKEAIAMETEK SFFEDLLHLLK LTLQMRNSITGTTTD YLISP VHDSKGNF YDSRIC DNSLPANADANGAYNIARKGLMLIQQIKDSTSSNRFKFSPITNKDWLIFAQEKPYLND (SEQ ID NO; 100) [001506] >EKE28449_(modified) hypothetical protein ACD_3COOO58GOO15 [uncultured bacterium (geode 4)] [001507] MFKGDAFTGLYEVQKTLRFELVPIGLTQSYLENDWVIQKDKEVEENYGKIKA

YFDLIHKEFVRQSLENAWLCQLDDFYEKYIELHNSLETRKDKNLAKQFEKWKSLKKEF

VSFFDAKWNEWKQKFSFLKKWWIDVLNEKEVLDLMAEFYPDEKELFDKFDKFFTYFSN

FKESRKNFYADDGRAWAIATRAIDENLITFIKNIEDFKKLNSSFREFVNDNFSEEDKQIFEI dfynncllqpwidkynkiwwyslenwekvqwlnekinnfkqnqnksnskdlkfprm:

KLLYKQILGDKEKKVYIDEIRDDKNLIDLIDNSKRRNQIKIDNANDIINDFINNNAKFELD

KIYLTRQSINTISSKYFSSWDYIR.WYFWTGELQEFVSFYDLKETFWKIEYETLENIFKDCY

VKGINTESQNNIVFETQGIYENFLNIFKFEFNQNiSQiSLLEWELDKIQNEDIKKNEKQVEV

IKNYFDSVMSVYKMTKYFSLEKWKKRA/ELDTDNNFYNDFNEYLEGFErWKDYNLVRN

YITKKQVNTDKIKLNFDNSQFLTWWDKDKENERLGIILRRE.WKYYLWILKKWNTLNFG

DYLQKEWEIFYEKMNYKQLNNVYRQLPRLLFPLTKKLNELKWDELKKYLSKYIQNFW

YNEEIAQIKIEFDIFQESKEKWEKFDIDKLRKLIEYYKKWVLALYSDLYDLEFIKYKNYD

DLSIFYSDVEKKMYNLNFTKIDKSLIDGKVKSWELYLFQIYNKDFSESKKEWSTENIHTK

YFKLLFNEKNLQNLVVKLSWWADIFFRDKTENLKFKKDKNGQEILDHRRFSQDKIMFHI

SITLNANCWDKYWFNQYVNEYMNKERDIKIIWIDRWEKHLAYYCVIDKSWKIFNNEIW

TLNELNWVNYLEKLEKIESSRKDSRISWWEIENIKELKNGYISQVINKLTELIVKYNAIIVF

EDENIWFKRWRQKIEKQiYQKLELALAKKLNYLTQKDKKDDEILWNLKALQLVPKVND

YQDIWNYKQSWIMFYWANYTSVTCPNCWLRKNLYISNSATKENQKKSLNSIAIKYND

WKFSFSYEIDDKSWKQKQSLNKKKFIVYSDIERFVYSPLEKLTKVIDVNKKLLELFRDFN

LSLDINKQIQEKDLDSVFFKSLTHLFNLILQLRNSDSKDNKDYISCPSCYYHSNNWLQWF

EFNWDANWAYNIARKGIILLDRIRKNQEKPDLYVSDIDWDNFVQSNQFPNTKPIQNIEKQ

VPLNIKI (SEQ ID NO: 101) [001508] >WP 018359861 (modified) hypothetical protein [Porphyromonas macacae]

557

WO 2016/205711

PCT/US2016/038181 [001509] MKTQHFFEDFTSLYSLSKTIRFELKPIGKTLENIKKNGLIRRDEQRLDDYEKEK KVIDEYHEDFIANILSSFSFSEEILQSYIQNLSESEARAKIEKTMRDTLAKAFSEDERYKSIF

KKELVKKDIPVWCPAYKSLCKKFDNFTTSLVPFHENRKNLYTSNEITASIPYRIVHVNLP

KFIQNIEALCELQKKMGADLYLEMMENLRNVWPSFVKTPDDLCNLKTYNHLMVQSSIS

EYNRFVGGYSTEDGTKHQGINEWINIYRQRNKEMRLPGLVFLHKQILAKVDSSSFISDTL

ENDDQVFCVLRQFRKLFWNTVSSKEDDAASLKDLFCGLSGYDPEAIYVSDAHLATISKN

IFDRWNYISDAIRRKTEVLMPRKKESVERYAEKISKQIKKRQSYSLAELDDLL.AHYSEES

I,PAGFSLLSYFTSLGGQKYI,VSDGEVfoYEEGSNIWDEA^rLIAFRDLQVILDKDFTEKKLG

KDEEAVSVIKKALDSALRLRKFFDLLSGTGAEIRRDSSFYALYTDRMDKLKGLLKMYD

KV'RNYLTKKPYSIEKFKLHFDNPSLLSGWDKNKELNNLSVIFRQNGYYYLGIMTPKGKN

LFKTLPKLGAEEMFYEKMEYKQIAEPMLMLPKVFFPKKTKPAFAPDQSVVDIYNKKTFK

TGQKGFNKKDLYRLIDFYKEALTVHEWKLFNFSFSPTEQYRNIGEFFDEVREQAYKVSM

VNVPASYIDEAVENGKLYLFQIYNKDFSPYSKGIPNLHTLYWKALFSEQNQSRVYKLCG

GGELFYRKASLHMQDTTVHPKGISIHKKNLNKKGETSLFNYDLVKDKRFTEDKFFFHVP

ISINYKNKKITNWQMVRDYIAQNDDLQIIGIDRGERNLLYISRIDTRGNLLEQFSLNVIES

DKGDLRTDYQKILGDREQERLRRRQEWKSIESIKDLKDGYMSQVVHKICNMVVEHKAI

VVLENLNLSFMKGRKKVEKSVYEKFERMLVDKLNYLWDKKNLSNEPGGLYAAYQLT

NPLFSFEELHRYPQSGILFFVDPWNTSLTDPSTGFVNLLGRINYTNVGDARKFFDRFNAIR

YDGKGNILFDLDLSRFDVRVETQRKLWTLTTFGSRIAKSKKSGKWMVERIENLSLCFLE

LFEQFNIGYRVEKDLKKAILSQDRKEFYVRLIYLFNLMMQIRNSDGEEDYILSPALNEKN

LQFDSRLIEAKDLPVDADANGAYNVARKGLMWQRIKRGDHESIHRIGRAQWLRYVQE

GIVE (SEQ ID NO; 102) [001510] >WP_01328299l_(modified) hypothetical protein [Butyrivibrio proteoclastieus] [001511 ] MLLYENYTKRNQITK SLRLELRPQGKTLRNIKELNLLEQDKAIYALLERLKP V

IDEGIKDIARDTLKNCELSFEKLYEHFLSGDKKAYAKESERLKKEIVKTLIKNLPEGIGKIS

EINSAKYLNGVLYDFIDKIHKDSEEKQNILSDILETKGYLALFSKFLTSRITTLEQSMPKR

VIENFEIYAANIPKMQDALERGAVSFAIEYESICSVDYYNQILSQEDIDSYNRLISGIMDED

GAKEKGINQTISEKNIKIKSEHLEEKPFRILKQLHKQILEEREKAFTIDHIDSDEEVVQVTK

EAFEQTKEQWENIKKINGFYAKDPGDn'LFIVVGPNQTHVLSQLIYGEHDRIRLLLEEYEK

NTLEVLPRRTKSEKARYDKFVNAVPKKVAKESHTFDGLQKMTGDDRLFILYRDELARN

YMRIKEAYGTFERDILKSRRGIKGNRDVQESLVSFYDIiLTKFRSALRIINSGNDEKADPIF

558

WO 2016/205711

PCT/US2016/038181

YNTFDGEFEKANRTYKAENLCRNYVTKSPADDARIMASCLGTPARLRTHWWNGEENFA

INDVAMnFRGDEYYYFVLTPDVKPVDLKTKDETDAQIFVQRKGAKSFLGLPKALFKCIL

EPYFESPEHKNDKNCVIEEYVSKPLTIDRRAYDIFKNGTFKKTNIGIDGLTEEKFKDDCRY

LIDVYKEFIAVYTRYSCFNMSGLKRADEYNDIGEFFSDVDTRLCTMEWIPVSFERINDMV

DKKEGLLFLVRSMFLYNRPRKPYERTFIQLFSDSNMEHTSMLLNSRAMIQYRAASLPRR

VTHKKGSILVALRDSNGEHIPMHIREAIYKMKNNFDISSEDFIMAKAYLAEHDVAIKKAN

EDIIRNRRYTEDKFFLSLSYTKNADISARTLDYINDKVEEDTQDSRMAVIVTRNLKDLTY

VAVVDEKNNVREEKSLNEIDGVNYRELLKERTKIKYHDKTRLWQYDVSSKGLKEAYVE

LAVTQISKLATKYNAVWVESMSSTFKDKFSFLDEQIFKAFEARLCARMSDLSFNTIKEG

EAGSISNPIQVSNNNGNSYQDGVIYFLNNAYTRTLCPDTGFYDVFDKTRLITMQSKRQFF

AKMKDIRIDDGEMLFTFNLEEYPTKRLLDRKEWTVKIAGDGSYFDKDKGEYVYVNDIV

REQnPALLEDKAVFDGNMAEKFLDKTAISGKSVELiYKWFANALYGin'KKDGEKIYRSP

ITGTEIDVSKNTTYNFGKKFMFKQEYRGDGDFLDAFLNYMQAQDIAV (SEQ ID NO: 103) [001512] >AIZ56868 (modified) hypothetical protein Mptl c09950 [Candidate

Methanoplasma termitum] [001513] MNNYDEFTKL YPIQKTIRFELKPQGRTMEHLETFNEFEEDRDRAEK YKILKE A

EDEYHKKFEDEHLTNMSLDWNSLKQISEKYYKSREEKDKKVFLSEQKRMRQEIVSEFKK

DDRFKDLF SKKLF SELLKEEIYKKGNHQEID ALKSFDKF SGYFIGLHENRKNM YSDGDEI

TAISNRIVNENFPKFLDNEQKVOEARKKYPEWnKAESALVAHNIKMDEVFSEEYENKVE

NQEGIQRYNLALGGYVTKSGEKMMGLNDALNLAHQSEKSSKGRIHMTPLFKQILSEKES

F S YIPDVFTEDSQLLP SIGGFF AQIENDKDGNIFDRALELIS S YAEYDTERIYIRQADINRVS

NVIFGEWGTLGGLMREYKADSINDINLERTCKKVDKWLDSKEFALSDVLEAIKRTGNN

DAFNEYISKMRTAREKIDAARKEMKFISEKISGDEESIHIIKTLLDSVQQFLHFFNLFKAR

QDIPLDGAFYAEFDEVHSKEFAIVPLYNKAARNYI.nKNNLNTKKIKLNFKNPTLANGWDQ

NKVYD YASLIFLRDGNYYLGIINPKRKKNIKFEQGSGNGPF YRKMVYKQIPGPNKNLPR

VFLTSTKGKKEYKPSKEIIEGYEADKHIRGDKFDLDFCHKLIDFFKESIEKHKDWSKFNF

YFSPTESYGDISEFYLDVEKQGYRMHFENISAETIDEYVEKGDLFLFQIYNKDFVKAATG

KKDMHTIYWNAAFSPENLQDVWKLNGEAELFYRDKSDIKEIVHREGEILVNRTYNGRT

PVPDKIHKKLTDYHNGRTKDLGEAKEYLDKVRYFKAHYDITKDERYLNDKIYFHVPLT

LNFKANGKKNLNKMVIEKFLSDEKAHIIGIDRGERNLLYYSIIDRSGKIIDQQSLNVIDGF

DYREKLNQREIEMKDARQSWNAIGKIKDLKEGYLSKAVHEITKMAIQYNAIVVMEELN

559

WO 2016/205711

PCT/US2016/038181

YGFKRGRFKVEKQIYQKFENMLIDKMNYLVFKDAPDESPGGVLNAYQLTNPLESFAKL GKQTGILFYVPAAYTSKIDPTTGFVNLFNTSSKTNAQERKEFLQKFESISYSAKDGGIFAF AFDYRKFGTSKTDHKNVWTAYTNGERMRYIKEKKRNELFDPSKEIKEALTSSGIKYDGG QNILPDILRSNNNGLIYTMYSSFIAAIQMRVYDGKEDYIISPIKNSKGEFFRTDPKRRELPI DADANGAYNIALRGELTMRAIAEKFDPDSEKMAKLELKHKDWFEFMQTRGD (SEQ ID NO: 104) [001514] >WP_027407524_(niodified) hypothetical protein [Anaerovibrio sp. RM50] [001515] M\^AFIDEFVGQYPVSKTLRFEARPVPETKKWLESDQCS\ffiFNDQK.RNEYYG

VLKELLDDYYRAYIEDALTSFTLDKALLENAYDLYCNRDTNAFSSCCEKLRKDLVKAFG

NLKDYLLGSDQLKDLVKLKAKVDAPAGKGKKKIEVDSRLINWLNNNAKYSAEDREKYI

KAIESFEGFVTYLTNYKQARENMFSSEDKSTAIAFRVIDQNMVTYFGNIRIYEKIKAKYP

ELYSALKGFEKFFSPTAYSEILSQSKIDEYNYQCIGRPIDDADFKGVNSLINEYRQKNGIK

ARELPVMSMLYKQILSDRDNSFMSEVINRNEEAIECAKNGYKVSYALFNELLQLYKKIF

TEDNYGNIYVKTQPLTELSQALFGDWSILRNALDNGKYDKDIINLAELEKYFSEYCKVL

DADDAAKIQDKFNLKDYFIQKNALDATLPDLDKITQYKPI-ffiDAMLQAIRKYKLFSMYN

GRKKMD VPENGIDF SNEFNAIYDKLSEF SIL YDRIRNFATKKPYSDEKMKLSFNMPTML

AGWDYNNETANGCFLFIKDGKYFLGVADSKSKNIFDFKKNPHLLDKYSSKDIYYKVKY

KQVSGSAKMLPKVVFAGSNEKIFGHLISKKILEiREKKLYTAAAGDRKAVAEWIDFMKS

AIAIHPEWNEYFKFKFKNTAEYDNANKFYEDIDKQTYSLEKVEIPTEYIDEMVSQHKLYL

FQLYTKDFSDKKKKKGTDNLHTMYWHGVFSDENLKAVTEGTQPIIKLNGEAEMFMRNP

SIEFQVTHEHNKPIANKNPLNTKKESVFNYDLIKDKRYTERKFYFHCPITLNFRADKPIKY

NEKINRFVENNPDVCTIGIDRGERHLLYYTVINQTGDILEQGSLNKISGSYINDKGEKVNK

ETDYHDLLDRKEKGKHVAQQAWETIENIKELKAGYLSQWYKLTQLMLQYNAVIVLEN

LNVGFKRGRTKYTiKQVYQKFEKAMIDKLNYLYTKDRGYEMNGSYAKGLQLTDKFESF

DKIGKQTGCIYYVIPSYTSHIDPKTGFVNLLNAKLRYENITKAQDTIRKFDSISYNAKADY

FEFAFDYRSFGVDMARNEWWCTCGDLRWEYSAKTRETKAYSVTDRLKELFKAHGID

YVGGENLVSmTEVWDKHFLSTELFYLRLVLKMRYTVSGTENENDFILSPVEYAPGKFFD

SREATSTEPMNADANGAYHIALKGLMTIRGIEDGKLHNYGKGGENAAWFKFMQNQEY

KNNG (SEQ ID NO: 105) [001516] >WP 044910712 (modified) hypothetical protein [Lachnospiraceae bacterium MC2017]

560

WO 2016/205711

PCT/US2016/038181 [001517] MDYGNGQFERRAPLTKTITLRLKPIGETRETIREQKLLEQDAAFRKLVETVTPI

VDDCIRKIADNALCHFGTEYDFSCLGNAISKNDSKAIKKETEKVEKLLAKVLTENLPDGL

RK\⁷NDINSA,AFIQDTLTSFVQDDADKRVLIQELKGKTVLMQRFLTTRITALT\AVLPDRV

FENFNIFIENAEKMRILLDSPLNEKIMKFDPDAEQYASLEFYGQCLSQKDIDSYNLIISGIY

ADDEVKNPGINEIVKEYNQQIRGDKDESPLPKLKKLHKQILMPVEKAFFVRVLSNDSDA

RS1LEKILKDTEM EPSKIIEAMKEADAGDIA VYGSRLHELSHVIYGDHGKLSQIIYDKESK

RISELMETLSPKERKESKKRLEGLEEHIRKSTYTFDELNRYAEKNVMAAYIAAVEESCAE

IMRKEKDLRTLLSKEDVKIRGNRHNTLIVKNYFNAWTVFRNLIRILRRKSEAEIDSDFYD

VLDDSVEVLSLTYKGENLCRSYITKKIGSDLKPEIATYGSALRPNSRWWSPGEKFNVKFH

TIVRRDGRLYYFILPKGAKPVELEDMDGDIECLQMRKIPNPTIFLPKLVFKDPEAFFRDNP

EADEFVFLSGMKAPVTITRETYEAYRYKLYTVGKLRDGEVSEEEYKRALLQVLTAYKEF

LENRMIYADLNFGFKDLEEYKDSSEFIKQVETHNTFMCWAKVSSSQLDDLVKSGNGLLF

EIWSERLESYYKYGNEKVLRGYEGVLLSILKDENLVSMRTLLNSRPMLVYRPKESSKPM

WHRDGSRWDRFDKDGKYIPPEVHDELYRFFNNLLIKEKLGEKARKILDNKKVKVKV

LESER VKWSKFYDEQFAVTFSVKKNADCLDTTKDLNAEVMEQYSESNRLILIRNTTD IL

YYLVLDKNGKVLKQRSLNIINDGARDVDWKERFRQVIKDRNEGYNEWDYSRTSNDLK

EVYLNYALKEIAEAVIEYNAILIIEKMSNAFKDKYSFLDDVTFKGFETKLLAKLSDLHFR

GIKDGEPCSFTNPLQLCQNDSNKILQDGVIFMVPNSMT’RSLDPDTGFIFAINDHNIRTKKA

KLNFLSKFDQLKVSSEGCLIMKYSGDSLPTHNTDNRVWNCCCNHPITNYDRETKKVEFI

EEPVEELSR.VLEENGIETDTELNKLNERENVPGKVVDAIYSLVLNYLRGTVSGVAGQRA

VYYSPVTGKKYDISFIQAMNLNRKCDYYRIGSKERGEWTDFVAQLIN (SEQ ID NO: 106) [001518] >WP_027216152_(modifted) hypothetical protein [Butyrivihrio fibrisolvens] [001519] MYYESLTKLYPIKKTIRNELVPIGKTLENIKKNNILEADEDRKIAYIRVKAIMD

DYHKRLINEALSGFALIDLDKAANLYLSRSKSADDIESFSRFQDKLRKAIAKRLREHENF

GKIGNKDIIPLLQKLSENEDDYNALESFKNFYTYFESYNDVRLNLYSDKEKSSTVAYRLI

NENLPRFLDNIRAYDAVQKAGITSEELSSEAQDGLFLVNTFNNVLIQDGINTYNEDIGKL

NVAINLYNQKNASVQGFRKVPKMKVLYKQILSDREESFIDEFESDTELLDSLESHYANL

AKYFGSNKVQLLFTALRESKGVNVYVKNDIAKTSFSNWFGSWSRIDELINGEYDDNNN

RKKDEKYYDKRQKELKKNKSYTIEKIITLSTEDVDVIGKYIEKLESDIDDIRFKGKNFYEA

VLCGHDRSKKLSKNKGAVEAIKGYLDSVKDFERDLKLINGSGQELEKNLWYGEQEAV

LSELSGIDSLYNMTRNYI.HKKPFSTEKIKLNFNKPTFLDGWDYGNEEAYI.GFFMIKEGN

561

WO 2016/205711

PCT/US2016/038181

YFLA\/MDANA'⁷NKEFRNIPSVDKSDCYKKVIYKQISSPEKSIQNLMVIDGKTVKKNGRKE

KEGIHSGENLILEELKNTYLPKKINDIRKRRSYLNGDTFSKKDLTEFIGYYKQRVIEYYNG

YSFYFKSDDDYASFKEFQEDVGRQAYQISYVDVPVSFVDDLINSGKLYLFRVYNKDFSE

YSKGRLNLHTLYFKMLFDERNLKNVVYKLNGQAEVFYRPSSiKKEELIAIdRAGEEIKNK

NPKRAAQKPTRRLDYDIVKDRRYSQDKFMLHTSIIMNFGAEENVSFNDIVNGVLRNEDK

VNVIGIDRGERNLLYVVVIDPEGKILEQRSLNCITDSNLDIETDYHRLLDEKESDRKIARR

DWTTIENIKELKAGYLSQVVHIVAELVLKYNAIICLEDLNFGFKRGRQKVEKQVYQKFE

KMLIDKLNYLYMDKSREQLSPEKISGALNALQLTPDFKSFKVLGKQTGIIYYWAYLTSK

IDPMTGFANLFYVKYENVDKAKEFFSKFDSIKYNKDGKNWNIKGYFEFAFDYKKFTDR

AYGRVSEWTVCTVGERUKFKNKEKNNSYDDKVIDLTNSLKELFDSYKVTYESEVDLKD

AILAIDDPAFYRDLTRRLQQTLQMRNSSCDGSRDYIISPVKNSKGEFFCSDNNDDTTPND

ADANGAFNIARKGLWVLNEIRNSEEGSKINLAMSNAQWLEYAQDNTI (SEQ ID NO:

107) [001520] >WP 016301126 (modified) hypothetical protein [Lachnospiraceae bacterium COE1] [001521] MHENNGKIADNFIGIYPVSKTLRFELKP VGKTQEYIEKHGILDEDLKRAGD YK

SVKKUDAYHKYFIDEALNGIQLDGLKNYYELYEKKRDNNEEKEFQKIQMSLRKQIVKRF

SEHPQYKYLFKKELIKNVLPEFTKDNAEEQTLVKSFQEFTTYFEGFHQNRKNMYSDEEK

STAlAYRVVHQNLPKYIDNMRIFSMILNTDIRSDLTELFNNLKTKMDITIVEEYFAIDGFN

KVVNQKGIDVYNTILGAFSTDDN TKIKGLNEYINLYNQKNKAKLPKLKPLFKQILSDRD

KISFIPEQFDSDTEVLEAVDMFYNRLLQFVIENEGQITISKLLTNFSAYDLNKIYVKNDTTI

SAISNDLFDDWSYISKAVRENYDSENVDKNKRAAAYEEKKEKALSKIKMYSIEELNFFV

KKYSCNECHIEGYFERRILEILDKMRYAYESCKILHDKGLINNISLCQDRQAISELKDFLD

SIKEVQWLLKPLV1IGQEQADKEEAFYTELLRIWEELEPITLLYNKWNYVTKKPYTLEKV

KLNFYKSTLLDGWDKNKEKDNLGIILLKDGQYYLGIMNRRNKKLADDAPLAKTDNVYR

KMEYKLLTKVSANLPRIFLKDKYNPSEEMLEKYEKGTHLKGENFCIDDCRELIDFFKKGI

YNKDFSPYSKGTKNLHTLYWEMLFSQQNLQNIVYKLNGNAEIFYRKASINQKDWVHK

ADLPIKNKDPQNSKKESMFDYDIIKDKRFTCDKYQFHVPITMNFKALGENHFNRKVNRL

IHDAENMHnGIDRGERNLIYLCMIDMKGNIVKQISLNEnSYDKNKLEHKRNYHQLLKTR

EDENKSARQSWQTIHTIKELKEGYLSQVIHVITDLMkTYNAIVYTEDLNFGFKQGRQKFE

562

WO 2016/205711

PCT/US2016/038181

RQVYQKFEKMLIDKLNYI.AOKSKGMDEDGGLLHAYQLTDEFKSFKQLGKQSGFLYYIP

AWNTSKLDPTTGFVNLFYTKYESVEKSKEFINNFTSILYNQEREYFEFLFDYSAFTSKAE GSRLKWTVCSKGERVETYRNPKKNNEWDTQKIDLTFELKKLFNDYSISLLDGDLREQM GKIDKADFYKKFMKLFAL1VQMRNSDEREDKL1SPVLNKYGAFFETGKNERMPLDADA NGAYNIARKGLWIIEKIKNTDVEQLDKVKLTISNKEWLQYAQEHIL (SEQ ID NO: 108) [001522] >WP_035635841_(modified) hypothetical protein [Lachnospiraceae bacterium ND2006] [001523] MSKLEKFINCYSLSKTLRFKAIPVGKTQENIDNKRLLVEDEKRAEDYKGVKK

LLDRYYLSFINDVLHSrKLKNLNNYISLFRKKTRTEKENKELENLEINLRKEIAKAF'KGNE

GYKSLFKKDIIETILPEFLDDKDEIALVNSFNGFTTAFTGFFDNRENMFSEEAKSTSIAFRC

INENLTRYISNMDIFEKVDAIFDKHEVQEIKEKILNSDYDVEDFFEGEFFNFVLTQEGIDV

YNAIIGGFVTESGEKIKGLNEYINLYNQKTKQKLPKFKPLYKQVLSDRESLSFYGEGYTS

DEEVLEVFRNTENKNSEIFSSIKKLEKLFKNFDEYSSAGIFVKNGPAISTISKDIFGEWNVI

RDKWNAEYDDIHLKKKAWTEKYEDDRRKSFKKIGSFSLEQLQEYADADLSVVEKLKE

IIIQKVDEIYKVYGSSEKLFDADFVLEKSLKKNDAWAIMKDLLDSVKSFENYIKAFFGE

GKETNRDESFYGDFVLAYDILLKVDHIYDA1RNYVTQKPYSKDKFKLYFQNPQFMGGW

DKDKETDYRATILRYGSKYYI.AIMDKKYAKCLQKIDKDDVNGNYEKINYKLLPGPNKM

LPKVFFSKKWMAYYNPSEDIQKIYKNGTFKKGDMFNLNDCHKLIDFFKDSISRYPKWSN

AYDFNF SETEKYKDIAGF YREVEEQGYK VSFES ASKKEVDKLVEEGKLYMFQIYNKDF S

DKSHGTPNLHTMYFKLLFDENNHGQIRLSGGAELFMRRASLKKEELVVHPANSPIANKN

PDNPKKTTTLSYDVYKDKRFSEDQYELHIPIAINKCPKNIFKINTEVRVLLKHDDNPYVIG

IDRGERNLLYIVVVDGKGNIVEQYSLNEIINNFNGIRIKTDYHSLLDKKEKERFEARQNW

TSIENIKELKAGYISQVVHKICELVEKYDAVIALEDLNSGFKNSRVKVEKQVYQKFEKML

IDKLNYMVDKKSNPCATGGALKGYQITNKFESFKSMSTQNGFIFYIPAWLTSKIDPSTGF

VNLLKTKYTSIADSKKFISSFDRIMYVlffiEDLFEFALDYKNFSRTDADYIKKWKLYSYGN

RIRIFRNPKKNNVFDWEEVCLTSAYKELFNKYGINYQQGDIRALLCEQSDKAFYSSFMA

LMSLMLQMRNSITGRTDVDFLISPVKNSDGIFYDSRNYEAQENA1LPKNADANGAYNIA

RKVLWAIGQFKKAEDEKLDKVKIAISNKEWLEYAQTSVKH (SEQ ID NO: 109) [001524] >WP_015504779_(modified) exonuclease SbcC [Candidatus Methanomethylophilus alvus]

563

WO 2016/205711

PCT/US2016/038181 [001525] MDAKEFTGQYPLSKTLRFELRPIGRTWDNLEASGYLAEDRHRAECYPRAKEL LDDNHRAFLNRVLPQIDMDWHl’IAEAFCKVHKNPGNKELAQDYNLQLSKRRKEISAYL

QDADGYKGLFAKPALDEAMKIAKENGNESDIEVLEAFNGFSVYFTGYHESRENIYSDED

MVSVAYRITEDNFPRFVSNALIFDKLNESHPDIISEVSGNLGVDDIGKYFDVSNYNNFLSQ

AGIDDYNHIIGGHTTEDGLIQAFNWLNLRHQKDPGFEKIQFKQLYKQILSVRTSKSYIPK

QFDNSKEMVDCICDYVSKIEKSETVERALKLVRNISSFDLRGIFVNKKNLRILSNKLIGD

WDAIETALMHSSSSENOKKSVYDSAEAFILDDIFSSVKKFSDASAEDIGNRAEDICRVISE

TAPFINDLRAVDLDSLNDDGYEAAVSKIRESLEPYMDLFHELEIFSVGDEFPKCAAFYSE

LEEVSEQLIEIIPLFNKARSFCTRKRYSTDKIKVNLKFPTLADGWDLNKERDNKAAILRKD

GKYYLAILDMKKDLSSIRTSDEDESSFEKMEYKLLPSPVKMLPKIFVKSKAAKEKYGLT

DRMLECYDKGMHKSGSAFDLGFCHELIDYYKRCIAEYPGWDVFDFKFRETSDYGSMKE

FNEDVAGAGYYMSLRKIPCSEVYRLLDEKSIYLFQIYNKDYSENAHGNKNMHTMYWEG

LFSPQNLESPVFKLSGGAELFFRKSSIPNDAKTVHPKGSVLVPRNDVNGRRJPDSIYRELT

RYFNRGDCRISDEAKSYLDKVKTKKADHDIVKDRRFTVDKMMFHVPIAMNFKAISKPN

LNKKVIDGIIDDQDLKIIGIDRGERNLIYVTMVDRKGNILYQDSLNILNGYDYRKALDVR

EYDNKEARRNWTKVEGIRKMKEGYLSLAVSKLADMIIENNAiiVMEDLNHGFKAGRSKi

EKQVYQKFESMLINKLGYMVLKDKSIDQSGGALHGYQLANHVTTLASVGKQCGVOYi

PAAFTSKEDPTTGFADLFALSNVKNVASMREFFSKMKSVIYDKAEGKFAFTFDYLDYNV

KSECGRTLWTVYTVGERFTYSRVNREYVRKVPTDIIYDALQKAGISVEGDLRDRIAESD

GDTLKSIFYAFKYALDMRVENREEDYIQSPVKNASGEFFCSKNAGKSLPQDSDANGAYN

IALKGILQLRMLSEQYDPNAESIRLPLITNKAWLTFMQSGMKTWKN (SEQ ID NO: 110) [001526] >WP_044910713_(modifted) hypothetical protein [Lachnospiraceae bacterium

MC2017] [001527] MGLYDGFVNRYSVSKTLRFELIPQGRTREYIETNGILSDDEERAKDYKTIKRLI DEYHKDYISRCLKNVNISCLEEYYHLYNSSNRDKRHEELDALSDQMRGEIASFLTGNDE

YKEQKSRDniNERIINFASTDEELAAVKRFRKFTSYFTGFFTNRENMYSAEKKSTAIAHRI

IDVNLPKYVDNIKAFNTAIEAGVFDIAEFESNFKAITDEHEVSDLLDITKYSRFIRNEDIIIY

NTLLGGISMKDEKIQGLNELINLHNQKHPGKKVPLLKVLYKQILGDSQTHSFVDDQFED

DQQVINAVKAVTDTFSETLLGSLKHINNIGHYDLDR1YIKAGQDITTLSKRALNDWHIITE

CLESEYDDKFPKNKKSDTYEEMRNRYVKSFKSFSIGRLNSLVTTYTEQACFLENYLGSF

GGDTDKNCLTDFTNSLMEYTHLLNSEYPVTNRLITDYESYRILKRLLDSEMEVIHFLKPL

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LGNGNESDKDLVFYGEFEAEYEKLLPVIKVYNRVRNYLIRKPFSTEKIKLNFNSPTLLCG

WSQSKEKEYMGVILRKDGQYYLGIMTPSNKKIFSEAPKPDEDCYEKMVLRY1PHPYQM

LPKVFFSKSNIAFFNPSDEILRIKKQESFKKGKSFNRDDCHKFIDFYKDSINRHEEWRKFN

FKFSDTDSYED1SRFYKEVENQAFSMSFTKIPTVY1DSLVDEGKLYLFKLHNKDFSEHSK

GKPNLHTVYWNALFSEYNLQNTVYQLNGSAEIFFRKASIPENERVIHKKNVPITRKVAEL

NGKKEVSVFPYDIIKNRRYTVDKFQFHVPLKMNFKADEKKRINDDVIEAIRSNKGIHVIG

IDRGERNLLYLSLINEEGRIIEQRSLNIIDSGEGHTQNYRDLLDSREKDREKARENWQEIQ

EIKDLKTGYLSQAIHTITKWMKEYNAIIVLEDLNDRFTNGRKKVEKQVYQKFEKMLIDK

LNYYVDKDEEFDRMGGTHRALQLTEKFESFQKLGRQTGFIFYVPAWNTSKLDPTTGFV

DLLYPKYKSWATKDFIKKEDFIRFNSEKNYFEFGLHYSNFTERAIGCRDEWffiCSYGNRI

VNFRNAAKNNSWDYKEIDrrKQLLDEFEKNGIDVKQENLIDSICEMKDKPFFKSLIANIK

LILQIRNSASGTDIDYMISPAMNDRGEFFDTRKGLQQLPLDADANGAYNIAKKGLWIVD

QIRNTTGNNVKMAMSNREWMHFAQESRLA (SEQ ID NO: 111) [001528] >KKQ36153 (modified) hypothetical protein US52 C0007G0008 [candidate division WS6 bacterium GW2011 GWA2 37 6] [001529] MKNVFGGFTNLYSLTKTLRFELKPTSKTQKLMKRNNVIQTDEEIDKLYHDEM

KPILDEIHRRFINDALAQKIFISASLDNFLKWKNYKVESAKKNIKQNQVKLLQKEITIKT

LGLRREVVSGFrrVSKKWKDKYVGLGIKLKGDGYKVLTEQAVLDILKIEFPNKAKYIDK

FRGFWTYFSGFNENRKNYYSEEDKATSIANRIVNENLSRYIDNIIAFEEILQKIPNLKKFK

QDLDITSYNYYLNQAGIDKYNKIIGGYIVDKDKKIQGINEKVNLYTQQTKKKLPKLKFLF

KQIGSERKGFGIFEIKEGKEWEQLGDLFKLQRTKINSNGREKGLFDSLRTMYREFFDEIKR

DSNSQARYSLDKIYFNKASVN TISNSWFTNWNKFAELENIKEDKKNGEKKIPEQISIEDIK dslsdpkenleelfkltnrekhdrtrffgsnawvtflniwqneieesfnkleekekdfkk naaikfqknnlvqknyikevcdrmlaiermakyhlpkdsnlsreedfywiidnlseqre iykyynafrnyiskkpynkskniklnfengnllggwsdgqernkagvilrngnkyyeg vlinrgifrtdkinnei yrtg s skwerlilsnlkfqtlagkgflgkhgvs ygnmnpeks V pslqkfirenylkkypqltevsntkflskkdfdaaikealkecftmnfiniaenklleaed kgdlylfeitnkdfsgkksgkdnihtiywkylfsesnckspiiglnggaeiffregqkdkl

HTKLDKKGKKVFDAKRYSEDKLFFHVSrriNYGKPKNIKFRDIINQLITSMNWIIGIDRG

EKHLLYYSVIDSNGIILKQGSLNKIRVGDKEVDFNKKLTERANEMKKARQSWEQIGNIK

NFKEGYLSQAIHEIYQLM]KYNAim.EDLNTEFKAKRLSKVEKSVYKKFELKLARKLNH

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LmKDRNTNEIGGVLKAYQLTPTIGGGDVSKFEKAKQWGMMFYVRANYTSTTDPVTGW RKHLYISNFSNNSVIKSFFDPTNRDTGIEIFYSGKYRSWGFRYVQKETGKKWELFATKEL ERFKYNQTTKLCEKINLYDKFEELFKGIDKSADIYSQLCNVLDFRWKSLVYLWNLLNOI RNVDKNAEGNKNDFIQSPVYPFFDSRRTDGKTEPINGDANGALNIARKGLMLVERIKNN PEKYEQLIRDTEWDAWIQNFNKVN (SEQ ID NO: 112) [001530] >WP_044919442_(modified) hypothetical protein [Lachnospiraceae bacterium MA2020] [001531 ] MYYESLAKQYPVSKTIRNELIPIGKTLDNIRQNNILESDVKRKQNYEHVKGILD

EYHKQLINEALDNCTLPSLKIAAEIYLKNQKEVSDREDFNKTQDLLRKEVVEKLKAHEN

FTKIGKKDILDLLEKLPSISEDDYNALESFRNFYTYFTSYNKVRENLYSDKEKSSTVAYRL

INENFPKFLDWKSYRiWKTAGILADGLGEEEQDSLFlVETFNK TLTQDGIDTYNSQVGKI

NSSINLYNQKNQKANGFRKIPKMKMLYKQILSDREESFIDEFQSDEVLIDNVESYGSVLIE

SLKSSKVSAFFDALRESKGKNVYVKNDLAKTAMSNIVFENWRTFDDLLNQEYDLANEN

KKKDDKYFEKRQKELKKNKSYSLEHLCNLSEDSCNLIENYIHQISDDIENIIINNETFLRIV

INEHDRSRKLAKNRKAVKAJKDFLDSIKVLERELKLINSSGQELEKDLIVYSAHEELLVEL

KQVDSLYNMTRNYLTKKPFSTEKVKLNFNRSTLLNGWDRNKETDNLGVLLLKDGKYY

LGIMNTSANKAFVNPPVAKTEKVFKKVDYKLLPVPNQMLPKVFFAKSNIDFYNPSSE]A^rS

NYKKGTHKKGNMFSLEDCHNLIDFFKESISKHEDWSKFGFKFSDTASYNDISEFYREVE

KQGYKLTYTDIDETYINDLIERNELYLFQIYNKDFSMYSKGKLNLHTLYFMMLFDQRNI

DDVVYKLNGEAEVFYRPASISEDEU1HKAGEEIKNKNPNRARTKETSTFSYD1VKDKRY

SKDKFTLHIPITMNFGVDEVKRFNDAVNSAIRIDENVNVIGIDRGERNLLYWVIDSKGNI

LEQISLNSHNKEYDIETDYHALLDEREGGRDKARK.DWNTVENIRDLKAGYLSQVVNVV

AKLVLKYNAIICLEDLNFGFKRGRQKVEKQVYQKFEKMLIDKLNYLVIDKSREQTSPKE

LGGALNALQLTSKFKSFKELGKQSGVIYYVPAYLTSKIDPTTGFANLFYMKCENVEKSK

RFFDGFDFIRFNALENVFEFGFDYRSFTQRACGINSKWTVCTNGERIIKYRNPDKNNMFD

EKVVVVTDEMKNLFEQYKIPYEDGRNVKDMIISNEEAEFYRRLYRELQQTLQMRNSTSD

GTRDYIISPVKNKREAYFNSELSDGSVPKDADANGAYNIARKGLWVLEQIRQKSEGEKI

NLAMTNAEWLEY AQTHLL (SEQ ID NO: 113) [001532] >WP_035798880_(modified) hypothetical protein [Butyrivibrio sp. NC3005] [001533] MYYQNLTKKYPVSKTIRNELIPIGKTLENIRKNNILESDVKRKQDYEHVKGIM DEYHKQLINEALDNYMLPSLNQAAEIYLKKHVDVEDREEFKKTQDLLRREVTGRLKEH

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ENYTKIGKKDELDLLEKLPSISEEDYNALESFRNFYTYFTSYNKVRENLYSDEEKSSTVAY

RLINENLPKFLDNIKSYAFVKAAGVLADCIEEEEQDALFMVETFNMTLTQEGIDMYNYQI

GKVNSAINLYNQKNHKVEEFKKIPKMKVLYKQILSDREEVFIGEFKDDETLLSSIGAYGN

VLMTYLKSEKINIFFDALRESEGKNVYVKNDLSKTTMSNIVFGSWSAFDELLNQEYDLA

NENKKKDDKYFEKRQKELKKNKSYTLEQMSNLSKEDISPIENYIERISEDIEKICIYNGEF

EKIVVNEHDSSRKLSKNIKAVKVIKDYLDSIKELEHDIKLINGSGQELEKNLVVYVGQEE

ALEQLRPVDSLYNLTRNYLTKKPFSTEKVKLNFNKSTLLNGWDKNKETDNLGILFFKDG

KYYLGIMNTTANKAFVNPPAAKTEm/FKKVDYKLLPGSNKMLPKVFFAKSNIGYYNPS

TELYSNYKKGTHKKGPSFSIDDCHNLIDFFKES1KKHEDWSKFGFEFSDTADYRDISEFYR

EVEKQGYKLTFTDIDESYINDLIEKNELYLFQIYNKDFSEYSKGKLNLHTLYFMMLFDQR

NLDNVVYKLNGEAEVFYRPASIAENELVIHKAGEGIKNKNPNRAKVKETSTFSYDIVKD

KRYSKYKFTLHIPITMNFGVDEVRRFNDVINNALRTDDNVNVIGIDRGERNLLYVWINS

EGKILEQISLNSIINKEYDIETNYHALLDEREDDRNKARKDWNTFENIKELKTGYLSQVVN

WAKLVLKYNAIICLEDLNFGFKRGRQKVEKQVYQKFEKMLIEKLNYLVIDKSREQVSP

EKMGGALNALQLTSKFKSFAELGKQSGIIYYVPAYLTSKIDPTTGFVNLFYIKYENIEKA

KQFFDGFDFIRF'NKKDDMFEFSFDYKSFTQKACGIRSKWIVYTNGERIIKYPNPEKNNLF

DEKVINVTDEIKGLFKQYRIPYENGEDIKEIIISKAEADFYKRLFRLLHQTLQMRNSTSDG

TRDYnSPVKNDRGEFFCSEFSEGTMPKDADANGAYNIARKGLWVLEQIRQKDEGEKVN

LSMTNAEWLKYAQLHLL (SEQ ID NO: 114) [001534] >WP 027109509 (modified) hypothetical protein [Lachnospiraceae bacterium NC2008] [001535] MENYYDSLTRQYPVTKTIRQELKPVGKTLENIKNAEIIEADKQKKEAYVK VK ELMDEFHKSIIEKSLVGIKLDGLSEFEKLYKIKTKTDEDKNRISELFYYMRKQIADALKNS

RDYGYVDNKDLIEKILPERVKDENSLNALSCFKGFTTYFTDYYKNRKNIYSDEEKHSTV

GYRCINENLLIFMSNIEVYQIYKKANIKNDNYDEETLDKTFMIESFNECLTQSGVEAYNS

VVASIKTATNLYIQKNNKEENFVRVPKMKVEFKQILSDRTSLFDGLHESDDELLDKLCSF

SAEVDKFLPINIDRYIKTLMDSNNGTGIYVKNDSSLTTLSNYLTDSWSSIRNAFNENYDA

KYTGKVNDKYEEKREKAYKSNDSFELNYIQNLLG1NV1DKY1ERINFDIKE1CEAYKEM T

KNCFEDHDKTKKLQKNIKAVASlKSYLDSLKNIERDiKLLNGTGLESRNEFFYGEQSTVL

EEITKVDELYNITRNYLTKKPFSTEKMKLNFNNPQLLGGWDVNKERDCYGVILIKDNNY

YLGIMDKSANKSFLNIKESKNENAYKKVNCKLLPGPNKMFPKVFFAKSNIDYYDPTHEI

KKLYDKGTFKKGNSFNLEDCHKLIDFYKESIKKNDDWKNFNFNFSDTKDYEDISGFFRE

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NLKDLCIKMNGEAEVFYRPASILDEDKVVHKANQKII'NKNTNSKKKESIFSYDIVKDKR

YTVDKFFIHLPITLNYKEQNVSRFNDYIREILKKSKNIRVIGIDRGERNLLYVVVCDSDGSI

LY QRS ΓΝΕΪ VSGSHKTDYH KLLDNKEKERLS SRRDWKTIENiKDLK AG YM SQ VVNEIYN

LILKYNAIWLEDLNIGFKNGRKKVEKQVYQNFEKALIDKLNYLCIDKTREQLSPSSPGG

VLNAYQLTAKFESFEKIGKQTGCIFYVPAYLTSQIDPTTGFVNLFYQKDTSKQGLQLFFR

KFKKINFDKVASNFEFVFDYNDFTNKAEGTKTNWTISTQGTRIAKYRSDDANGKWISRT

VHPTDIIKEALNREKINYNDGHDLIDEIVSIEKSAVLKEIYYGFKLTLQLRNSTLANEEEQE

DYIISPVKNSSGNYFDSRITSKELPCDADANGAYNIARKGLWALEQIRNSENVSKVKLAI

SNKEWFEYTQNNIPSL (SEQ ID NO: 1581) [001536] >WP_0292020I8_(modified) hypothetical protein [Oribacterium sp. NK2B42] [001537] MYYDGLTKQYALSKTIRNELVPIGKTLDNIKKNRILEADIKRKSDYEHVKKL

MDMYHKKIINEALDNFKLSVLEDAADIYFNKQNDERDIDAFLKIQDKLRKEIVEQLKGH

TDYSKVGNKDFLGLLKAASTEEDRILIESFDNFYTYFTSYNKVRSNLYSAEDKSSTVAYR l:ineni..pkffdnikayrtwnagvisgdmsiveqdelfevdtfnhtltqygidtynfimig

QLNSAINLYNQKMHGAGSFKKLPKMKELYKQLLTEREEEFIEEYTDDEVLITSVHNYVS

YLIDYI.>NSDKVESFFDTLRKSDGKEATIKNDVSKTTMSNILFDNW^?STIDDLlNIiEYDSAP envkktkddkyfekrqkdlkknksyslskiaalcrdttilekyirrlvddiekiytsnnv

FSDIVLSKHDRSKKLSKNTNAVQAIKNMLDSIKDFEHDVMLINGSGQEIKKNLNVYSEQ

EALAGILRQVDHIYNLTRNYLTKKPFSTEK1KLNFNRPTFLDGWDKNKEEANLGILL1KD

NRYYLGIMNTSSNKAFVNPPKAISNDIYKKVDYKLLPGPNKMLPKVFFATKNIAYYAPS eellskyrkgthkkgdsfsiddcrnlidffkssinkntdwstfgfnfsdtnsyndisdfyr

EVEKQGYKLSFTDIDACYIKDLVDNNELYLFQIYNKDFSPYSKGKLNLHTLYFKMLFDQ

RNLDNVVYKLNGEAEVFYRPASIESDEQIfflKSGQNIKNKNQKRSNCKKTSTFDYDIVKD

RRYCKDKFMLHLPn'VNFGTNESGKFNELVNNAIRADKDVNVIGIDRGERNLLYVVVVD

PCGKIIEQISLNTIVDKEYDIETDYHQLLDEKEGSRDKARKDWNTIENIKELKEGYLSQW

NnAKLVLKYDAIICLEDLNFGFKRGRQKVEKQVYQKFEKMLlDKMNYLVLDKSRKQES

PQKPGGALNALQLTSAFKSFKELGKQTGIIYYVPAYLTSKIDPTTGFANLFYIKYESVDK

ARDFFSKFDF1RYNQMDNYFEFGFDYKSFTERASGCKSKWIACTNGERIVKYRNSDKNN

SFDDKTVILTDEYRSLFDKYLQNYIDEDDLKDQILQIDSADFYKNLIKLFQLTLQMRNSSS

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DGKRDYIISPVKNYEEEFFCSEFSDDTFPRD AD ANGAYNIARKGLWVIKQIKETKSGTKI NLAMSNSEWLEYAQCNLL (SEQ ID NO: 115) [001538] >WP 028248456 (modified) hypothetical protein [Pseudobutyrivibrio ruminis] [001539] MYYQNLTKMYPISKTLRNELIPVGKTLENIRKNG1LEADIQRKADYEHVKKL MDNYHKQLINEALQGVHLSDLSDAYDLY [001540] FNLSKEKNSVDAFSKCQDKLRKEIVSLLKNHENFPKIGNKEIIKLLQSLYDNDT DYKALDSFSNFYTYFSSYNEVRKNLYSDEEKSSTVAYRLINENLPKFLDNIKAYAIAKKA

GVRAEGLSEEDQDCLFIIETFERTLTQDGIDNYNAAIGKLNTAINLFNQQNKKQEGFRKV

PQMKCLYKQILSDREEAFIDEFSDDEDLITNIESFAENMNVFLNSEIITDFKIALVESDGSL

VYIKNDVSKTSFSNTVFGSWNAIDEKLSDEYDLANSKKKKDEKYYEKRQKELKKNKSY

DLETnGLFDDNSDVIGKYlEKLESDlTAIAEAKNDFDEIVLRKHDKNKSLRKNTNAVEAI

KSYLDTVKDFERDIKLINGSGQEVEKNLWYAEQENILAEIKNVDSLYNMSRNYLTQKP

FSTEKFKLNFNRA TLLNGWDKNKETDNLGILFEKDGMYYLGIMNTKANKIFVNIPKATS

NDVYHKVNYKLLPGPNKMLPKVFFAQSNLDYYKPSEELLAKYKAGTHKKGDNFSLED

CHALIDFFKASIEKHPDWSSFGFEFSETCTYEDLSGFYREVEKQGYKITYTDVDADYITSL

VERDEL YLFQIYNKDFSPYSKGNLNLHTIYLQMLFDQRNLNNWYKLNGEAEVFYRPAS

INDEEVIfflKAGEEIKNKNSKRAVDKPTSKFGYDIIKDRRYSKDKFMLHIPVTMNFGVDE

TRRFNDWNDALRNDEKVRVIGIDRGERNLLYWWDTDGTILEQISLNSIINNEYSIETD

YHKLLDEKEGDRDRARKNWTTIENIKELKEGYLSQWNVIAKLVLKYNAIICLEDLNFG

FKRGRQKVEKQVYQKFEKMLIDKLNYLV1DKSRKQDKPEEFGGALNALQLTSKFTSFK

DMGKQTGIIYYVPAYLTSKIDPTTGFANLFYVKYENVEKAKEFFSRFDSISYNNESGYFE

FAFDYKKFTDRACGARSQWTVCTYGERIIKFRNTEKNNSFDDKTIVLSEEFKELFSIYGIS

YEDGAELKNKIMSVDEADFFRSLTRLFQQTMQMRNSSNDVTRDYIISPIMNDRGEFFNSE

ACDASKPKDADANGAFNLARKGLWVLEQIRNTPSGDKLNLAMSNAEWLEYAQRNQI (SEQ ID NO: 116) [001541] >WP 028830240 (modified) hypothetical protein [Proteocatella sphenisci] [001542] MENFKNLYPINKTLRFELRPYGKTLENFKKSGLLEKDAFKANSRRSMQAIIDE

KFKETIEERLKYTEFSECDLGNMTSKDKKITDKAATNLKKQVILSFDDEIFNNYLKPDKN

IDALFKNDPSNPVISTFKGFTTYFVNFFEIRKHIFKGESSGSMAYRIIDENLTTYLNNIEKIK

KLPEELKSQLEGIDQIDKLNNYNEFITQSGITHYNEIIGGISKSENVKIQGINEGINLYCQKN

KVKLPRLTPLYKMILSDRVSNSFVLDTIENDTELIEMISDLrNKTEISQDVIMSDIQNIFIKY

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KQLGNLPGIS Y S SIVNAIC SD YDNNFGDGKRKKS YENDRKKI-foETNVYSINYISELLTDT

DVSSNIKMRYKELEQNYQVCKENFNATNWMN1KN1KQSEKTNL1KDLLDILKSIQRFYD

LFDIVDEDKNPSAEFYTWLSKNAEKLDFEFNSVYNKSRNYLTRKQYSDKKIKLNFDSPT

LAKGWDANKEIDNSTnMRKFNNDRGDYDYFLGiWNKSTPANEKnPLEDNGLFEKMQY

KLYPDPSKMLPKQFLSKIWKAKHPTTPEFDKKYKEGRHKKGPDFEKEFLHELIDCFKHG

LVNHDEKYQDVFGFNLRN TEDYNSYTEFLEDVERCNYNLSFNKLADTSNLINDGKLYVF

QIWSKDFSIDSKGTKNLNTIYFESLFSEENMIEKMFKLSGEAEIFYRPASLNYCEDIIKKGH

HHAELKDKFDYPIIKDKRYSQDKFFFHVPMVINYKSEKLNSKSLNNRTNENLGQFTHIIGI

DRGERHLIYLTVVDVSTGEIVEQKHLDEirN TDTKGVEHKl'HYLNKLEEKSKTRDNERKS

WEAIETIKELKEGYISHVINEIQKLQEKYNALIVMENLNYGFKNSRIKVEKQVYQKFETA

LIKKFNYIIDKKDPETYIHGYQLTNPITTLDKIGNQSGIVLYiPAWNTSKIDPVTGFVNLLY

ADDLKYKNQEQAKSFIQKIDNIYFENGEFKFDIDFSKWNNRYSISKTKWTLTSYGTRIQT

FRNPQKNNKWDSAEYDLTEEFKLILNIDGTLKSQDVETYKKFMSLFKLMLQLRNSVTGT

DIDYMISPVTDKTGTHFDSRENIKNLPADADANGAYNIARKGIMAIENIMNGISDPLKISN

EDYLKYIQNQQE (SEQ ID NO: 117) [001543] Applicants generated vector constructs as shown in Figures 40A-L (e.g. PACYC184 fnCpfl (PY001)) and Figures 41A-E (e.g. PaCpfl).

[001544] PAM Challenge Assay for detection of putative PAM sequences for FnCpfl (Figure 42): Applicants isolated the Cpfl loci from Francisella novicida (Fn) (Figure 43) and transformed it into E.coli. The locus was expressed in E.coli from pACYC184 similar to the experiment described in Sapranauskas et al.

E.coli with pACYC-FnCpfl locus ^:;= Cpfl +

E.coli with empty pACYC184 = control [001545] Applicants transformed Cpfl+ and control E.coli with ΡΑΜΙ library plasmids. Two PAM libraries were obtained (Figure 44). ΡΑΜΙ libraries are pUC19 plasmids containing a 31 bp proto-spacer sequence which matches spacer 1 in FnCpfl locus. PAM left library had a 8 nt degenerate ΡΑΜΙ at the 5’ end of the proto-spacer. ΡΑΜΙ right library had a 7 nt degenerate PAM at the 3’ end of the proto-spacer. Applicants plated Cpfl+ and control E.coli and harvested all colonies after ~12h. Each colony represented a PAMI-pUC19 transformation event that did not result in cutting/interference by Cpfl. These PAM-pUC19 plasmids do not carry a recognizable PAM. Applicants determined from sequencing of all colonies which PAM-pUC19 plasmids were

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[001546] Cloning of pYOOOl: pYOOOl is a pACYC184 backbone (from NEB) with a partial FnCpfl locus. pYOOOl contains the endogenous FnCpfl locus from 255bp of the acetyltransferase 3’ sequence to the 4th spacer sequence. Only spacer 1-3 are potentially active since spacer 4 is not longer flanked by direct repeats.

[001547] Applicants PCR amplified the FnCpfl locus in 3 pieces and cloned into Xbal & Hind3 cut pACYC184 using Gibson assembly.

[001548] Cpfl PAM Screen Computational Analysis

After sequencing of the screen DNA, Applicants extracted the regions corresponding to either the left PAM or the right PAM. For each sample, the number of PAMs present in the sequenced library were compared to the number of expected PAMs in the library (4^Λ8 for the left library, 4^Λ7 for the right).

The left library showed PAM depletion. To quantify this depletion, Applicants calculated an enrichment ratio. For both conditions (control pACYC or FnCpfl containing pACYC), Applicants calculated the ratio for each PAM in the library as:

, sample 4- 0,01 ratio = ~~ logo ““ initial library + 0,01 [001549] Applicants determined that plotting the distribution showed little enrichment in the control sample and enrichment in both bioreps. Applicants collected all PAMs above a ratio of 8, and plotted the frequency distributions, revealing a 5’ YYN PAM (Figures 45A-E). Applicants confirmed that the PAM is TTN, where N is A/C/G or T.

[001550] Applicants performed RNA-sequencing on Francisella tolerances Cpfl locus and the RNAseq analysis showed that the CRISPR locus was actively expressed (Figure 46). A further depiction of the RNAseq analysis of the FnCpfl locus is shown in Figure 86. In addition to the Cpfl and Cas genes, two small non-coding transcripts were highly transcribed, which Applicants surmised were putative tracrRNAs. The CRISPR array is also expressed. Both the putative tracrRNAs and CRISPR array are transcribed in the same direction as the Cpfl and Cas genes. Here all RNA transcripts identified through the RNAseq experiment are mapped against the locus. Zooming into the Cpfl CRISPR array Applicants identified many different short transcripts. In this plot, all identified RNA transcripts are mapped against the Cpfl locus (Figure

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47). After selecting transcripts that are less than 85 nucleotides long, Applicants identified two putative tracrRNAs (Figure 48). Figure 49 shows a zoomed in perspective of putative tracrRNA I and the CRISPR array. Figure 50 shows a zoomed in perspective of putative tracrRNA 2. Putative crRNA sequences are indicated in Figure 51.

[001551] Applicants test for function in mammalian cells using U6 PCR products: spacer (DRspacer-DR) (in certain aspects spacers may be referred to as crRNA or guide RNA or an analogous term as described in this application) and tracr for other identified Cpfl loci.

Example 4: Further validation experiments for FnCpfl [001552] Applicants confirmed the predicted FnCpfl PAM is TTN in vivo by using the assay outlined in Figure 52. Applicants transformed FnCpfl locus carrying cells and control cells with pUC19 encoding endogenous spacer 1 with 5’ TTN PAM (Figure 53). Briefly, in the in vivo PAM confirmation assay, 50 μ! of competent E.coli with FnCpfl locus (test strain) or with empty pACYC184 (control strain) were transformed wdth lOng proto-spacer 1 carrying plasmids. Preceding the proto-spacer sequence are predicted PAM sequences (TTC, TTG, TTA and TTT). After transformation cells were diluted 1:2000 and plated on LB agar plates containing ampicillin and chloramphenicol. Only cells wdth intact proto-spacer plasmid can form colonies. Plates with colonies were imaged ~14h after plating and colonies were counted using the Image! software.

[001553] Applicants performed Cell Lysate Cleavage Assays to further validate FnCpfl cleavage. The protocol for the cell lysate cleavage assay is as follows:

[001554] In vitro cleavage reaction. Cleavage buffer: 100 mM HEPES pH 7.5, 500 mM KC1, 25 mM MgC12, 5 mM DTT, 25% glycerol. The stock may be made without DTT.

[001555] Making cell lysate [001556] Lysis buffer: 20 mM Hepes pH 7.5, 100 mM potassium chloride [KC1], 5 mM magnesium chloride [MgCh], 1 mA! dithiothreitol [DTT], 5% glycerol, 0.1% Triton X-100, supplemented wdth lOx Roche Protease Inhibitor cocktail. Concentrated stock of lysis buffer w/o Roche Protease Inhibitor and DTT may be maintained. Keep at -20°C.

[001557] Transfect HEK cells wdth recommended amount of DNA wdth Lipofectamine 2000

- 500ng per 24 well

- 2000ng per 6 well [001558] Harvest cells wdth lysis buffer 24-72 hours post transfection

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- Aspirate off media

- Wash gently with DPBS

- Aspirate off DPBS

- Use 50ul of lysis buffer per 24 well or 250ul per 6 well

- Let sit on ice for 5min

- Transfer into Eppendorf tube

- Ice for 15 minutes

- Sonicate at high power, 50% duty cycle for 5-10min

- Spin down cold at max speed for 20min

- Transfer supernatant to new tube

- Aliquot in PCR strip tubes, lOul per strip and freeze at -80C [001559] In vitro transcription of guide RNA [001560] Kit protocol: Information may be accessed at the website www.neb.com/products/e2030-hiscribe-t7-in-vitro-transcription-kit

Take lOOuM stock oligo

Anneal in lOul reaction:

lul of T7 “forward” strand == “XRP2649” lul of T7 “reverse” oligo lul TaqB buffer

7ul water [001561] Run the PNK PCR program without the 37°C incubation step (basically heat up to 95°C for 5min and do slow cool to 4°C but not as slow as surveyor anneal). Nanodrop annealed oligos: normalize with water to 500ng/ul (usually 1000-2000ng/ul for a 120nt oligo) [001562] For T7 transcription follow kit instructions (but cut down size by 4x) [001563] 1 Oul reaction lul 1 Ox buffer lul T7 transcriptase

0.5ulrNTP

0.5ui BMW mix lul DNA template (annealed)

6ul water

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PCT/US2016/038181 [001564] Transcribe in 42°C (preferably thermocycler) for at least 2-3 hours, let run overnight. Yield should be around 1000-2000ng/ul of RNA. It is normal for white residues to form.

[001565] Preparation of DNA

For pUC19, linearize with Hindlll and column purify

--> will need 300-400ng of plasmid per reaction, so cut amount necessary

For gDNA, amplify wt cell DNA with PCR —> do several PCR reactions, pool and column purify concentrate the product so around 100-200ng/ul

Keep at -20C [001566] 20ul reaction lOul of lysate (this is pre-aliquoted)

2ul of cleavage buffer (NEB buffer 3) lul of RNA (directly from above, don’t need to purify) lul of DNA (from above)

6ul of water

Incubate at 37°C for 1-2 hour (30min is enough) [001567] Column purify the reaction [001568] Run out on a 2% E-gel [001569] The cell lysate cleavage assay used tracrRNA at positions 1, 2, 3, 4 and 5 as indicated in Figure 54, Cell Lysate Cleavage Assay (1) (Figure 55) is a gel indicating the PCR fragment with a TTa PAM and proto-spacer 1 sequence incubated in cell lysate. Cell Lysate Cleavage Assay (2) (Figure 56) is a gel showing the pUC-spacerl with different PAMs incubated in cell lysate. Cell Lysate Cleavage Assay (3) (Figure 57) is a gel showing the BasI digestion after incubation in cell lysate. Cell Lysate Cleavage Assay (4) (Figure 58) is a gel showing digestion results for three putative crRNA sequences.

[001570] Applicants also determined the effect of spacer length on cleavage efficiency. Applicants tested different lengths of spacer against a piece of target DNA containing the target site: 5'-TTAgagaagtcatttaataaggccactgttaaaa-3' (SEQ ID NO: 119). For this experiment, pUC19 plasmid containing the spacer (5’-TTcgagaagucauuuaauaaggccacuguuaaaa-3’ (SEQ ID NO: 120)) was treated to the following conditions:

2ul cell lysate containing Cpfl

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2ul pUC19 DNA with spacer (300ng) lul crRNA (500 ng)

2ul NEBuffer 3

2ul 40mM DTT

0.3ul Bsal

I0.7ul ddH20 [001571] Incubated at 37C for 30 minutes, followed by treatment with RNase for 5 minutes. Then the reaction was cleaned up using Qiagen PCR Purification Kit and analyzed on 2% Invitrogen E-gel EX. Figure 59 is a gel showing that crRNAs 1-7 mediated successful cleavage of the target DNA in vitro with FnCpfl, whereas crRNAs 8-13 did not facilitate cleavage of the target DN A.

[001572] Applicants arrived at the minimal Fn Cpfl locus (Figure 60) and also elucidated the minimal Cpfl guide (Figure 61), Applicants also cleaved a PCR amplicon of the human Emxl locus (Figure 81). The EMX amplicon was treated to the following conditions:

2ul cell lysate containing Cpfl

3ul pUC 19 DNA with spacer (3OOng) lul crRNA (500 ng)

2ul NEBuffer 3

2ul 40mM DTT

0.3ui Bsal

9.7ul ddH₂O [001573] Incubated at 37°C for 30 minutes, followed by treatment with RNase for 5 minutes.

Then the reaction was cleaned up using Qiagen PCR Purification Kit and analyzed on 2% Invitrogen E-gel EX.

[001574] Applicants further studied the effect of truncation in 5’ DR on cleavage activity (Figure 82A-B). For this experiment, pUC19 plasmid containing the spacer (5’TTcgagaagucauuuaauaaggccacuguuaaaa-3’ (SEQ ID NO: 121)) was treated to the following conditions:

2ul cell lysate containing Cpfl

2ul pUC 19 DNA with spacer (3 OOng) lul crRNA (500 ng)

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2ul NEBuffer 3

2ul 40mM DTT

0.3ul Bsal

10,7u! ddH20 [001575] Incubated at 37°C for 30 minutes, followed by treatment with RNase for 5 minutes.

Then the reaction was cleaned up using Qiagen PCR Purification Kit and analyzed on 2% Invitrogen E-gel EX. Applicants determined that crDNA deltaDRS disrupted the stem loop at the 5’ end and this shows that the stemloop at the 5’ end is essential for cleavage activity (Figure

82B).

[001576] Applicants investigated the effect of crRNA-DNA target mismatch on cleavage efficiency (Figure 83). For this experiment, pUC19 plasmid containing the spacer (5’TTcgagaagucauuuaauaaggccacuguuaaaa-3’ (SEQ ID NO: 122)) was treated to the following conditions:

2ul cell lysate containing Cpfl

2ul pUC19 DNA with spacer (300ng) lul crRNA (500 ng)

2ul NEBuffer 3

2ul 40mM DTT

0.3ul Bsal

10.7ul ddH2O [001577] Incubated at 37C for 30 minutes, followed by treatment with RNase for 5 minutes. Then the reaction was cleaned up using Qiagen PCR Purification Kit and analyzed on 2% Invitrogen E-gel EX. Each lane in the gel shown in Figure 83 consists of Cpfl-containing cell lysate, pUC19 with TTc protospacer, and the corresponding crRNA, indicated as 1-11.

[001578] Applicants studied the FnCpflp RuvC domain and have identified amino acid mutations that may convert the FnCpfl effector protein into a nickase, whereby the effector protein has substantially reduced nuclease activity and only one strand of DNA is nicked and/or cleaved. The amino acid positions in the FnCpflp RuvC domain include but are not limited to D917A, E1006A, E1028A, D1227A, D1255A, N1257A, D917A, E1006A, E1028A, D1227A, D1255A and N1257A. The amino acid positions in AsCpfl correspond to AsD908A, AsE993A, AsD1263A. The amino acid positions in LbCpfl correspond to LbD832A

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PCT/US2016/038181 [001579] Applicants have also identified a putative second nuclease domain which is most similar to PD-(D/E)XK nuclease superfamily and Hindi endonuclease like. The point mutations to be generated in this putative nuclease domain to substantially reduce nuclease activity include but are not limited to N580A, N584A, T587A, W609A, D610A, K613A, E614A, D616A, K624A, D625A, K627A and Y629A.

[001580] Applicants perform plasmid cleavage experiments with FnCpflp and sequencing of said plasmids will provide information as to whether the cut site is sticky or blunt. Applicants will elucidate further details on the various domains of FnCpflp from the crystal structure of this protein in a suitable complex. For optimization of FnCpfl loci components for activity in human cells. Applicants will tty different architectures of crRNAs and try more targets than described herein, [001581] Applicants cleaved DNA using purified Francisella and Prevotella Cpfl (Figure 84). For this experiment, pUC19 plasmid containing the spacer (5’TTcgagaagucauuuaauaaggccacuguuaaaa-3’ (SEQ ID NO: 123)) was treated to the following conditions:

2ul purified protein solution

2ul pUC19 DNA with spacer (300ng) lul crRNA (500 ng)

2ul NEBuffer 3

2ul 40mM DTT

0.3ul Bsal

10,7u! ddH2O [001582] Incubated at 37°C for 30 minutes, foHovved by treatment with RNase for 5 minutes.

Then the reaction was cleaned up using Qiagen PCR. Purification Kit and analyzed on 2% Invitrogen E-gel EX. Alaysis of the gel shown in Figure 84 indicates that PaCpfl can work with FnCpfl crRNA, although the activity is not as high as FnCpfl. Applicants concluded that this makes sense given the the stem-loop sequences for PaCpfl and FnCpfl are almost identical (only 1 base difference) (see Figures 85A-B). This is further highlighted in the mature crRNA sequences for FnCpfl and PaCpfl shown in Figures 87A-B, In preferred embodiments of the invention, biochemical or in vitro cleavage may not require a tracr sequence for effective

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PCT/US2016/038181 function of a Cpflp CRISPR system. Inclusion of a stem loop or a further optimized stem loop strusture is important for cleavage activity.

[001583] DNA cleavage by human codon optimized Francisella novicida FnCpflp.

[001584] Applicants also showed that FnCpflp cleaves DNA in human cells. 400ng human codon optimized FnCpflp and lOOng U6::crRNA were transfected per well of HEK293T cells (-240,000 cells) in 24 well plates. Five crRNAs comprising spacer sequences of length 20-24nt based on 5’-ctgatggtccatgtctgttactcg-3’ (SEQ ID NO: 124) (i.e., the first 20, 21, 22, 23, or all 24 nt) were employed. The crRNAs further comprised 20nt of the 5’ repeat sequence of PaCpfl at the 5’ of the spacer. Applicants earlier determined that the repeat seqence from PaCpfl can be recognized by FnCpf l.

[001585] DNA was harvested after ~60h and analyzed by SURVEYOR nuclease assay. The SURVEYOR primers for DNMT1 were 5’-ctgggactcaggcgggtcac-3’ (SEQ ID NO: 125) (forward) and 5’-cctcacacaacagcttcatgtcagc-3’ (SEQ ID NO: 126) (reverse). Cleaved DNA fragments coinciding with expected cleavage products of ~345bp and ~261bp were observed for all five crRNAs (spacer lengths 20-24nt). (Figure 88).

Example 5: Further validation experiments for PaCpfl [001586] A PAM computational screen was performed for Prevotella albensis Cpfl(PaCpfl) similar to the screen performed for FnCpfl as detailed in Example 3. After sequencing of the screen DNA, the regions corresponding to either the left PAM or the right PAM were extracted. For each sample, the number of PAMs present in the sequenced library' were compared to the number of expected PAMs in the library⁷ (4^Λ7). The left library showed very slight PAM depletion. To quantify this depletion, an enrichment ratio was calculated. For both conditions (control pACYC or PaCpfl containing pACYC) the ratio was calculated for each PAM in the library as ratio log sample 4- 0.01 initial library + 0.01 [001587] [001588] Plotting the distribution shows little enrichment in the control sample and enrichment in both bioreps. All PAMs above a ratio of 4.5 were collected, and the frequency distributions were plotted, revealing a 5’ TTTV PAM, where V is A or C or G (Figure 62A-E).

[001589] Applicants will elucidate further details on the various domains of PaCpflp from the crystal structure of this protein in a suitable complex. For optimization of PaCpfl loci

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PCT/US2016/038181 components for activity in human cells, Applicants will work with different crRNA (guideRNA) architectures and different optimized PaCpfl effector proteins. Applicants have human codon optimized the PaCpfl sequence as follows:

[001590] NLS (underline) [001591] GS linker (bold) [001592] 3xHA tag (italics) [001593] AT GGC C C C A A AG A AG A AGC GGAA GGT C GGT AT C C A C GGAGTC C C A GC AG

CCggtagtAACATCAAAAACTTTACCGGGCTCTACCCCCTCAGCAAAACTTTGCGCTTT

GAACTCAAGCCTATTGGCAAAACCAAGGAAAACATCGAGAAAAATGGCATCCTGAC

CAAGGACGAGCAACGGGCTAAAGACTACCTCATAGTCAAAGGCTTTATTGACGAGT

ATCACAAGCAGTTCATCAAAGACAGGCTTTGGGACTTTAAATTGCCTCTCGAAAGTG

AGGGGGAGAAGAACAGTCTCGAAGAATACCAGGAACTGTACGAGCTCACTAAGCGC

AACGATGCCCAGGAGGCCGACTTCACCGAGATTAAAGATAACCTTCGCAGCTCTATT

ACCGAACAGCTCACGAAGTCTGGATCTGCGTACGATCGGATTTTTAAAAAAGAGTTC

ATTAGAGAAGACCTGGTCAACTTCCTCGAAGATGAAAAAGATAAAAATATCGTGAA

ACAGTTCGAGGACTTTACTACATATTTTACGGGTTTTTATGAAAATAGGAAGAACAT

GTACTCTAGCGAAGAGAAGTCCACGGCCATCGCATACCGGCTTATCCATCAGAATCT

GCCAAAATTCATGGACAACATGAGAAGTTTTGCCAAAATTGCAAATTCCAGTGTTTC

CGAGCACTTTAGCGACATCTATGAAAGCTGGAAGGAATATCTGAATGTAAATAGCA

TCGAGGAAATCTTCCAGCTCGACTATTTTAGCGAAACCTTGACTCAGCCACATATTG

AGGTGTATAACTATATTATCGGGAAGAAAGTCCTGGAAGACGGAACCGAGATAAAG

GGCATCAACGAGTATGTGAACCTCTACAATCAGCAGCAGAAAGATAAGAGTAAACG

ACTGCCTTTCCTGGTGCCACTGTATAAGCAAATTTTGTCTGATAGGGAAAAACTCTC

CTGGATTGCTGAAGAGTTCGACAGCGACAAGAAGATGCTGAGCGCTATCACCGAGT

CTTACAACCACCTGCACAACGTGTTGATGGGTAACGAGAACGAAAGCCTGCGAAAT

CTGCTGCTGAATATTAAGGACTATAACCTGGAGAAAATTAATATCACAAACGACTTG

TCTCTCACCGAAATCTCCCAGAATCTTTTTGGCCGATATGATGTATTCACAAATGGG

ATCAAAAACAAGCTGAGAGTGTTGACTCCAAGGAAGAAAAAGGAGACGGACGAAA

ATTTTGAGGACCGCATTAACAAAATTTTTAAGACCCAGAAGTCCTTCAGCATCGCTT

TTCTGAACAAGCTGCCTCAGCCCGAAATGGAGGATGGGAAGCCCCGGAACATTGAG

GACTATTTCATTACACAGGGGGCGATTAACACCAAATCTATACAGAAAGAAGATAT

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CTTCGCCCAAATTGAGAATGCATACGAGGATGCACAGGTGTTCCTGCAAATTAAGG

ACACCGACAACAAACTTAGCCAGAACAAGACGGCGGTGGAAAAGATCAAAACTTTG

CTGGACGCCTTGAAGGAACTCCAGCACTTCATCAAACCGCTGCTGGGCTCTGGGGA

GGAGAACGAGAAAGACGAACTGTTCTACGGTTCCTTCCTGGCCATCTGGGACGAAC

TGGACACCATTACACCACTTTATAACAAAGTGAGAAATTGGCTGACCCGAAAACCA

TATTCAACAGAAAAAATCAAATTGAATTTCGACAACGCTCAGCTGCTGGGAGGGTG

GGA I’GTC AATAAAGAACACGACTGTGC AGGT A TC TI GT IGCGGAAAAACGATAGCT

ACTATCTCGGAATTATCAATAAGAAAACCAACCACATCTTTGATACGGATATTACGC

CATCAGATGGCGAGTGCTATGACAAAATCGACTACAAGCTCCTTCCCGGGGCGAAC

AAAATGCTTCCAAAGGTGTTTTTTAGTAAGTCCCGAATCAAAGAGTTCGAGCCATCA

GAGGCCATAATCAATTGCTATAAGAAGGGGACACACAAAAAAGGAAAAAACTTTAA

CCTGACGGACTGTCACCGCCTGATCAACTTTTTTAAGACCTCAATCGAGAAACACGA

GGATTGGTCAAAATTCGGATTCAAGTTCTCCGATACCGAAACGTATGAGGATATTAG

CGGTTTTTATAGAGAGGTCGAGCAGCAGGGATACAGGCTGACGAGCCATCCAGTCA

GTGCCAGCTATATACATAGTCTGGTCAAGGAAGGAAAACTGTACCTCTTCCAAATCT

GGAACAAGGACTTTTCTCAATTCTCCAAGGGGACCCCTAACTTGCACACTCTCTATT

GGAAGATGCTGTTTGACAAACGGAATCTTAGCGATGTGGTTTATAAGCTGAATGGCC

AGGCTGAAGTGTTCTATAGAAAGAGCTCCATTGAACACCAGAACCGAATTATCCAC

CCCGCTCAGCATCCCATCACAAATAAGAATGAGCTTAACAAAAAGCACACTAGCAC

CTTCAAATACGATATCATCAAAGATCGCAGATACACGGTGGATAAATTCCAGTTCCA

TGTGCCCATTACTATAAATTTTAAGGCGACCGGGCAGAACAACATCAACCCAATCGT

CCAAGAGGTGATTCGCCAAAACGGTATCACCCACATCATAGGCATCGATCGAGGTG

AACGCCATCTTCTGTACCTCTCTCTCATCGATTTGAAAGGCAACATCATCAAGCAGA

TGACTCTCAACGAAATTATTAATGAGTATAAGGGTGTGACCTATAAGACCAACTACC

ATAACCTCCTGGAGAAGAGGGAGAAGGAGCGGACCGAGGCCAGACACTCCTGGAG

TAGTATTGAAAGCATAAAAGAACTGAAGGATGGATACATGTCACAGGTGATTCACA

AAATTACGGACATGATGGTTAAGTACAATGCGATTGTGGTCCTGGAGGACCTCAAC

GGGGGGTTTATGCGAGGCCGCCAGAAGGTCGAGAAGCAGGTGTACCAGAAATTTGA

AAAAAAGTTGATCGACAAGCTGAACTATCTCGTTGACAAGAAACTCGACGCTAACG

AGGTCGGCGGAGTACTGAATGCTTATCAGCTGACCAACAAGTTCGAGTCTTTCAAGA

AGATTGGGAAACAAAGCGGATTTTTGTTCTACATCCCCGCCTGGAACACAAGCAAA

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ATCGATCCTATAACAGGGTTCGTTAATCTGTTCAACACCAGGTACGAGTCTATCAAG

GAGACAAAAGTTTTTTGGTCTAAGTTTGATATTATCCGATACAATAAAGAGAAGAAT

TGGTTCGAGTTCGTCTTCGATTACAATACCTTTACGACTAAAGCGGAGGGAACACGC

ACTAAGTGGACTCTGTGCACCCACGGCACTCGCATCCAGACATTCCGGAACCCAGA

AAAGAATGCCCAGTGGGACAATAAAGAGATCAATTTGACTGAGTCCTTCAAAGCTC

TGTTTGAAAAGTACAAGATCGATATCACCAGTAATCTCAAGGAATCCATCATGCAGG

AAACCGAGAAGAAGTTCTTCCAGGAACTGCATAATCTGCTCCACCTGACCCTGCAG

ATGAGGAATAGCGTTACTGGAACCGACATAGACTATTTGATCAGCCCCGTTGCCGAT

GAGGATGGAAATTTCTATGATAGTCGCATAAATGGCAAAAATTTTCCGGAGAATGC

CGATGCCAATGGCGCGTACAACATCGCACGAAAGGGTCTGATGCTTATTCGGCAGA

TCAAGCAAGCAGATCCACAGAAGAAATTCAAGTTTGAGACAATCACCAATAAAGAC

TGGCTGAAATTCGCCCAAGACAAGCCCTATCTTAAAGATggcagcgggAAAAGGCCGGC

GGCC ACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGggatcc/HCCCri TACGA TGT'T

CCAGATTACGCTTA TCCCTACGACGTGCCTGA TTA TGCA TACCCA TACGA TGTCCCCGACT

ATGCCTAA. (SEQ ID NO: 127) [001594] The vector map for human codon optimized PaCpfl sequence is provided in Figure 63.

Example 6: Cpfl orthologs [001595] Applicants analyzed an expanding pool of Cpfl orthologs (Figure 64). Human codon optimized sequences were obtained for several Cpfl loci components (Figures 65-79). Applicants also arrived at the Direct Repeat (DR) sequences for each ortholog and their predicted fold structure (Figure 80A-I).

[001596] Applicants further study Cpfl orthologs based on size of the effector protein, i.e. smaller effector proteins allow for easier packaging into vectors and on PAM composition. All aspects allow for further optimization in prokaryotic and eukaryotic cells, preferably for effective activity in mammalian cells, i.e. human cells.

[001597] Applicants showed that the effector protein orthologs of the following loci showed activity in the in vitro cleavage assay: Peregrinibacteria bacterium GW2011 _GWA2__33 10 Cpfl, Acidaminococcus sp. BV3L6 Cpfl, Francisalla tularensis 1 Cpfl, Moraxella bovocuii 237 Cpfl, Lachnospiraceae bacterium ND2006 Cpfl, Lachnospiraceaa bacterium MA2020 Cpfl,

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Porphyromonas macacee Cpfl, Porphyromonas crevlorlcanls 3 Cpfl, Prevotella albensis Cpfl (Figure 64).

[001598] In the in vitro cleavage assay by orthologs, HEK293 cells expressing Cpfl orthologs were harvested and the lysate was incubated with predicted mature crRNA targeting an artificial spacer cloned into the pUC19 plasmids. The spacer was preceded by 8 degenerate bases to allow for determination of the PAM via sequencing. The lower bands signify cleavage by the Cpfl enzyme (Figure 89).

[001599] Applicants identified computationally derived PAMs from the in vitro cleavage assay (Figure 90). Uncut DNA from Figure 89 (the higher band) was excised and amplified for next generation sequencing. The abundance of each 8-mer was calculated and the log ratio compared to the input library was used to quantify enrichment. Individual 8-mers with a log ratio greater than 4 were compiled and used to determine the consensus PAM using Weblogo.

[001600] Applicants further identified that Cpflp effector proteins cut in a staggered fashion with 5’ overhangs. Purified FnCpfl protein was harvested and incubated with crRNA and the corresponding target cloned into pUC19. The cleaved product was gel extracted and submitted for Sanger sequencing. The asymmetric reads show that there is a staggered cut (Figure 91). In a preferred embodiment of the invention, Applicants demonstrate in vivo staggered ligation with a template (e.g. an exogenous template).

[001601] Applicants also determined the effect of spacer length on the cutting ability of the effector protein (Figure 92) , Purified FnCpfl protein was harvested and incubated with crRNA and the corresponding target cloned into pUC19. Spacer lengths greater than 17 nt cut to completion, while the 17 nt spacer shows reduced activity and spacers less than 17 nt are not active.

[001602] Applicants demonstrated that FnCpfl mediates indel formation in I?IEK293T cells. [001603] -280,000 HEK cells/ 24 well were transfected with 350ng of huFnCpfl plasmid and 150ng U6::crRNA. Cells were harvested three days after transfection and analyzed by SURVEYOR nuclease assay. Uncleaved PCR fragment size is 606bps. Expected fragment sizes are ~418bp and ~188bp for crRNA DNMT1-1 and ~362bp and ~244bp for crRNA DNMT1-3 (Figure 93) .

[001604] DNMT1-1 spacer sequence: cctcactcctgctcggtgaattt (SEQ ID NO: 128) [001605] DNMT1-3 spacer sequence: ctgatggtccatgtctgttactc (SEQ ID NO: 129)

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PCT/US2016/038181 [001606] Applicants identified the required components of the Cpfl system to achieve cleaveage by determining if transcripts were processed when certain sequences of the locus were deleted (Figure 94A-F). The deleted sequences may include but are not limited to the Cast gene, the Cas2 gene and the tracr. Hence, in a preferred embodiment of the invention, Applicants demonstrated that the tracr is not a required component of a functional Cpfl system or complex to achieve cleavage.

Example 7: Procedures

Generation of heterologous plasmids [001607] To generate the FnCpfl locus for heterologous expression, genomic DNA from Francisella. Novicida was PCR amplified using Herculase II polymerase (Agilent Technologies) and cloned into pACYC-184 using Gibson cloning (New England Biolabs). Cells harboring plasmids were made competent using the Z-competent kit (Zymo).

Bacterial RNA-sequencing [001608] RNA was isolated from stationary phase bacteria by first resuspending F. novicida (generous gift from David Weiss) or E. coli in TRIzol and then homogenizing the bacteria with zirconia/silica beads (BioSpec Products) in a BeadBeater (BioSpec Products) for 3 one-minute cycles. Total RNA was purified from homogenized samples with the Direct-Zol RNA miniprep protocol (Zymo), DNase treated with TURBO DNase (Life Technologies), and 3’ dephosphorylated with T4 Polynucleotide Kinase (New England Biolabs). rRNA was removed with the bacterial Ribo-Zero rRNA removal kit (Illumina). RNA libraries were prepared from rRNA-depleted RNA using NEBNext® Small RNA Library’ Prep Set for Illumina (New England Biolabs) and size selected using the Pippin Prep (Sage Science) [001609] For heterologous E. coli expression of the FnCpfl locus, RNA sequencing libraries were prepared from rRNA-depleted RNA using a derivative of the previously described CRISPR RNA sequencing method (Heidrich et al., 2015. Briefly, transcripts were poly-A tailed with E. coli Poly(A) Polymerase (New England Biolabs), ligated with 5’ RNA adapters using T4 RNA Ligase 1 (ssRNA Ligase) High Concentration (New England Biolabs), and reverse transcribed with AffinityScript Multiple Temperature Reverse Transcriptase (Agilent Technologies). cDNA was PCR amplified with barcoded primers using Herculase II polymerase (Agilent Technologies) RNA-sequencing analysis

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PCT/US2016/038181 [001610] The prepared cDNA libraries were sequenced on a MiSeq (Illumina). Reads from each sample were identified on the basis of their associated barcode and aligned to the appropriate RefSeq reference genome using BWA (Li and Durbin, 2009). Paired-end alignments were used to extract entire transcript sequences using Picard tools (http://broadinstitute.github.io/picard), and these sequences were analyzed using Geneious 8.1.5. In vivo FnCpfl PAM Screen [001611] Randomized PAM plasmid libraries were constructed using synthesized oligonucleotides (IDT) consisting of 7 randomized nucleotides either upstream or downstream of the spacer 1 target (Supplementary Table S8). The randomized ssDNA oligos 'were made double stranded by annealing to a short primer and using the large Klenow fragment (New⁷ England Biolabs) for second strand synthesis. The dsDNA product was assembled into a linearized pL^TC19 using Gibson cloning (New England Biolabs). Competent Stbl3 E. coli (Invitrogen) were transformed with the cloned products, and more than 10⁷ cells were collected and pooled. Plasmid DNA was harvested using a Maxi-prep kit (Qiagen). We transformed 360 ng of the pooled library/ into E. coli cells carrying the FnCpfl locus or pACYC184 control. After transformation, cells were plated on ampicillin. After 16 hours of growth, >4* 10⁶ cells were harvested and plasmid DNA was extracted using a Maxi-prep kit (Qiagen). The target PAM region eras amplified and sequenced using a MiSeq (Illumina) with single-end 150 cycles. Computational PAM discovery pipeline [001612] PAM regions were extracted, counted, and normalized to total reads for each sample. For a given PAM, enrichment was measured as the log ratio compared to pACYC184 control, with a 0.01 psuedocount adjustment. PAMs above a 3.5 enrichment threshold were collected and used to generate sequence logos (Crooks et al., 2004).

PAM validation [001613] Sequences corresponding to both PAMs non-PAMs were cloned into digested pUC19 and ligated with T4 ligase (Enzymatics). Competent E. coli with either the FnCpfl locus plasmid or pACYC184 control plasmid were transformed with 20ng of PAM plasmid and plated on LB agar plates supplemented with ampicillin and chloramphenicol. Colonies were counted after 18 hours.

Synthesis of crRNAs and gRNAs

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PCT/US2016/038181 [001614] All crRNA and gRNAs used in vitro were synthesized using the HiScribe™ T7 High Yield RNA Synthesis Kit (NEB). ssDNA oligos corresponding to the reverse complement of the target RNA sequence were synthesized from IDT and annealed to a short T7 priming sequence. T7 transcription was performed for 4 hours and then RNA was purified using the MEGAclear™ Transcription Clean-Up Kit (Ambion).

Purification of Cpfl Protein [001615] FnCpfl protein was cloned into a bacterial expression vector (6-His-MBP-TEV-Cpfl, a pET based vector kindly given to Applicants by Doug Daniels) (6-His disclosed as SEQ ID NO: 130). Two liters of Terrific Broth growth media with 100 pg/mL ampicillin was inoculated with 10 mL overnight culture Rosetta (DE3) pLyseS (EMD Millipore) cells containing the Cpfl expression construct. Growth media plus inoculant was grown at 37 °C until the ceil density reached 0.2 OD600, then the temperature was decreased to 21 °C. Growth was continued until OD600 reached 0,6 when a final concentration of 500 μΜ IPTG was added to induce MBP-Cpfl expression. The culture was induced for 14-18 hours before harvesting cells and freezing at 80°C until purification.

[001616] Cell paste was resuspended in 200 mL of Lysis Buffer (50 mM Hepes pH 7, 2M NaCl, 5 mM MgCI?., 20 mM imidazole) supplemented with protease inhibitors (Roche cOmplete, EDTA-free) and lysozyme. Once homogenized, cells were lysed by sonication (Branson Sonifier 450) then centrifuged at 10,000g for I hour to clear the lysate. The lysate was filtered through 0.22 micron filters (Millipore, Stericup) and applied to a nickel column (HisTrap FF, 5 mL), washed, and then eluted with a gradient of imidazole. Fractions containing protein of the expected size were pooled, TEV protease (Sigma) was added, and the sample was dialyzed overnight into TEV buffer (500 mM NaCl, 50 mM Hepes pH 7, 5 mM MgCI, 2 mM DTT). After dialysis, TEV cleavage was confirmed by SDS-PAGE, and the sample was concentrated to 500 μΕ prior to loading on a gel filtration column (HiLoad 16/600 Superdex 200) via FPLC (AKTA Pure). Fractions from gel filtration were analyzed by SDS-PAGE, fractions containing Cpfl were pooled and concentrated to 200 μΕ and either used directly for biochemical assays or frozen at -80°C for storage. Gel filtration standards were run on the same column equilibrated in 2M NaCl, Hepes pH 7,0 to calculate the approximate size of FnCpfl.

Generation of Cpfl Protein Lysate

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PCT/US2016/038181 [001617] Cpfl proteins codon optimized for human expression were synthesized with an Nterminal nuclear localization tag and cloned into the pcDNAS.l expression plasmid by Genscript. 2000ng of Cpfl expression plasmids were transfected into 6-well plates of HEK293FT cells at 90% confluency using Lipofectamine 2000 reagent (Life Technologies), 48 hours later, cells were harvested by washing once with DPBS (Life Technologies) and scraping in lysis buffer [20mM Hepes pH 7.5, lOOmM KC1, 5mM MgCl₂, 1 mM DTT, 5% glycerol, 0.1% Triton X-I00, IX cOmplete Protease Inhibitor Cocktail Tablets (Roche)]. Lysate was sonicated for 10 minutes in a Biorupter sonicator (Diagenode) and then centrifuged. Supernatant was frozen for subsequent use in in vitro cleavage assays.

In vitro cleavage assay [001618] Cleavage in vitro was performed either with purified protein or mammalian lysate with protein at 37°C in cleavage buffer (NEBuffer 3, 5mM DTT) for 20 minutes. The cleavage reaction used 500ng of synthesized crRNA or sgRNA and 200ng of target DNA. Target DNA involved either protospacers cloned into pUC19 or PCR amplicons of gene regions from genomic DNA isolated from HEK293 cells. Reactions were cleaned up using PCR purification columns (Qiagen) and run on 2% agarose E-gels (Life Technologies). For native and denaturing gels to analyze cleavage by nuclease mutants, cleaned-up reactions were run on TBE 6% polyacrylamide or TBE-Urea 6% polyacrylamide gels (Life Technologies)

In vitro Cpfl-family protein PAM Screen [001619] In vitro cleavage reactions with Cpfl-family proteins were run on 2% agarose E-gels (Life Technologies). Bands corresponding to un-cleaved target were gel extracted using QIAquick Gel Extraction Kit (Qiagen) and the target PAM region was amplified and sequenced using a MiSeq (Alumina) with single-end 150 cycles. Sequencing results were entered into the PAM discovery pipeline.

Activity of Cpfl cleavage in 293FT cells [001620] Cpfl proteins codon optimized for human expression were synthesized with an Nterminal nuclear localization tag and cloned into the pcDNA3.I CMV expression plasmid by Genscript. PCR amplicons comprised of a U6 promoter driving expression of the crRNA sequence were generated using Herculase 11 (Agilent Technologies). 400ng of Cpfl expression plasmids and lOOng of the crRNA PCR products were transfected into 24-well plates of

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HEK293FT ceils at 75-90% confluency using Lipofectamine 2000 reagent (Life Technologies). Genomic DNA was harvested using QuickExtract™ DNA Extraction Solution (Epicentre). SURVEYOR nuclease assay for genome modification [001621] 293FT cells were transfected with 400ng Cpfl expression plasmid and lOOng U6::crRNA PCRfragments using Lipofectamin 2000 reagent (Life Technologies). Cells were incubated at 37 °C for 72 h post-transfection before genomic DNA extraction. Genomic DNA was extracted using the QuickExtract DNA Extraction Solution (Epicentre) following the manufacturer’s protocol. The genomic region flanking the CRISPR target site for each gene was PCR amplified, and products w-ere purified using QiaQuick Spin Column (Qiagen) following the manufacturer’s protocol. 200 - 500 ng total of the purified PCR products were mixed with 1 μΐ I0x Taq DNA Polymerase PCR buffer (Enzymatics) and ultrapure water to a final volume of 10 μΐ, and subjected to a re-annealing process to enable heteroduplex formation: 95 °C for 10 min, 95 °C to 85 °C ramping at -2 °C/s, 85 °C to 25 °C at -0.25 °C/s, and 25 °C hold for 1 min. After reannealing, products were treated with SURVEYOR nuclease and SURVEYOR enhancer S (Integrated DNA Technologies) following the manufacturer’s recommended protocol, and analyzed on 4-20% Novex TBE polyacrylamide gels (Life Technologies). Gels w'ere stained with SYBR Gold DNA stain (Life Technologies) for 10 min and imaged with a Gel Doc gel imaging system (Bio-rad). Quantification was based on relative band intensities. Indel percentage was determined by the formula, 100 χ (I - (I - (b + c)/(a + b + c)) 1/2), where a is the integrated intensity of the undigested PCR product, and b and c are the integrated intensities of each cleavage product.

Deep sequencing to characterize Cpfl indel patterns in 293FT cells [001622] HEK293FT cells were transfected and harvested as described for assessing activity of Cpfl cleavage. The genomic region flanking DNMT1 targets were amplified using a two-round PCR region to add Illumina P5 adapters as well as unique sample-specific barcodes to the target amplicons. PCR products were ran on 2% E-gel (Invitrogen) and gel-extracted using QiaQuick Spin Column (Qiagen) as per the manufacturer’s recommended protocol. Samples w^zere pooled and quantified by Qubit 2.0 Fluorometer (Life Technologies). The prepared cDNA libraries were sequenced on a MiSeq (Illumina), Indels were mapped using a Python implementation of the Geneious 6.0.3 Read Mapper.

Computational Analysis of Cpfl loci

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PCT/US2016/038181 [001623] PSI-BLAST program (Altschul et al., 1997) was used to identify Cpfl homologs in the NCBI NR database using several known Cpfl sequences as queries with the Cpfl with the Evalue cut-off of 0.01 and low⁷ complexity filtering and composition based statistics turned off. The TBLASTN program with the E-value cut-off of 0.01 and low complexity filtering turned off parameters was used to search the NCBI WGS database using the Cpfl profile (Marakova et al., 2015) as the query. Results of all searches w⁷ere combined. The HHpred program was used with default parameters to identify remote sequence similarity using a subset of representative Cpfl sequences queries (Soding et al., 2006). Multiple sequence alignment w^?ere constructed using MUSCLE (Edgar, 2004) wdth manual correction based on pairwise alignments obtained using PSI-BLAST and HHpred programs. Phylogenetic analysis was performed using the FastTree program with the WAG evolutionary model and the discrete gamma model with 20 rate categories (Price et al., 2010). Protein secondary structure was predicted using Jpred 4 (Drozdetskiy et al., 2015).

[001624] CRISPR repeats w⁷ere identified using PILER-CR (Edgar, 2007) and CRISPRfinder (Grissa et al, 2007). The spacer sequences were searched against the NCBI nucleotide NR databases using MEGABLAST (Morgulis et al, 2008) with default parameters except that the word size was set at 20 and E-value cutoff 0.0001.

Table 1. Endogenous F. novicida spacer sequences
Spacer number	Sequence
1	GAGAAGTCATTTAATAAGGCCACTGTTAAAA (SEQ 11) NO: 131)
2	GCTACTATTCCTGTGCCTTCAGATAA.TTCA (SEQ ID NO: 132)
3	GTCTAGAGCCTTTTGTATTAGTAGCCG (SEQ ID NO: 133)

Table 2. ssDNA oligos and primer for generation of PAM library
Oligo/primer name	Sequence
PAM library7 5’ (+)	GGCCAGTGAATTCGAGCTCGGTACCCGGG NNNNNNNNGAGAAGTCATTTAATAAGGC CACTGTTAAAAAGCTTGGCGTAATCATGG TCATAGCTGTTT (SEQ ID NO: 134)
PAM library/ 3 ’ (+)	GGCCAGTGAATTCGAGCTCGGTACCCGGG GAGAAGTCATTTAATAAGGCCACTGTTAA

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	AANNNNNNNNAGCTTGGCGTAATCATGG TCATAGCTGTTT (SEQ ID NO: 135)
PAM library' (-)	GCTGACATGAAGCTGTTGTGTGAGG (SEQ ID NO: 136)

Table 3, Primers used for pUC19 sequencing and SURVEYOR assay
Primer name	Sequence
NGS pUC For	GGCCAGTGAATTCGAGCTCGG (SEQ ID NO: 137)
NGS pUC Rev	CAATTTCACACAGGAAACAGCTATGACC (SEQ ID NO: 138)
Sanger pUC For	CGGGGCTGGCTTAACTATGCG (SEQ ID NO: 139)
Sanger pUC Rev	GCCCAATACGCAAACCGCCT (SEQ ID NO: 140)
EMX1 For	CCATCCCCTTCTGTGAATGT (SEQ ID NO: 141)
EMX1 Rev	TCTCCGTGTCTCCAATCTCC (SEQ ID NO: 142)
DNMT1 For	CTGGGACTCAGGCGGGTCAC (SEQ ID NO: 143)
DNMT1 Rev	GCTGACATGAAGCTGTTGTGTGAGG (SEQ ID NO: 144)

Table 4. Truncated guides for in vitro cleavage assay
Truncated guide number	Sequence
1	GAGAAGTCATTTAATAAGGCCACT (SEQ ID NO: 145)
9	GAGAAGTCATTTAATAAGGCC.A (SEQ ID NO: 146)
3	GAGAAGTCATTTAATAAGGC (SEQ ID NO: 147)
4	GAGAAGTCATTTAATAAG (SEQ ID NO: 148)
5	GAGAAGTCATTTAATAA. (SEQ ID NO: 149)
6	GAGAAGTCATTTAATA (SEQ ID NO: 150)

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Table 5. Mismatched guides for in vitro cleavage assay
Mismatched guide number	Sequence
1	GATAAGTCATTTAATAAGGCCACT (SEQ ID NO: 151)
2	GAGAAGGCATTTAATAAGGCCACT (SEQ ID NO: 152)
.>	GAGAAGTCATGTAATAAGGCCACT (SEQ ID NO: 153)
4	GAGAAGTCATTTAAGAAGGCCACT (SEQ ID NO: 154)
5	GAGAAGTCATTTAATAAGTCCACT (SEQ ID NO: 155)
6	GAGAAGTCATTTAATAAGGCCAAT (SEQ ID NO: 156)

Table 6. Truncated direct repeat guides for in vitro cleavage assay
Direct repeat length	Sequence
+18	ATTTCTACTGTTGTAGATGAGAAGTCATTTAATAAGGCC ACT (SEQ ID NO: 157)
+17	TTTCTACTGTTGTAGATGAGAAGTCATTTAATAAGGCCA CT (SEQ ID NO: 158)
+16	TTCTACTGTTGTAGATGAGAAGTCATTTAATAAGGCCAC T (SEQ ID NO: 159)
+ 15	TCTACTGTTGTAGATGAGAAGTCATTTAATAAGGCCACT (SEQ ID NO: 160)
	CTGTTGTAGATGAGAAGTCATTTAATAAGGCCACT (SEQ ID NO: 161)
+7	TGT AGATGAGA AGTC ATTTAAT AAGGCC ACT (SEQ ID NO: 162)

Table 7. Direct repeat stem mutations for in vitro cleavage assay
Direct repeat stem mutant number	Sequence
1	AATTTCTGCTGTTGCAGAT (SEQ ID NO: 163)
A,	AATTTCCACTGTTGTGGAT (SEQ ID NO: 164)
J	AATTCCTACTGTTGTAGGT(SEQ ID NO:

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	165)
4	AATTTATACTGTTGTAGAT( SEQ ID NO: 166)
5	AATTTCGACTGTTGTAGAT AATTTCGACTGTTGTAGAT (SEQ ID NO: 167)
6	AATTTCTAGTGTTGTAGAT (SEQ ID NO: 168)

Table 8. Direct repeat loop mutations for in vitro cleavage assay
Direct repeat loop mutant number	Sequence
1	AATTTCTACTATTGTAGAT (SEQ ID NO: 169)
9	AATTTCTACTGCTGTAGAT (SEQ ID NO: 170)
3	AATTTCTACTTTGTAGAT (SEQ ID NO: 171)
4	AATTTCTACTTGTAGAT (SEQ ID NO: 172)
5	AATTTCTACTTTTGTAGAA (SEQ ID NO: 173)
6	AATTTCTACTTTTGTAGAC (SEQ ID NO: 174)

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Table 9. Ortholog specific DNMT1 targeting guides for mammalian cells
Nuclease	Name	5’ Direct Repeat	Sequence
AsCpfl	DNMT1 target 1	5’ Direct Repeat	Sequence
AsCpfl	DNMT1 target 2	TAATTTCTACTGTTGTAGAT (SEQ ID NO: 175)	CCTCACTCCTGC TCGGTGAATTT (SEQ ID NO: 176)
AsCpfl	DNMT1 target 3	TAATTTCTACTGTTGTAGAT (SEQ ID NO: 177)	AGGAGTGTTCAG TCTCCGTGAAC (SEQ ID NO: 178)
AsCpfl	DNMT1 target 4	TAATTTCTACTGTTGTAGAT (SEQ ID NO: 179)	CTGATGGTCCAT GTCTGTTACTC (SEQ ID NO: 180)
Lb3Cpfl	DNMT1 target 1	TAATTTCTACTGTTGTAGAT (SEQ ID NO: 181)	TTTCCCTTCAGCT AAAATAAAGG (SEQ ID NO: 182)
LbSCpfl	DNMT1 target 2	TAATTTCTACTAAGTGTAGAT (SEQ ID NO: 183)	CCTCACTCCTGC TCGGTGAATTT (SEQ ID NO: 184)
LbSCpfl	DNMT1 target 3	ΤΆΛTTTCTACTAA.GTGTAGAT (SEQ ID NO: 185)	AGGAGTGTTCAG TCTCCGTGAAC (SEQ ID NO: 186)
LbSCpfl	DNMT1 target 4	TAATTTCTACTAAGTGTAGAT (SEQ ID NO: 187)	CTGATGGTCCAT GTCTGTTACTC (SEQ ID NO: 188)
SpCas9	DNMT1 target 1	TAATTTCTACTAAGTGTAGAT (SEQ ID NO: 189)	TTTCCCTTCAGCT AAAATAAAGG (SEQ ID NO: 190)
SpCas9	DNMT1 target 2	na	TCACTCCTGCTC GGTGAATT (SEQ ID NO: 191)
SpCas9	DNMT1 target 3	na	AACCCTCTGGGG ACCGTTTG (SEQ ID NO: 192)
SpCas9	DNMT1 target 4	na	AGTACGTTAATG TTTCCTGA (SEQ ID NO: 193)

Table 10, Ortholog specific direct repeats for crRNAs targeting proto-spacer 1 and DNMT 1 targets
Direct repeat origin	Sequence

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FnCpfi	TAATTTCTACTGTTGTAGAT (SEQ ID NO: 195)
Lb 1 Cpfl	AGAAATGCATGGTTCTCATGC (SEQ ID NO: 196)
BpCpfl	AAAATTACCTAGTAATTAGGT (SEQ ID NO: 197)
PeCpfl	GGATTTCTACTTTTGTAGAT (SEQ ID NO: 198)
PbCpfl	AAATTTCTACTTTTGTAGAT (SEQ ID NO: 199)
SsCpfl	CGCGCCCACGCGGGGCGCGAC (SEQ ID NO: 200)
AsCpfl	TAATTTCTACTGTTGTAGAT (SEQ ID NO: 201)
Lb2Cpfl	GAATTTCTACTATTGTAGAT (SEQ ID NO: 202)
CMtCpfl	GAATCTCTACTCTTTGTAGAT (SEQ ID NO: 203)
EeCpfl	TAATTTCTACTTTGTAGAT (SEQ ID NO: 204)
MbCpfl	AAATTTCTACTGTTTGTAGAT (SEQ ID NO: 205)
Li Cpfl	GAATTTCTACTTTTGTAGAT (SEQ ID NO: 206)
LbSCpfl	TAATTTCTACTAAGTGTAGAT (SEQ ID NO: 207)
PeCpfl	TAATTTCTACTATTGTAGAT (SEQ ID NO: 208)
PdCpfl	TAATTTCTACTTCGGTAGAT (SEQ ID NO: 209)
PmCpfl	TAATTTCTACTATTGTAGAT (SEQ ID NO: 210)

Example 8: Cloning of Francisella tularensis subsp. novicida U112 Cpfl (FnCpfi) [001625] Applicants cloned the Francisella tularensis subsp. novicida U112 (Figure 95A) Cpfl (FnCpfi) locus into low-copy plasmids (pFnCpfl) to allow heterologous reconstitution in Escherichia coli. Typically, in currently characterized CRISPR-Cas systems, there are two requirements for DNA interference: (i) the target sequence has to match one of the spacers present in the respective CRISPR array, and (ii) the target sequence complementary to the spacer (hereinafter protospacer) has to be flanked by the appropriate Protospacer-Adjacent Motif (PAM), Given the completely uncharacterized functionality of the FnCpfi CRISPR locus, a plasmid depletion assay was designed to ascertain the activity of Cpfl and identify PAM sequence and its respective location relative to the protospacer (5’ or 3’) (Figure 95B). Two libraries of plasmids carrying a protospacer matching the first spacer in the FnCpfi CRISPR array were constructed with the 5’ or 3’ 7 bp sequences randomized. Each plasmid library was transformed into E. coli that heterologously expressed the FnCpfi locus or into a control E. coli strain carrying the empty vector. Using this assay, the PAM sequence and location was

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PCT/US2016/038181 determined by identifying nucleotide motifs that are preferentially depleted in cells heterologously expressing the FnCpfl locus. The PAM for FnCpfl was found to be located upstream of the 5’ end of displaced strand of the protospacer and has the sequence 5’-TTN (Figures 95C-D and 102). The 5’ location of the ΡΑΜΙ is also observed in type I CRISPR systems, but not in type II systems, where Cas9 employs PAM sequences that are on the 3’ end of the protospacer (Mojica et a!., 2009; Garneau et al., 2010. Beyond the identification of the PAM, the results of the depletion assay clearly indicate that heterologously expressed Cpfl loci are capabl e of efficient interference with plasmid DNA.

[001626] To further characterize the ΡΑΜΙ, plasmid interference activity was analyzed by transforming cpfl-locus expressing cells with plasmids carrying protospacer 1 fl anked by 5’TTN PAMs. All 5’-TTN PAMs were efficiently targeted (Figure IE). In addition, 5’-CTA but not 5’-TCA was also efficiently targeted (Figure 95E), suggesting that the middle T is more critical for PAM recognition than the first T and that, in agreement with the sequence motifs depleted in the PAM discover)⁷ assay (Figure 102D), the PAM might be more relaxed than 5’TTN.

Example 9: The Cpfl CRISPR array is processed independent of tracrRNA [001627] Small RNAseq was used to determine the exact identity of the crRNA produced by the cpfl -based CRISPR loci. By sequencing small RNAs extracted from a Francisella tularensis suhsp. novicida U112 culture, it was found that the CRISPR array is processed into short mature crRNAs of 42-44 nt in length. Each mature crRNA begins with 19 nt of the direct repeat followed by 23-25 nt of the spacer sequence (Figure 96A). This crRNA arrangement contrasts with that in type II CRISPR-Cas systems where the mature crRNA begins with 20-24 nt of spacer sequence followed by ~22 nt of direct repeat (Deltcheva et al., 2011; Chylinski et al., 2013). Unexpectedly, apart from the crRNAs, we did not observe any robustly expressed small transcripts near the Francisella cpfl locus that might correspond to tracrRNAs, which are associated with Cas9-based systems.

[001628] To confirm that no additional RNAs are required for crRNA maturation and DNA interference, an expression plasmid was constructed using synthetic promoters to drive the expression of Francisella cpfl (FnCpfl) and the CRISPR array (pFnCpflmin). Small RNAseq of E. coli expressing this plasmid still showed robust processing of the CRISPR array into mature crRNA (Figure 96B), indicating that FnCpfl and its CRISPR array are sufficient to

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PCT/US2016/038181 achieve crRNA processing. Furthermore, £. coli expressing pFnCpfl min as well as pFnCpfl_ACas, a plasmid with all of the cas genes removed but retaining native promoters driving the expression of FnCpfl and the CRISPR array, also exhibited robust DNA interference, demonstrating that FnCpfl and crRNA are sufficient for mediating DNA targeting (Figure 96C). By contrast, Cas9 requires both crRNA and tracrRNA to mediate targeted DNA interference (Deltcheva et al., 2011; Zhang et al., 2013).

Example 10: Cpfl is a single crRNA-gnided endonuclease [001629] The finding that FnCpfl can mediate DNA interference with crRNA alone is highly surprising given that Cas9 recognizes crRNA through the duplex structure between crRNA and tracrRNA (Jinek et al., 2012; Nishimasu et al., 2014), as well as the 3’ secondary structure of the tracrRNA (Hsu et al., 2013; Nishimasu et al., 2014). To ensure that crRNA is indeed sufficient for forming an active complex with FnCpfl and mediating RNA-guided DNA cleavage, FnCpfl supplied only with crRN A was tested for target DNA cleavage in vitro. Purified FnCpfl (Figure

103) was assayed for its ability to cleave the same protospacer 1-containing plasmid used in the bacterial DNA interference experiments (Figure 97A). FnCpfl with an in vitro transcribed mature crRNA targeting protospacer 1 was able to efficiently cleave the target plasmid in a Mgⁱ⁺- and crRNA-dependent manner (Figure 97B). Moreover, FnCpfl was able to cleave both supercoiled and linear target DNA (Figure 97C). These results clearly demonstrate the sufficiency of FnCpfl and crRNA for RNA-guided DNA cleavage.

[001630] The cleavage site of FnCpfl was also mapped using Sanger sequencing of the cleaved DNA ends. FnCpfl-mediated cleavage results in a 5-nt 5’ overhang (Figures 97A, 97D, and

104) , which is distinct from the blunt cleavage product generated by Cas9 (Garneau et al., 2010; Jinek et al., 2012; Gasiunas et al., 2012). The staggered cleavage site of FnCpfl is distant from the PAM: cleavage occurs after the 18th base on the non-targeted (+) strand and after the 23rd base on the targeted (-) strand (Figures 97A, 97D, and 104). Using double-stranded oligo substrates with different PAM sequences, we also found that FnCpfl cleave the target DNA when the 5’-TTN PAM to be in a duplex form (Figure 97E), in contrast to the PAMs of Cas9 (Sternberg et al., 2014).

Example 11: The RuvC-like domain of Cpfl mediates RNA-guided DNA cleavage [001631] The RuvC-like domain of Cpfl retains all the catalytic residues of this family of endonucleases (Figures 98A and 105) and is thus predicted to be an active nuclease. Three

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PCT/US2016/038181 mutants, FnCpfl (D917 A), FnCpfl (El 006A), and FnCpfl(D1225A) (Figure 98A) were generated to test whether the conserved catalytic residues are essential for the nuclease activity of FnCpfl. The D917A and El006A mutations completely inactivated the DNA cleavage activity of FnCpfl, and D1255A significantly reduced nucleolytic activity (Figure 98B). These results are in contrast to the mutagenesis results for Streptococcus pyogenes Cas9 (SpCas9), where mutation of the RuvC (D10A) and HNH (N863A) nuclease domains converts SpCas9 into a DNA nickase (i.e. inactivation of each of the two nuclease domains abolished the cleavage of one of the DNA strands) (Jinek et al., 2012; Gasiunas et al., 2012) (Figure 98B). These findings suggest that the RuvC-like domain of FnCpfl cleaves both strands of the target DNA, perhaps in a dimeric configuration (Figure 103B).

Example 12: Sequence and structure of the Cpfl crRNA [001632] Compared with the guide RNA for Cas9, which has elaborate RNA secondary structure features that interact with Cas9 (Nishimasu et al,, 2014), the guide RNA for FnCpfl is notably simpler and only comprises a single stem loop in the direct repeat sequence (Figure 97A).

[001633] The sequence and structural requirements of crRNA for mediating DNA cleavage with FnCpfl were explored. The length of the guide sequence was examined. A 16 nt guide sequence was observed to achieve detectable DNA cleavage and guide sequences of 18 nt achieved efficient DNA cleavage in vitro (Figure 99A). These lengths are similar to those demonstrated for SpCas9 where a 16 to 17 nt spacer sequence is sufficient for DNA cleavage (Cencic et al., 2014; Fu et al., 2014). The seed region of the FnCpfl guide RNA was observed within the first 6 or 7 nt on the 5’ end of the spacer sequence (Figure 9913).

[001634] The effect of direct repeat mutations on the RNA-guided DNA cleavage activity was investigated. The direct repeat portion of mature crRNA is 19 nt long (Figure 96A). Truncation of the direct repeat revealed that 16nt is sufficient, but optimally more than 17 nt of the direct repeat is effective for cleavage. Mutations in the stem loop that preserved the RNA duplex did not affect the cleavage activity, whereas mutations that disrupted the stem loop duplex structure abolished cleavage (Figure 99D). Finally, base substitutions in the loop region did not affect nuclease activity, whereas substitution of the U immediately 5’ of the spacer sequence reduced activity substantially (Figure 5E). Collectively, these results suggest that FnCpfl recognizes the crRNA through a combination of sequence-specific and structural features of the stem loop.

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Example 13: Cpfl-family proteins from diverse bacteria share common crRNA structures and PAMs [001635] To investigate the use of Cpfl as a genome editing tool, the diversity of Cpfl-family proteins available in the public sequences databases wase exploited. A BLAST search of the WGS database at the NCBI revealed 46 non-redundant Cpfl-family proteins (Figure 64). 16 were chosen based on our phylogenetic reconstruction (Figure 64), as representative of Cpfl diversity (Figure 100A-100B and 106). These Cpfl-family proteins span a range of lengths between -1200 and -1500 amino acids.

[001636] The direct repeat sequences for each of these Cpfl-family proteins show⁷ strong conservation in the 19 nucleotides at the 3’ of the direct repeat, the portion of the repeat that is included in the processed crRNA (Figure 100C). The 5’ sequence of the direct repeat is much more diverse. Of the 16 Cpfl-family proteins chosen for analysis, three (2 - Lachnospiraceae bacterium MC2017, Lb3Cpfl; 3 - Butyrivihrio proieoclasticus, BpCpfl; and 6 - Smithella sp. SC K08D17, SsCpfl) were associated with direct repeat sequences that are notably divergent from the FnCpfl direct repeat (Figure 100C). Notably, these direct repeat sequences preserved stem loop structures that were identical or nearly-identical to the FnCpfl direct repeat (Figure 100D).

[001637] Orthologous direct repeat sequences are tested for the ability to support FnCpfl nuclease activity in vitro. Direct repeats that contained conserved stem sequences were able to function interchangeably with FnCpfl. The direct repeat from candidate 3 (BpCpfl) supported a low level of FnCpfl nuclease activity (Figure 100E), possibly due to the conservation of the 3’most U.

[001638] An in vitro PAM identification assay (Figure 107A) was used to determine the PAM sequence for each Cpfl-family protein. PAM sequences were identified for 7 new Cpfl-family proteins (Figures 100E and 107B-C), and the screen confirmed the PAM for FnCpfl as 5’-TTN. The PAM sequences for the Cpfl-family proteins were predominantly T-rieh, varying primarily in the number of Ts constituting each PAM (Figure 100F and 107B-C).

Example 14: Cpfl can be harnessed to facilitate genome editing in human cells [001639] Cpfl-family proteins were codon optimized and attached a C-terminal nuclear localization signal (NLS) for optimal expression and nuclear targeting in human cells (Figure 101A). To test the activity of each Cpfl-family protein, a guide RNA target site was selected

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PCT/US2016/038181 within the DNMT1 gene (Figure 10 IB). Each of the Cpfl-family proteins along with its respective crRNA designed to target DNMT1 was able to cleave a PCR amplicon of the DNMT1 genomic region in vitro (Figure 101C). When tested in human embryonic kidney 293FT (HEK 293FT) cells, 2 of the Cpfl-family proteins (7 - AsCpfl and 13 - LbCpfl) exhibited detectable levels of nuclease-induced indels under the conditions employed (Figure 101C and D).

[001640] Each Cpfl-famiiy protein was tested with additional genomic targets. AsCpfl and LbCpfl consistently mediated robust genome editing in HEK293FT cells (Figures 101E and 108). When compared to Cas9, AsCpfl and LbCpfl mediated comparable levels of indel formation (Figure 101E). .Additionally, we used in vitro cleavage followed by Sanger sequencing of the cleaved DNA ends and found that 7 - AsCpfl and 13 - LbCpfl also generated staggered cleavage sites (Figures 101D and 107E), [001641] Following are nucleotide and amino acid sequences of FnCpfl constructs and orthologs:

[001642] FnCpfl locus sequences [001643] pFnCpfl [001644] 5 'end of endogenous F. novicida acetyltranferase (upstream of FnCpfl locus) [001645] FnCpfl [001646] Cas4 [001647] Cas I [001648] Cas2 [001649] Direct [001650] Spacer [001651 ] CATCAAGGAATTGGTTCTAAGCTTATAGAAGCAATGATTAAGGAAGCCAAMAA AA TAA TA T1GATGCAA.TA TTTGTCTTAGGTCA.TCCAAGTTA TTA TCCAAAA TTTGGTTTTAAA CCAGCCACAGAA TATCAGA TAAAA TGTGAATA TGA TG TCCCAGCGGA TGTTTTTA TGGTACT AGATTTGTCAGCTAAAGTAGCTAGTTTAAAAGGACAAACTGTCTACTATGCCGATGAGTTTG GC/EEF47777777GATCTACAAAATTATAAACTAAATAAAGATTCTTATAATAACTTTA

TATATAATCGAAATGTAGAGAATTTTATAAGGAGTCTTTATCATGTCAATTTATCAA

GAATTTGTTAATAAA TATAGTTTAAGTAAAACTCTAAGATTTGAGTTAATCCCACAG

GGTAAAACACTTGAAAACATAAAAGCAAGAGGTTTGATTTTAGATGATGAGAAAAG

AGCTAAAGACTACAAAAAGGCTAAACAAATAATTGATAAATATCATCAGTTTTTTAT

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AGAGGAGATATTAAGTTCGGTTTGTATTAGC:GAAG.ATTTATTACAAAACTATTCTGA

TGTTTATTTTAAACTTAAAAAGAGTGATGATGATAATCTACAAAAAGATTTTAAAAG

TGCAAAAGATACGATAAAGAAACAAATATCTGAATATATAAAGGACTCAGAGAAAT

TTAAGAATTTGTTTAATCAAAACCTTATCGATGCTAAAAAAGGGCAAGAGTCAGATT

TAATTCTATGGCTAAAGCAATCTAAGGATAATGGTATAGAACTATTTAAAGCCAATA

GTGATATCACAGATATAGATGAGGCGTTAGAAATAATCAAATCTTTTAAAGGTTGGA

CAACTTATTTTAAGGGTTTTCATGAAAATAGAAAAAATGTTTATAGTAGCAATGATA

TTCCTACATCTATTATTTATAGGATAGTAGATGATAATTTGCCTAAATTTCTAGAAAA

TAAAGCTAAGTATGAGAGTTTAAAAGACAAAGCTCCAGAAGCTATAAACTATGAAC

AAATTAAAAAAGATTTGGCAGAAGAGCTAACCTTTGATATTGACTACAAAACATCT

GAAGTTAATCAAAG-AGTTTTTTCACTTG-ATGAAGTTTTTGAGATAGCAAACTTTAAT

AATTATCTAAATCAAAGTGGTATTACTAAATTTAATACTATTATTGGTGGTAAATTTG

TAAATGG-TGAAAATACAAAGAGAAAAGGTATAAATG-AATATATAAATCTATACTCA

CAGCAAATAAATGATAAAACACTCAAAAAATATAAAATGAGTGTTTTATTTAAGCA

AATTTTAAGTGATACAGAATCTAAATCTTTTGTAATTGATAAGTTAGAAGATGATAG

TGATGTAGTTACAACGATGCAAAGTTTTTATGAGCAAATAGCAGCTTTTAAAACAGT

AGAAGAAAAATCTATTAAAGAAACACTATCTTTATTATTTGATGATTTAAAAGCTCA

AAAACTTGATTTGAGTAAAATTTATTTTAAAAATGATAAATCTCTTACTGATCTATCA

CAACAAGTTTTTGATGATTATAGTGTTATTGGTACAGCGGTACTAGAATATATAACT

CAACAAATAGCACCTAAAAATCTTGATAACCCTAGTAAGAAAGAGCAAGAATTAAT

AGCCAAAAAAACTGAAAAAGCAAAATACTTATCTCTAGAAACTATAAAGCTTGCCT

TAGAAGAATTTAATAAGCATAGAGATATAGATAAACAGTGTAGGTTTGAAGAAATA

CTTGCAAACTTTGCGGCTATTCCGATGATATTTGATGAAATAGCTCAAAACAAAGAC

AATTTGGCACAGATATCTATCAAATATCAAAATCAAGGTAAAAAAGACCTACTTCA

AGCTAGTGCGGAAGATGATGTTAAAGCTATCAAGGATCTTTTAGATCAAACTAATAA

TCTCTTACATAAACTAAAAATATTTCATATTAGTCAGTCAGAAGATAAGGCAAATAT

TTTAGACAAGG-ATGAG-CATTTTTATCTAG-TATTTGAGGAGTGCTACTTTGAGCTAGC

GAATATAGTGCCTCTTTATAACAAAATTAGAAACTATATAACTCAAAAGCCATATAG

TGATGAGAAATTTAAGCTCAATTTTGAGAACTCGACTTTGGCTAATGGTTGGGATAA

AAATAAAGAGCCTGACAATACGGCAATTTTATTTATCAAAGATGATAAATATTATCT

GGGTGTGATGAATAAGAAAAATAACAAAATATTTGATGATAAAGCTATCAAAGAAA

599

WO 2016/205711

PCT/US2016/038181

ATAAAGGCGAGGGTTATAAAAAAATTGTTTATAAACTTTTACCTGGCGCAAATAAA

ATGTTACCTAAGGTTTTCTTTTCTGCTAAATCTATAAAATTTTATAATCCTAGTGAAG

ATATACTTAGAATAAGAAATCATTCCACACATACAAAAAATGGTAGTCCTCAAAAA

GGATATGAAAAATTTGAGTTTAATATTGAAGATTGCCGAAAATTTATAGATTTTTAT

AAACAGTCTATAAGTAAGCATCCGGAGTGGAAAGATTTTGGATTTAGATTTTCTGAT

ACTCAAAGATATAATTCTATAGATGAATTTTATAGAGAAGTTGAAAATCAAGG-CTAC

AAACTAACTTTTGAAAATATATCAGAGAGCTATATTGATAGCGTAGTTAATCAGGGT

AAATTGTACCTATTCCAAATCTATAATAAAGATTTTTCAGCTTATAGCAAAGGGCGA

CCAAATCTACATACTTTATATTGGAAAGCGCTGTTTGATGAGAGAAATCTTCAAGAT

GTGGTTTATAAGCTAAATGGTGAGGCAGAGCTTTTTTATCGTAAACAATCAATACCT

AAAAAAATCACTCACCCAGCTAAAGAGG-CAATAGCTAATAAAAACAAAGATAATCC

TAAAAAAGAGAGTGTTTTTGAATATGATTTAATCAAAGATAAACGCTTTACTGAAGA

TAAGTTTTTCTTTCACTGTCCTATTACAATCAATTTTAAATCTAGTGGAGCTAATAAG

TTTAATGATGAAATCAATTTATTGCTAAAAGAAAAAGCAAATGATGTTCATATATTA

AGTATAGATAGAGGTGAAAGACATTTAGCTTACTATACTTTGGTAGATGGTAAAGGC

AATATCATCAAACAAGATACTTTCAACATCATTGGTAATGATAGAATGAAAACAAA

CTACCATGATAAGCTTGCTGCAATAGAGAAAGATAGGGATTCAGCTAGGAAAGACT

GGAAAAAGATAAATAACATCAAAGAGATGAAAGAGGGCTATCTATCTCAGGTAGTT

CATGAAATAGCTAAGCTAGTTATAGAGTATAATGCTATTGTGGTTTTTGAGGATTTA

AATTTTGGATTTAAAAGAGGGCGTTTCAAGGTAGAGAAGCAGGTCTATCAAAAGTT

AGAAAAAATGCTAATTGAGAAACTAAACTATCTAGTTTTCAAAGATAATGAGTTTGA

TAAAACTGGGGGAGTGCTTAGAGCTTATCAGCTAACAGCACCTTTTGAGACTTTTAA

AAAGATGGGTAAACAAACAGGTATTATCTACTATGTACCAGCTGGTTTTACTTCAAA

AATTTGTCCTGTAACTGGTTTTGTAAATCAGTTATATCCTAAGTATGAAAGTGTCAGC

AAATCTCAAGAGTTCTTTAGTAAGTTTGACAAGATTTGTTATAACCTTGATAAGGGC

TATTTTGAGTTTAGTTTTGATTATAAAAACTTTGGTGACAAGGCTGCCAAAGGCAAG

TGGACTATAGCTAGCTTTGGGAGTAGATTGATTAACTTTAGAAATTCAGATAAAAAT

CATAATTGGGATACTCGAGAAGTTTATCCAACTAAAGAGTTGGAGAAATTGCTAAA

AGATTATTCTATCGAATATGGGCATGGCGAATGTATCAAAGCAGCTATTTGCGGTGA

GAGCGACAAAAAGTTTTTTGCTAAGCTAACTAGTGTCCTAAATACTATCTTACAAAT

GCGTAACTCAAAAACAGGTACTGAGTTAGATTATCTAATTTCACCAGTAGCAGATGT

600

WO 2016/205711

PCT/US2016/038181

AAATGGCAATTTCTTTGATTCGCGACAGGCGCCAAAAAATATGCCTCAAGATGCTGA

TGCCAATGGTGCTTATCATATTGGGCTAAAAGGTCTGATGCTACTAGGTAGGATCAA

AAATAATCAAGAGGGCAAAAAACTCAATTTGGTTATCAAAAATGAAGAGTATTTTG

AGTTCGTGCAGAATAGGAATAACTAATTCATTCAAGAATATATTACCCTGTCAGTTT

AGCGACTATTACCTCTTTAATAATTTGCAGGGGAATTATTTTAGTAATAGTAATATA

CACAAGAGTTATTGATTATATGGAAAATTATATTTAGATAACATGGTTAAATGATTT

TATATTCTGTCCTTACTCGATATATTTGCATAATATCTATAGTAATGCCICAGATACT

ACATACTATTCATCTAGCCAAACAAAAGGGCGCGATGCTCATAAAAGTATCGATAA

AGGAATCTATAGTACCAAAAAAGATGACCTGATCGGTATCGATGTTATTAACCATAA

ATATGGTTXGGXTGGTAAAATTGATGJXTTJCATA^GATAAGGGCTTACTTGTGGA

GAGAAAAAGC^AAATCAAGACTATCTATGAT^CTATAAATATCAGCITTTATGCGC

AATATTXTTGTCTXCAAGAGATGGGCTATGATGTCAAAGCCATTAAAT.TTTATT_CGAT iOTTCATAATAAATCATACCCAATAGCTATACCAACTTCAGCTGAGTTAGAAAAGTT

TGAAAAACATATTCAAACAATCAAGCAATATAATCGAATGGAXAACTCATTTAGGC aaaatattgaaaagtgtaaattjtctatatatgcaaacttatgtgataaaacggact

TGJAGATTATGTTTAGTAAAAATGATATTGAATCAAAGAATATAGTTTTTGTTAATA tttttgatggagtgaaacttagtctatcattggggaatatagttataaaagataaag aaactgatgaggtgaaaactaagctttctgttcataaagttcttgcattgtttatcgt aggtaatatgacgatgacctcgcaacttttagagacctgtaagaaaaatgctatac

AGCTAGTTTTTATGAAAAATAGCTTTAGACCATATCTATGTTTTGGTGATATTGCTGA

GGCTAATTTTTTAGCTAGATATAAGCAATATAGTGTAGTTGAGCAAGATATAAGTTT

AGCAAGGATTTTTATAACATCAAAGATACGCAATCAACATAACTTAGTCAAAAGCCT

AAGAGA T AAAAC TCCAGAGCAGCAAGAGA1AGTCAAAAAGAAT AAACAGCTAATA

GCAGAGTTAGAAAATACAACAAGCCTAGCGGAGCTAATGGGTATAGAGGGCAATGT

TGCCAAAAATTTCTTCAAAGGATTCTATGGACATTTAGATAGTTGGCAAGGGCGCAA

ACCTAGAATAAAACAGGATCCATATAATGTTGTTTTAGACTTGGGCTATAGTATGTT

GTTTAATTTTGTAGAGTGTTTTTTGCGACTTTTTGGCTTTGATTTATACAAGGGCTTTT

GTCATCAGACTTGGTATAAGCGTAAATCCCTAGTTTGTGACTTTGTTGAGCCATTTAG

ATGTATAGTGGATAACCAAGTTAGAAAATCATGGAATCTCGGGCAATTTTCTGTAGA

GGATTTTGGTTGCAAAAATGAGCAGTTTTATATAAAAAAAGATAAAACAAAAGACT

ACTCAAAAATACTTTTTGCCGAGATTATCAGCTACAAGCTAGAGATATTTGAATATG

601

WO 2016/205711

PCT/US2016/038181

TAAGAGAATTTTATCGTGCCTTTATGCGAGGCAAAGAAATTGCAGAGTATCCAATAT

TTTGTTATGAAACTAGGAGGGTGTATGTTGATAGTCAGTTATGATTTTAGTAATAAT

AAAGTACGTGCAAAGTTTGCCAAATTTCTAGAAAGTTATGGTGTACGTTTACAATAT

TCGGTATTTGAGCTCAAATATAGCAAGAGAATGTTAGACTTGATTTTAGCTGAGATA

GAAAATAACTATGTACCACTATTTACAAATGCTGATAGTGTTTTAATCTTTAATGCTC

CAGATAAAGATGTGATAAAATATGGTTATGCGATTCATAGAGAACAAGAGGTTGTT

TTTATAGACTAAAAATTGCAAACCTTAGTCTTTATGTTAAAATAACTACTAAGTTCTT

AGAGATATTTAAAAATATGACTGTTGTTATATATCAAAATGCTAAAAAAATCATAGA

TTTTAGGTCTTTTTTTGCTGATTTAGGCAAAAACGGGTCTAAGAACTTTAAATAATT

TCTACTGTTGTAGATGAGAAGTCATTTAATAAGGCCACTGTTAAAAGTCTAAGAA

CTTTAAATAATTTCTACTGTTGTAGATGCTACTATTCCTGTGCCTTCAGATAATTCA

GTCTAAGAACTTTAAATAATTTCTACTGTTGTAGATGTCTAGAGCCTTTTGTATTA

GTAGCCGGTCTAAGAACTTTAAATAATTTCTACTGTTGTAGATTAGCGATTTATG

AAGGTCATTTTTTTGTCT (SEQ ID NO: 211) [001652] pFnCpfl min [001653] Lae prompter [001654] Shine-Dalgamo sequence [001655] FnCpfl [001656] J23119 promoter [001657] Direct repeats [001658] Spacer [001659] TTlACACTJTATGCTlCm^ GGA GGTCTTTATCATGTCAATTTATC

AAGAATTTGTTAATAAATATAGTTTAAGTAAAACTCTAAGATTTGAGTTAATCCCACAGGGT

AAAACACTTGAAAACATAAAAGCAAGAGGTTTGATTTTAGATGATGAGAAAAGAGCTAAAG

ACTACAAAAAGGCTAAACAAATAATTGATAAATATCATCAGTTTTTTATAGAGGAGATATTA

AGTTCGGTTTGTATTAGCGAAGATTTATTACAAAACTATTCTGATGTTTATTTTAAACTTAAA

AAGAGTGATGATGATAATCTACAAAAAGATTTTAAAAGTGCAAAAGATACGATAAAGAAAC

AAATATCTGAATATATAAAGGACTCAGAGAAATTTAAGAATTTGTTTAATCAAAACCTTATC

GATGCTAAAAAAGGGCAAGAGTCAGATTTAATTCTATGGCTAAAGCAATCTAAGGATAATG

GTATAGAACTATTTAAAGCCAATAGTGATATCACAGATATAGATGAGGCGTTAGAAATAATC

TAGTAGCAATGATATTCCTACATCTATTATTTATAGGATAGTAGATGATAATTTGCCTAAATT

602

WO 2016/205711

PCT/US2016/038181

TCTAGAAAATAAAGCTAAGTATGAGAGTTTAAAAGACAAAGCTCCAGAAGCTATAAACTAT

GAACAAATTAAAAAAGATTTGGCAGAAGAGCTAACCTTTGATATTGACTACAAAACATCTG

AAGTTAATCAAAGAGTTTTTTCACTTGATGAAGTTTTTGAGATAGCAAACTTTAATAATTATC

TAAATCAAAGTGGTATTACTAAATTTAATACTATTATTGGTGGTAAATTTGTAAATGGTGAA

AATACAAAGAGAAAAGGTATAAATGAATATATAAATCTATACTCACAGCAAATAAATGATA

AAACACTCAAAAAATATAAAATGAGTGTTTTATTTAAGCAAATnTAAGTGATACAGAATCT

TTATGAGCAAATAGCAGCTTTTAAAACAGTAGAAGAAAAATCTATTAAAGAAACACTATCTT

TATTA’nTGATGATTTAAAAGCTCAAAAACTTGATTTGAGTAAAATTTATTTTAAAAATGATA

AATCTCTTACTGATCTATCACAACAAGTTTTTGATGATTATAGTGTTATTGGTACAGCGGTAC

TAGAATATATAACTCAACAAATAGCACCTAAAAATCTTGATAACCCTAGTAAGAAAGAGCA

AGAATTAATAGCCAAAAAAACTGAAAAAGCAAAATACTTATCTCTAGAAACTATAAAGCTT

GCCTTAGAAGAATTTAATAAGCATAGAGATATAGATAAACAGTGTAGGTTTGAAGAAATAC

TTGCAAACTTTGCGGCTATTCCGATGATATTTGATGAAATAGCTCAAAACAAAGACAATTTG

GCACAGATATCTATCAAATATCAAAATCAAGGTAAAAAAGACCTACTTCAAGCTAGTGCGG

AAGATGATGTTAAAGCTATCAAGGATCTTTTAGATCAAACTAATAATCTCTTACATAAACTA

AAAATATTTCATATTAGTCAGTCAGAAGATAAGGCAAATATTTTAGACAAGGATGAGCATTT

TTATCTAGTATTTGAGGAGTGCTACTTTGAGCTAGCGAATATAGTGCCTCTTrATAACAAAAT

TAGAAACTATATAACTCAAAAGCCATATAGTGATGAGAAATTTAAGCTCAATTTTGAGAACT

CGACTTTGGCTAATGGTrGGGATAAAAATAAAGAGCCTGACAATACGGCAATTTTAITTATC

AAAGATGATAAATATTATCTGGGTGTGATGAATAAGAAAAATAACAAAATATTTGATGATA

AAGCTATCAAAGAAAATAAAGGCGAGGGTTATAAAAAAATTGTTTATAAACTTTTACCTGGC

GAAGATATACTTAGAATAAGAAATCATTCCACACATACAAAAAATGGTAGTCCTCAAAAAG

GATATGAAAAATTTGAGTTTAATATTGAAGATTGCCGAAAATTTATAGATTTTTATAAACAG

TCTATAAGTAAGCATCCGGAGTGGAAAGATTTTGGATTTAGATTITCTGATACTCAAAGATA

TAATTCTATAGATGAATTr'TATAGAGAAGTTGAAAATCAAGGCTACAAAC'TAACTTTTGAAA

ATATATCAGAGAGCTATATTGATAGCGTAGTTAATCAGGGTAAATTGTACCTATTCCAAATC

TATAATAAAGATTTTTCAGCTTATAGCAAAGGGCGACCAAATCTACATACTTTATATTGGAA

AGCGCTGITTGATGAGAGAAATCTTCAAGATGTGGTITATAAGCTAAATGGTGAGGCAGAGC

TTTTTTATCGTAAACAATCAATACCTAAAAAAATCACTCACCCAGCTAAAGAGGCAATAGCT

AACGCTTTACTGAAGATAAGTTTTTCTTTCACTGTCCTATTACAATCAATTTTAAATCTAGTG

GAGCTAATAAGTTTAATGATGAAATCAAITTATTGCTAAAAGAAAAAGCAAATGATGITCAT

603

WO 2016/205711

PCT/US2016/038181

ATATTAAGTATAGATAGAGGTGAAAGACATTTAGCTTACTATACTTTGGTAGATGGTAAAGG

CAATATCATCAAACAAGATACTTTCAACATCATTGGTAATGATAGAATGAAAACAAACTACC

ATGATAAGCTTGCTGCAATAGAGAAAGATAGGGATTCAGCTAGGAAAGACTGGAAAAAGAT

AAATAACATCAAAGAGATGAAAGAGGGCTATCTATCTCAGGTAGTTCATGAAATAGCTAAG

CTAGTTATAGAGTATAATGCTATTGTGGTTTTTGAGGATTTAAATTTTGGATTTAAAAGAGGG

CG ITICAAGGT AGAGAAGCAGG TCT ATCAAAAGTT AGAAAAAATGCT AATTGAGAAAC f AA 2AAAGATAATGAGTTTGATAAAACTGGGGGAGTGCTTAGAGCTTATCAG

CTAACAGCACCTTTTGAGACTTTTAAAAAGATGGGTAAACAAACAGGTATTATCTACTATGT

ACCAGCTGGTnTACTTCAAAAAITTGTCCTGTAACTGGTTTTGTAAATCAGTTATATCCTAA

GTATGAAAGTGTCAGCAAATCTCAAGAGTTCTTTAGTAAGTTTGACAAGATTTGTTATAACC

GGCAAGTGGACTATAGCTAGCTTTGGGAGTAGATTGATTAACITTAGAAATTCAGATAAAAA

TCATAATTGGGATACTCGAGAAGTTTATCCAACTAAAGAGTTGGAGAAATTGCTAAAAGAIT

ATTCTATCGAATATGGGCATGGGGAATGTATCAAAGCAGCTATTTGCGGTGAGAGCGACAA

CAGGTACTGAGTTAGATTATCTAATTTCACCAGTAGCAGATGTAAATGGCAATTTCTTTGATT

CGCGACAGGCGCCAAAAAATATGCCTCAAGATGCTGATGCCAATGGTGCTTATCATATTGGG

CTAAAAGGTCTGATGCTACTAGGTAGGATCAAAAATAATCAAGAGGGCAAAAAACTCAATT

TGGTTATCAAAAATGAAGAGTATTTTGAGTTCGTGCAGAATAGGAATAACTAATTGACAGCT

AGCTCAGTCCTAGGTATAATGCTAGCGCTGAITTAGGCAAAAACGGGTCTAAGAACTTTAA

ATAATTTCTACTGTTGTAGATGAGAAGTCATTTAATAAGGCCACTGTTAAAAGTCTA. ACTTTAAATAATTTCTACTGTTGTAGATGCTACTATTCCTGTGCCTTCAGATAATTCAGTCl

AAGAACTTTAAATAATTTCTACTGTTGTAGA

212) [001660] pFnCpfl ACas [001661] 5 ’end of endogenous F novicida ace tyltranferase (upstream of FnCpfl locus [001662] FnCpfl [001663] Direct repeats [001664] Spacer [001665] C7 GTCTACTATGCCGAl GA Gl TTGGCAAAA’l '11 TTTACIAXC I ACA AAA I TA TAAACT A AATAAAGATTCTTATAATAACTTTATATATAATCGAAATGTAGAGAATTTTATAAGGAGTCT

TTATCATGTCAATTTATCAAGAATTTGTTAATAAATATAGTTTAAGTAAAACTCTAAGATTTG

AGTTAATCCCACAGGGTAAAACACTTGAAAACATAAAAGCAAGAGGTTTGATTTTAGATGA

TGAGAAAAGAGCTAAAGACTACAAAAAGGCTAAACAAATAATTGATAAATATCATCAGTTT

604

WO 2016/205711

PCT/US2016/038181

TTTATAGAGGAGATATTAAGTTCGGTTTGTATTAGCGAAGATTTATTACAAAACTATTCTGAT

AGATACGATAAAGAAACAAATATCTGAATATATAAAGGACTCAGAGAAATTTAAGAATITG

TTTAATCAAAACCTTATCGATGCTAAAAAAGGGCAAGAGTCAGATTTAATTCTATGGCTAAA

GCAATCTAAGGATAATGGTATAGAACTATTTAAAGCCAATAGTGATATCACAGATATAGATG

AGGCGTTAGAAATAATCAAATCTTTTAAAGGTTGGACAACTTATTTTAAGGGTTTTCATGAA

AATAGAAAAAATGTTTATAGTAGCAATGATATTCCTACATCTATTATTTATAGGATAGTAGA

TGATAATTTGCCTAAATTTCTAGAAAATAAAGCTAAGTATGAGAGTTTAAAAGACAAAGCTC

CAGAAGCTATAAACTATGAACAAATTAAAAAAGATITGGCAGAAGAGCTAACCTTTGATAT

TGACTACAAAACATCTGAAGTTAATCAAAGAGTTTTTTCACTTGATGAAGinTTGAGATAG

CAAACTTTAATAATTATCTAAATCAAAGTGGTATTACTAAATTTAATACTATTATTGGTGGTA

AAITTGTAAATGGTGAAAATACAAAGAGAAAAGGTATAAATGAATATATAAATCTATACTC

ACAGCAAATAAATGATAAAACACTCAAAAAATATAAAATGAGTGTTTTATTTAAGCAAATTT

TAAGTGATACAGAATCTAAATCTTTTGTAATTGATAAGTTAGAAGATGATAGTGATGTAGTT

TTAAAGAAACACTATCTTTATTATTTGATGATTTAAAAGCTCAAAAACTTGATTTGAGTAAA

ATTTATTTTAAAAATGATAAATCTCTTACTGATCTATCACAACAAGTTTTTGATGATTATAGT

GTTATTGGTACAGCGGTACTAGAATATATAACTCAACAAATAGCACCTAAAAATCTTGATAA

CCCTAGTAAGAAAGAGCAAGAATTAATAGCCAAAAAAACTGAAAAAGCAAAATACTTATCT

CTAGAAACTATAAAGCTTGCCTTAGAAGAATITAATAAGCATAGAGATATAGATAAACAGT

GTAGGTITGAAGAAATACTTGCAAACTITGCGGCTATTCCGATGATAITTGATGAAATAGCT

CAAAACAAAGACAATTTGGCACAGATATCTATCAAATATCAAAATCAAGGTAAAAAAGACC

AGACAAGGATGAGCAITITTATCTAGTATTTGAGGAGTGCTACTTTGAGCTAGCGAATATAG

TGCCTCTITATAACAAAATTAGAAACTATATAACTCAAAAGCCATATAGTGATGAGAAATTT

AAGCTCAATITTGAGAACTCGACTTTGGCTAATGGTTGGGATAAAAATAAAGAGCCTGACAA

ACAAAATATTTGATGATAAAGCTATCAAAGAAAATAAAGGCGAGGGTTATAAAAAAATTGT

TTATAAACTTTTACCTGGCGCAAATAAAATGTTACCTAAGGTITTCTTTTCTGCTAAATCTAT

AAAATTTTATAATCCTAGTGAAGATATACTTAGAATAAGAAATCATTCCACACATACAAAAA

ATGGTAGTCCTCAAAAAGGATATGAAAAATTTGAGTTTAATATTGAAGATTGCCGAAAATTT

ATAGATTTTTATAAACAGTCTATAAGTAAGCATCCGGAGTGGAAAGATTTTGGATTTAGATT

TTCTGATACTCAAAGATATAATTCTATAGATGAATTTTATAGAGAAGITGAAAATCAAGGCT

605

WO 2016/205711

PCT/US2016/038181

ACAAACTAACTTTTGAAAATATATCAGAGAGCTATATTGATAGCGTAGTTAATCAGGGTAAA

ACATACTTTATATTGGAAAGCGCTGTTTGATGAGAGAAATCTTCAAGATGTGGTTTATAAGC

TAAATGGTGAGGCAGAGCTTTTTTATCGTAAACAATCAATACCTAAAAAAATCACTCACCCA

GCTAAAGAGGCAATAGCTAATAAAAACAAAGATAATCCTAAAAAAGAGAGTGTTTTTGAAT

ATGATTTAATCAAAGATAAACGCTTTACTGAAGATAAGTTTTTCTTTCACTGTCCTATTACAA

AAAGCAAATGATGTTCATATATTAAGTATAGATAGAGGTGAAAGACATTTAGCTTACTATAC

TTTGGTAGATGGTAAAGGCAATATCATCAAACAAGATACTTTCAACATCATTGGTAATGATA

GAATGAAAACAAACTACCATGATAAGCTTGCTGCAATAGAGAAAGATAGGGATTCAGCTAG

GAAAGACTGGAAAAAGATAAATAACATCAAAGAGATGAAAGAGGGCTATCTATCTCAGGTA

GTTCATGAAATAGCTAAGCTAGTTATAGAGTATAATGCTATTGTGGTTTTTGAGGATTTAAAT

TTTGGATTTAAAAGAGGGCGTTTCAAGGTAGAGAAGCAGGTCTATCAAAAGTTAGAAAAAA

TGCTAATTGAGAAACTAAACTATCTAGTTTTCAAAGATAATGAGTTTGATAAAACTGGGGGA

AGGTATTATCTACTATGTACCAGCTGGTTTTACTTCAAAAATTTGTCCTGTAACTGGTTTTGT

AAATCAGTTATATCCTAAGTATGAAAGTGTCAGCAAATCTCAAGAGTTCTTTAGTAAGTTTG

ACAAGATTTGTTATAACCTTGATAAGGGCTATTTTGAGTTTAGTTTTGATTATAAAAACTTTG GTGACAAGGCTGCCAAAGGCAAGTGGACTATAGCTAGCTTTGGGAGTAGATTGATTAACTTT

AGAAATTCAGATAAAAATCATAATTGGGATACTCGAGAAGTTTATCCAACTAAAGAGITGG

AGAAAITGCTAAAAGATTATTCTATCGAATATGGGCATGGCGAATGTATCAAAGCAGCTATT

TGCGGTGAGAGCGACAAAAAGTTTTTTGCTAAGCTAACTAGTGTCCTAAATACTATCITACA

AATGCGTAACTCAAAAACAGGTACTGAGTTAGATTATCTAATTTCACCAGTAGCAGATGTAA

ATGGCAATTTCTTTGATTCGCGACAGGCGCCAAAAAATATGCCTCAAGATGCTGATGCCAAT

GGTGCTTATCATAITGGGCTAAAAGGTCTGATGCTACTAGGTAGGATCAAAAATAATCAAGA

GGGCAAAAAACTCAATTTGGITATCAAAAATGAAGAGTATTTTGAGTTCGTGCAGAATAGG

AATAACTAATTCATTCAAGAATATATTACCCTGTCAGTTTAGCGACTATTACCTCTTTAATAA

TATATTTAGATAACATGGTTAAATGATTTTATATTCTGTCCTTACTCGATATATTTTTTATAGA

CTAAAAATTGCAAACCTTAGTCITTATGTTAAAATAACTACTAAGTTCTTAGAGATATTTAAA

AATATGACTGTTGTTATATATCAAAATGCTAAAAAAATCATAGATTTTAGGTCTTTTTTTGCT

GATTTAGGCAAAAACGGGTCTAAGAACTTTAAATAATTTCTACTGTTGTAGATGAGAAGT

CATTTA ATAAGGCCACTGTTA AAAGTCT A A GA A CTTT A A AT A ATTTCT A CTGTTGT A GA TG CTACTATTCCTGTGCCTTCAGATAATTCAGTCTAAGAACTTTAAATAATTTC

606

WO 2016/205711

PCT/US2016/038181

AGATGTCTAGAGCCTTTTGTATTAGTAGCCGGTCTAAGAACTTTAAATAATTTCTACTGTT ' (SEQ ID NO: 213) [001666] Nucleotide «Sequences of human codon optimized Cpfl orthologs [001667] Nuclear localization signal (NLS) [001668] Glycine-Serine linker [001669] 3x HA tag [001670] 1-1 [001671] ATGAGCATCTACCAGGAGTTCGTCAACAAGTATTCACTGAGTAAGACACTGCGGT TCGAGC TGAT CCCACAGGGCAAGACACTGGAGAACATCAAGGCCCGAGGCCTGAITCTGGA cgatgagaagcgggcaaaagactataagaaagccaagcagatcattgataaataccaccag

TTCTTTATCGAGGAAATTCTGAGCTCXXiTGTGCATCAGTGAGGATCTGCTGCAGAATTACTC agacgtgtacttcaagctgaagaagagcgacgatgacaacctgcagaaggacttcaagtcc

GCCA AGGAC AC CA TC AAGAAAC AGAT TAGCGAGIA CATC A AGG A CTCCGAAA AG TT' fA A AA

ATCTGTTCAACCAGAATCTGATCGATGCTAAGAAAGGCCAGGAGTCCGACCTGATCCTGTGG

CTGAAACAGTCTAAGGACAATGGGATTGAACTGTTCAAGGCTAACTCCGATATCACTGATAT

TGACGAGGCACTGGAAATCATCAAGAGCTTCAAGGGATGGACCACATACTTTAAAGGCTTC

CACGAGAACCGCAAGAACGTGTACTCCAGCAACGACATTCCTACCTCCATCATCTACCGAAT

CGTCGATGACAATCTGCCAAAGTTCCTGGAGAACAAGGCCAAATATGAATCTCTGAAGGAC

AAAGCTCCCGAGGCAATTAATTACGAACAGATCAAGAAAGATCTGGCTGAGGAACTGACAT

TCGATATCGACTATAAGACTAGCGAGGTGAACCAGAGGGTCTTTTCCCTGGACGAGGTGTIT

GAAATCGCCAATTTCAACAATTACCTGAACCAGTCCGGCATTACTAAATTCAATACCATCAT

TGGCGGGAAGTTTGTGAACGGGGAGAATACCAAGCGCAAGGGAATTAACGAATACATCAAT

CTGTATAGCCAGCAGATCAACGACAAAACTCTGAAGAAATACAAGATGTCTGTGCTGTTCAA

ACAGATCCTGAGTGATACCGAGTCCAAGTCTTTTGTCATTGATAAACTGGAAGATGACTCAG

ACGTGGTCACTACCATGCAGAGCTTTTATGAGCAGATCGCCGCTTTCAAGACAGTGGAGGAA

AAATCTATTAAGGAAACTCTGAGTCTGCTGTTCGATGACCTGAAAGCCCAGAAGCTGGACCT

GAGTAAGATCTACTTCAAAAACGATAAGAGTCTGACAGACCTGTCACAGCAGGTGTTTGATG

ACTATTCCGTGATTGGGACCGCCGTCCTGGAGTACATTACACAGCAGATCGCTCCAAAGAAC

CTGGATAATCCCTCTAAGAAAGAGCAGGAACTGATCGCTAAGAAAACCGAGAAGGCAAAAT

ATCTGAGTCTGGAAACAATTAAGCTGGCACTGGAGGAGTTCAACAAGCACAGGGATATTGA

AGATCGCCCAGAACAAAGACAATCTGGCTCAGATCAGTATTAAGTACCAGAACCAGGGCAA

GAAAGACCTGCTGCAGGCTTCAGCAGAAGATGACGTGAAAGCCATCAAGGATCTGCTGGAC

607

WO 2016/205711

PCT/US2016/038181

CAGACCAACAATCTGCTGCACAAGCTGAAAATCTTCCATATTAGTCAGTCAGAGGATAAGGC

TAATATCCTGGATAAAGACGAACACTTCTACCTGGTGTTCGAGGAATGTTACTTCGAGCTGG

CAAACATTGTCCCCCTGTATAACAAGATTAGGAACTACATCACACAGAAGCCTTACTCTGAC

GAGAAGTTTAAACTGAACTTCGAAAATAGTACCCTGGCCAACGGGTGGGATAAGAACAAGG

AGCCTGACAACACAGCTATCCTGTTCATCAAGGATGACAAGTACTATCTGGGAGTGATGAAT

AAGAAAAACAATAAGATCTTCGATGACAAAGCCATTAAGGAGAACAAAGGGGAAGGATAC

AAGAAAATCGTGTATAAGCTGCTGCCCGGCGCAAATAAGATGCTGCCTAAGGTGTTCTTCAG

CGCCAAGAGTATCAAATTCTACAACCCATCCGAGGACATCCTGCGGATTAGAAATCACTCAA

CACATACTAAGAACGGGAGCCCCCAGAAGGGATATGAGAAATTTGAGTTCAACATCGAGGA

TTGCAGGAAGTTTATTGACTTCTACAAGCAGAGCATCTCCAAACACCCTGAATGGAAGGATT

GAAAATCAGGGGTATAAGCTGACTTTTGAGAACATTTCTGAAAGTTACATCGACAGCGTGGT

CAATCAGGGAAAGCTGTACCTGTTCCAGATCTATAACAAAGATTTTTCAGCATACAGCAAGG

GCAGACCAAACCTGCATACACTGTACTGGAAGGCCCTGTTCGATGAGAGGAATCTGCAGGA

CGTGGTCTATAAACTGAACGGAGAGGCCGAACTGTTTTACCGGAAGCAGTCTATTCCTAAGA

AAATCACTCACCCAGCTAAGGAGGCCATCGCTAACAAGAACAAGGACAATCCTAAGAAAGA

GAGCGTGTTCGAATACGATCTGATTAAGGACAAGCGGTTCACCGAAGATAAGTTCTTTTTCC

ATTGTCCAATCACCATTAACTTCAAGTCAAGCGGCGCTAACAAGTTCAACGACGAGATCAAT

CTGCTGCTGAAGGAAAAAGCAAACGATGTGCACATCCTGAGCATTGACCGAGGAGAGCGGC

ATCTGGCCTACTATACCCTGGTGGATGGCAAAGGGAATATCAITAAGCAGGATACATTCAAC

ATCATTGGCAATGACCGGATGAAAACCAACTACCACGATAAACTGGCTGCAATCGAGAAGG

A TAGAGAC TCAGCT AGGAAGGACT GGAAGAAAATCAACAACA TT AAGGAGA TGAAGGAAG

GCTATCTGAGCCAGGTGGTCCATGAGATTGCAAAGCTGGTCATCGAATACAATGCCATTGTG

GTGTTCGAGGATCTGAACTTCGGCTTTAAGAGGGGGCGCTTTAAGGTGGAAAAACAGGTCTA

TCAGAAGCTGGAGAAAATGCTGATCGAAAAGCTGAATTACCTGGTGTTTAAAGATAACGAG

TTCGACAAGACCGGAGGCGTCCTGAGAGCCTACCAGCTGACAGCTCCCTTTGAAACTTTCAA

GAAAATGGGAAAACAGACAGGCATCATCTACTATGTGCCAGCCGGATTCACTTCCAAGATCT

GCCCCGTGACCGGCTTTGTCAACCAGCTGTACCCTAAATATGAGTCAGTGAGCAAGTCCCAG

GAATTTTTCAGCAAGTTCGATAAGATCTGTTATAATCTGGACAAGGGGTACTTCGAGTTTTCC

TTCGATTACAAGAACTTCGGCGACAAGGCCGCTAAGGGGAAATGGACCATTGCCTCCTTCGG

ATCTCGCCTGATCAACTTTCGAAATTCCGATAAAAACCACAATTGGGACACTAGGGAGGTGT

ACCCAACCAAGGAGCTGGAAAAGCTGCTGAAAGACTACTCTATCGAGTATGGACATGGCGA

ATGCATCAAGGCAGCCATCTGTGGCGAGAGTGATAAGAAATTTTTCGCCAAGCTGACCTCAG

TGCTGAATACAATCCTGCAGATGCGGAACTCAAAGACCGGGACAGAACTGGACTATCTGAT

608

WO 2016/205711

PCT/US2016/038181

TAGCCCCGTGGCTGATGTCAACGGAAACTTCTTCGACAGCAGACAGGCACCCAAAAATATG

CCTCAGGATGCAGACGCCAACGGGGCCTACCACATCGGGCTGAAGGGACTGATGCTGCTGG

GCCGGATCAAGAACAATCAGGAGGGGAAGAAGCTGAACCTGGTCATTAAGAACGAGGAAT

ACTTCGAGTTrGTCCAGAATAGAAATAACLLC4GGCCGGCGGCC4CCCWWiGGCCGGCCAG

GCLL4AL4G4A4A4GGGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACG [001672] 3- Lachnospiraceae bacterium MC2017 (Lb3Cpfl) [001673 ] ATGGATTACGGC AACGGCC AGTTTGAGCGGAGAGCCCCCCTGACC AAG ACA ATC ACCCTGCGCCTGAAGCCTATCGGCGAGACACGGGAGACAATCCGCGAGCAGAAGCTGCTGG

AGCAGGACGCCGCCITCAGAAAGCTGGTGGAGACAGTGACCCCTATCGTGGACGATTGTAT

CAGGAAGATCGCCGATAACGCCCTGTGCCACTTTGGCACCGAGTATGACTTCAGCTGTCTGG

GCAACGCCAT CT C TA AGA A TGACAGCAAGGCCA f CAAGAAGGAGACAGAGAAGGT GGAGA AGCTGCTGGCCAAGGTGCTGACCGAGAATCTGCCAGATGGCCTGCGCAAGGTGAACGACAT

CAATTCCGCCGCCTTTATCCAGGATACACTGACCTCTTTCGTGCAGGACGATGCCGACAAGC

GGGTGCTGATCCAGGAGCTGAAGGGCAAGACCGTGCTGATGCAGCGGTTCCTGACCACACG

GATCACAGCCCTGACCGTGTGGCTGCCCGACAGAGTGTTCGAGAACTTTAATATCTTCATCG

AGAACGCCGAGAAGATGAGAATCCTGCTGGACTCCCCTCTGAATGAGAAGATCATGAAGTT

TGACCCAGATGCCGAGCAGTACGCCTCTCTGGAGTTCTATGGCCAGTGCCTGTCTCAGAAGG

ACATCGATAGCTACAACCTGATCATCTCCGGCATCTATGCCGACGATGAGGTGAAGAACCCT

GGCATCAATGAGATCGTGAAGGAGTACAATCAGCAGATCCGGGGCGACAAGGATGAGTCCC

CACTGCCCAAGCTGAAGAAGCTGCACAAGCAGATCCTGATGCCAGTGGAGAAGGCCTTCTTT

GTGCGCGTGCTGTCTAACGACAGCGATGCCCGGAGCATCCTGGAGAAGATCCTGAAGGACA

CAGAGATGCTGCCCTCCAAGATCATCGAGGCCATGAAGGAGGCAGATGCAGGCGACATCGC

CGTGTACGGCAGCCGGCTGCACGAGCTGAGCCACGTGATCTACGGCGATCACGGCAAGCTG

TCCCAGATCATCTATGACAAGGAGTCCAAGAGGATCTCTGAGCTGATGGAGACACTGTCTCC

AAAGGAGCGCAAGGAGAGCAAGAAGCGGCTGGAGGGCCTGGAGGAGCACATCAGAAAGTC

TACATACACCTTCGACGAGCTGAACAGGTATGCCGAGAAGAATGTGATGGCAGCATACATC

GC AGCAGTGGAGGAGTCT TGTGCCGAGATC AIGAGAAAGGAGAAGGATCT GAGGACCCTGC

TGAGCAAGGAGGACG TGAAGATCCGGGGCAACAGACACAATACACTGATCGTGAAGAAC ΓΑ

CTTTAATGCCTGGACCGTGTTCCGGAACCTGATCAGAATCCTGAGGCGCAAGTCCGAGGCCG

AGATCGACTCTGACITCTACGATGTGCTGGACGATTCCGTGGAGGTGCTGTCTCTGACATAC

AAGGGCGAGAATCTGTGCCGCAGCTATATCACCAAGAAGATCGGCTCCGACCTGAAGCCCG

AGATCGCCACATACGGCAGCGCCCTGAGGCCTAACAGCCGCT GGTGGTCCCCAGGAGAGAA

609

WO 2016/205711

PCT/US2016/038181

GTTTAATGTGAAGTTCCACACCATCGTGCGGAGAGATGGCCGGCTGTACTATTTCATCCTGC

CCAAGGGCGCCAAGCCTGTGGAGCTGGAGGACATGGATGGCGACATCGAGTGTCTGCAGAT

GAGAAAGATCCCTAACCCAACAATCnTCTGCCCAAGCTGGTGTTCAAGGACCCTGAGGCCT

TCTTTAGGGATAATCCAGAGGCCGACGAGTTCGTGTTTCTGAGCGGCATGAAGGCCCCCGTG

ACAATCACCAGAGAGACATACGAGGCCTACAGGTATAAGCTGTATACCGTGGGCAAGCTGC

GCGA FGGCGAGG FGICCGAAGAGGAG fACAAGCGGGCCCTGC FGCAGG FGCTGACCGCCTA

CAAGGAGTTTCTGGAGAACAGAATGATCTATGCCGACCTGAATTTCGGCTTTAAGGATCTGG

AGGAGTATAAGGACAGCTCCGAGITTATCAAGCAGGTGGAGACACACAACACCTTCATGTG

CTGGGCCAAGGTGTCTAGCTCCCAGCTGGACGATCTGGTGAAGTCTGGCAACGGCCTGCTGT

TCGAGATCTGGAGCGAGCGCCTGGAGTCCT AC TAT AAGTACGGCAATGAGAAGGT GCTGCG

GGGCTATGAGGGCGTGCTGCTGAGCATCCTGAAGGATGAGAACCTGGTGTCCATGCGGACC

CTGCTGAACAGCCGGCCCATGCTGGTGTACCGGCCAAAGGAGTCTAGCAAGCCTATGGTGGT

GCACCGGGATGGCAGCAGAGTGGTGGACAGGTTTGATAAGGACGGCAAGTACATCCCCCCT

GAGGTGCACGACGAGC TGT ATCGCTfCTTTAACAATCTGC EGA ICAAGGAGAAGCTGGGCGA

GAAGGCCCGGAAGATCCTGGACAACAAGAAGGTGAAGGTGAAGGTGCTGGAGAGCGAGAG

AGTGAAGTGGTCCAAGTTCTACGATGAGCAGTTTGCCGTGACCITCAGCGTGAAGAAGAAC

GCCGATTGTCTGGACACCACAAAGGACCTGAATGCCGAAGTGATGGAGCAGTATAGCGAGT

CCAACAGACTGATCCTGATCAGGAATACCACAGATATCCTGTACTATCTGGTGCTGGACAAG

AATGGCAAGGTGCTGAAGCAGAGATCCCTGAACATCATCAATGACGGCGCCAGGGATGTGG

ACTGGAAGGAGAGGTTCCGCCAGGTGACAAAGGATAGAAACGAGGGCTACAATGAGTGGG

ATTATTCCAGGACCTCTAACGACCTGAAGGAGGTGTACCTGAATTATGCCCTGAAGGAGATC

GCCGAGGCCGTGATCGAGTACAACGCCATCCTGATCATCGAGAAGATGTCTAATGCCTTTAA

GGACAAGTATAGCTTCCTGGACGACGTGACCTTCAAGGGCTTCGAGACAAAGCTGCTGGCC

AAGCTGAGCGATCTGCACTTTAGGGGCATCAAGGACGGCGAGCCATGTTCCTTCACAAACCC

CCTGCAGCTGTGCCAGAACGATTCTAATAAGATCCTGCAGGACGGCGTGATCTTTATGGTGC

CAAATTCTATGACACGGAGCCTGGACCCCGACACCGGCTTCATCTTTGCCATCAACGACCAC

AATATCAGGACCAAGAAGGCCAAGCTGAACTTTCTGAGCAAGTTCGATCAGCTGAAGGTGT

CCTCTGAGGGCTGCCTGATCATGAAGTACAGCGGCGATTCCCTGCCTACACACAACACCGAC

AATCGCGTGTGGAACTGCTGTTGCAATCACCCAATCACAAACTATGACCGGGAGACAAAGA

AGGTGGAGTICATCGAGGAGCCCG IGGAGGAGCTG I CC CGCG TGCTGGAGGAGAA TGGCAT

CGAGACAGACACCGAGCTGAACAAGCTGAATGAGCGGGAGAACGTGCCTGGCAAGGTGGT

GGATGCCATCTACTCTCTGGTGCTGAATTATCTGCGCGGCACAGTGAGCGGAGTGGCAGGAC

AGAGGGCCGTGTACTATAGCCCTGTGACCGGCAAGAAGTACGATATCTCCTTTATCCAGGCC

ATGAACCTGAATAGGAAGTGTGACTACTATAGGATCGGCTCCAAGGAGAGGGGAGAGTGGA

610

WO 2016/205711

PCT/US2016/038181

CCGATTTCGTGGCCCAGCTGATCAACAAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAA ,M,Mf;4A4A4GGGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGC CTGATTATGCATACCCATATGATGTCCCCGACTATGCC (SEQ ID NO: 215) [001674] 4- Butyrivibrio proteoclasticos (BpCpfl) [001675] ATGAGCATCTACCAGGAGTTCGTCAACAAGTATTCACTGAGTAAGACACTGCGGT

TCGAGCTGATCCCACAGGGCAAGACACTGGAGAACATCAAGGCCCGAGGCCTGAITCTGGA

CGATGAGAAGCGGGCAAAAGACTATAAGAAAGCCAAGCAGATCATTGATAAATACCACCAG

TTCTTTATCGAGGAAATTCTGAGCTCCGTGTGCATCAGTGAGGATCTGCTGCAGAATTACTC

AGACGTGTACTTCAAGCTGAAGAAGAGCGACGATGACAACCTGCAGAAGGACTTCAAGTCC

GCCAAGGACACCATCAAGAAACAGAITAGCGAGTACATCAAGGACTCCGAAAAGTTTAAAA

ATCTGITCAACCAGAATCTGATCGATGCTAAGAAAGGCCAGGAGTCCGACCTGATCCTGTGG

CTGAAACAGTCTAAGGACAATGGGATTGAACTGTTCAAGGCTAACTCCGATATCACTGATAT

TGACGAGGCACTGGAAATCATCAAGAGCTTCAAGGGATGGACCACATACTTTAAAGGCTTC

CACGAGAACCGCAAGAACGTGTACTCCAGCAACGACAITCCTACCTCCATCATCTACCGAAT

CGTCGATGACAATCTGCCAAAGTTCCTGGAGAACAAGGCCAAATATGAATCTCTGAAGGAC

AAAGCTCCCGAGGCAATTAATTACGAACAGATCAAGAAAGATCTGGCTGAGGAACTGACAT

TCGATATCGACTATAAGACTAGCGAGGTGAACCAGAGGGTCTTTTCCCTGGACGAGGTGTTT

GAAATCGCCAATTTCAACAATTACCTGAACCAGTCCGGCATTACTAAATTCAATACCATCAT

TGGCGGGAAGTTTGTGAACGGGGAGAATACCAAGCGCAAGGGAATTAACGAATACATCAAT

CTGTATAGCCAGCAGATCAACGACAAAACTCTGAAGAAATACAAGATGTCTGTGCTGTTCAA

ACAGATCCTGAGTGATACCGAGTCCAAGTCTTTTGTCATTGATAAACTGGAAGATGACTCAG

ACGTGGTCACTACCATGCAGAGCTTTTATGAGCAGATCGCCGCTTTCAAGACAGTGGAGGAA

AAATCTATTAAGGAAACTCTGAGTCTGCTGTTCGATGACCTGAAAGCCCAGAAGCTGGACCT

GAGTAAGATCTACTTCAAAAACGATAAGAGTCTGACAGACCTGTCACAGCAGGTGTTTGATG

AC IATTCCGTGATTGGGACCGCCGTCCTGGAGTACAITACACAGCAGATCGCTCCAAAGAAC

CTGGATAATCCCTCTAAGAAAGAGCAGGAACTGATCGCTAAGAAAACCGAGAAGGCAAAAT

ATCTGAGTCTGGAAACAATTAAGCTGGCACTGGAGGAGTTCAACAAGCACAGGGATATTGA

CAAACAGTGCCGCTITGAGGAAATCCTGGCCAACTTCGCAGCCATCCCCATGATnTTGATG

AGAT CGCCCAGAAC AAAGACAAT C fGGCT CAGATCAGTAT fAAG fACCAGAACCAGGGCAA

GAAAGACCTGCTGCAGGCTTCAGCAGAAGATGACGTGAAAGCCATCAAGGATCTGCTGGAC

CAGACCAACAATCTGCTGCACAAGCTGAAAATCTTCCATATTAGTCAGTCAGAGGATAAGGC

TAATATCCTGGATAAAGACGAACACTTCTACCTGGTGTTCGAGGAATGTTACTTCGAGCTGG

CAAACATTGTCCCCCTGTATAACAAGATTAGGAACTACATCACACAGAAGCCTTACTCTGAC

611

WO 2016/205711

PCT/US2016/038181

GAGAAG FT' FAA AC I GA ACT FCGA A A A FAG IACCCIGGCC A ACGGGT GGG AI AAG A AC A AGG AGCCTGACAACACAGCTATCCTGTTCATCAAGGATGACAAGTACTATCTGGGAGTGATGAAT

AAGAAAAACAATAAGATCTTCGATGACAAAGCCATTAAGGAGAACAAAGGGGAAGGATAC

AAGAAAATCGTGTATAAGCTGCTGCCCGGCGCAAATAAGATGCTGCCTAAGGTGTTCTTCAG CGCCAAGAGTATCAAATTCTACAACCCATCCGAGGACATCCTGCGGATTAGAAATCACTCAA C ACAT AC TAAGAACGGGAGCCCCCAGAAGGGA TAT GAG AAA IT FGAGTTCAACATCGAGGA

TTGCAGGAAGTTTATTGACTTCTACAAGCAGAGCATCTCCAAACACCCTGAATGGAAGGATT

TTGGCTTCCGGTTTTCCGACACACAGAGATATAACTCTATCGACGAGTTCTACCGCGAGGTG

GAAAATCAGGGGTATAAGCTGACTTTTGAGAACATTTCTGAAAGTTACATCGACAGCGTGGT

CAATCAGGGAAAGCTGTACCTGTTCCAGATCTA fAACAAAGATTTTTCAGCATACAGCAAGG

GCAGACCAAACCTGCATACACTGTACTGGAAGGCCCTGTTCGATGAGAGGAATCTGCAGGA

CGTGGTCTATAAACTGAACGGAGAGGCCGAACTGTITTACCGGAAGCAGTCTATTCCTAAGA

AAATCACTCACCCAGCTAAGGAGGCCATCGCTAACAAGAACAAGGACAATCCTAAGAAAGA

GAGCGTGTTCGAATACGATCTGATTAAGGACAAGCGGTTCACCGAAGATAAGTTCTTTTTCC

ATTGTCCAATCACCATTAACTTCAAGTCAAGCGGCGCTAACAAGTTCAACGACGAGATCAAT

CTGCTGCTGAAGGAAAAAGCAAACGATGTGCACATCCTGAGCATTGACCGAGGAGAGCGGC

ATCTGGCCTACTATACCCTGGTGGATGGCAAAGGGAATATCATTAAGCAGGATACATTCAAC

ATCATTGGCAATGACCGGATGAAAACCAACTACCACGATAAACTGGCTGCAATCGAGAAGG

ATAGAGACTCAGCTAGGAAGGACTGGAAGAAAATCAACAACATTAAGGAGATGAAGGAAG

GCTATCTGAGCCAGGTGGTCCATGAGAITGCAAAGCTGGTCATCGAATACAATGCCAITGTG

GTGTTCGAGGATCTGAACTTCGGCTTTAAGAGGGGGCGCTTTAAGGTGGAAAAACAGGTCTA

TCAGAAGCTGGAGAAAATGCTGATCGAAAAGCTGAATTACCTGGTGTTTAAAGATAACGAG

TTCGACAAGACCGGAGGCGTCCTGAGAGCCTACCAGCTGACAGCTCCCTTTGAAACTTTCAA

GAAAATGGGAAAACAGACAGGCATCATCTACTATGTGCCAGCCGGATTCACTTCCAAGATCT

GCCCCGTGACCGGCITTGTCAACCAGCTGTACCCTAAATATGAGTCAGTGAGCAAGTCCCAG

GAATTTTTCAGCAAGTTCGATAAGATCTGTTATAATCTGGACAAGGGGTACTTCGAGTTTTCC

TTCGATTACAAGAACTTCGGCGACAAGGCCGCTAAGGGGAAATGGACCATTGCCTCCTTCGG

ATCTCGCCTGATCAACTTTCGAAATTCCGATAAAAACCACAATTGGGACACTAGGGAGGTGT

ACCCAACCAAGGAGCTGGAAAAGCTGCTGAAAGACTACTCTATCGAGTATGGACATGGCGA

ATGCATCAAGGCAGCCATCTGTGGCGAGAGTGATAAGAAATTTTTCGCCAAGCTGACCTCAG

TGCTGAATACAATCCTGCAGATGCGGAACTCAAAGACCGGGACAGAACTGGACTATCTGAT

TAGCCCCGTGGCTGATGTCAACGGAAACTTCTTCGACAGCAGACAGGCACCCAAAAATATG

CCTCAGGATGCAGACGCCAACGGGGCCTACCACATCGGGCTGAAGGGACTGATGCTGCTGG

GCCGGATCAAGAACAATCAGGAGGGGAAGAAGCTGAACCTGGTCATTAAGAACGAGGAAT

612

WO 2016/205711

PCT/US2016/038181

ACTTCGAGTTTGTCCAGAATAGAAATAACATATGGCCGGCGGCCTCGTTTTTGGCCGGCCTG GCUTTTTTGTTTTTGGGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACG TGCCTGATTATGCATACCCATATGATGTCCCCGACTATGCC (SEQ ID NO: 216) [001676] 5- Peregrinibacteria bacterium GW2011_GWA_33_10 (PeCpfl) [001677] ATGTCCAACTTCTTTAAGAATTTCACCAACCTGTATGAGCTGTCCAAGACACTGA GGTTTGAGCTGAAGCCCGTGGGCGACACCCTGACAAACATGAAGGACCACCTGGAGTACGA

TGAGAAGCTGCAGACCITCCTGAAGGATCAGAATATCGACGATGCCTATCAGGCCCTGAAG

CCTCAG ΓΤ CGACGAGATCCACGAGGAGT IT A FCACAGATT CTCIGGAGAGC AAGAAGGCCA

AGGAGATCGACTTCTCCGAGTACCTGGATCTGTTTCAGGAGAAGAAGGAGCTGAACGACTCT

GAGAAGAAGCTGCGCAACAAGATCGGCGAGACAITCAACAAGGCCGGCGAGAAGTGGAAG

AAGGAGAAGTACCCTCAGTATGAGTGGAAGAAGGGCTCCAAGATCGCCAATGGCGCCGACA

TCCTGTCTTGCCAGGATATGCTGCAGTTTATCAAGTATAAGAACCCAGAGGATGAGAAGATC aagaattacatcgacgatacactgaagggcttctttacctatttcggcggctttaatcagaa

CAGGGCCAACTACTATGAGACAAAGAAGGAGGCCTCCACCGCAGTGGCAACAAGGATCGTG cacgagaacctgccaaagttctgtgacaatgtgatccagtitaagcacatcatcaagcggaa gaaggatggcaccgtggagaaaaccgagagaaagaccgagtacctgaacgcctaccagtat ctgaagaacaataacaagatcacacagatcaaggacgccgagacagagaagatgatcgag tctacacccatcgccgagaagatcttcgacgtgtactacitcagcagctgcctgagccagaa gcagatcgaggagtacaaccggatcatcggccactataatctgctgatcaacctgtataac( aggccaagagatctgagggcaagcacctgagcgccaacgagaagaagtataaggacctgc

CTAAG II C AAGACCCI GT A F AAGCAGAT CGGCIGCGGCAAGAAGAAGGACCTG iTTTACAC aatcaagtgtgataccgaggaggaggccaataagtcccggaacgagggcaaggagtcccac tctgtggaggagatcatcaacaaggcccaggaggccatcaataagtacitcaagtctaata acgactgtgagaatatcaacaccgtgcccgacttcatcaactatatcctgacaaaggagaat IACGAGGGCGI GT A ft ggagcaaggccgccat gaacaccatct ccgacaagtacttcgcca attatcacgacctgcaggatagactgaaggaggccaaggtgtttcagaaggccgataagaa gtccgaggacgatatcaagatcccagaggccatcgagctgtctggcctgitcggcgtgctgg acagcctggccgattggcagaccacactgtttaagtctagcatcctgagcaacgaggacaa gctgaagatcatcacagattcccagaccccctctgaggccctgctgaagatgatcttcaatg acatcgagaagaacatggagtcctttctgaaggagacaaacgatatcatcaccctgaagaa gtataagggcaataaggagggcaccgagaagatcaagcagtggitcgactatacactggcc atcaaccggatgctgaagtactttctggtgaaggagaataagatcaagggcaactccctgg ataccaatatctctgaggccctgaaaaccctgatctacagcgacgatgccgagtggttcaag

613

WO 2016/205711

PCT/US2016/038181

TGG I ACGACGCCC TGAGAAACTArCTGACCCAGAAGCCT CAGGATGAGGCCAAGGAGAATA

AGCTGAAGCTGAATTTCGACAACCCATCTCTGGCCGGCGGCTGGGATGTGAACAAGGAGTG

CAGCAATTTTTGCGTGATCCTGAAGGACAAGAACGAGAAGAAGTACCTGGCCATCATGAAG

AAGGGCGAGAATACCCTGTTCCAGAAGGAGTGGACAGAGGGCCGGGGCAAGAACCTGACA

AAGAAGTCTAATCCACTGTTCGAGATCAATAACTGCGAGATCCTGAGCAAGATGGAGTATG

AC rrTTGGGCCGACGTGAGCAAGATGA FCCCCAAGTGTAGCACCCAGCTGAAGGCCG fGGT

GAACCACTTCAAGCAGTCCGACAATGAGTTCATCTTTCCTATCGGCTACAAGGTGACAAGCG

GCGAGAAGITTAGGGAGGAGTGCAAGATCTCCAAGCAGGACTTCGAGCTGAATAACAAGGT

GITTAATAAGAACGAGCTGAGCGTGACCGCCATGCGCTACGATCTGTCCTCTACACAGGAGA

AGCAGTATATCAAGGCCTTCCAGAAGGAGTACTGGGAGCTGCTGTTTAAGCAGGAGAAGCG

GGACACCAAGCTGACAAATAACGAGATCITCAACGAGTGGATCAATTTTTGCAACAAGAAG

TATAGCGAGCTGCTGTCCTGGGAGAGAAAGTACAAGGATGCCCTGACCAATTGGATCAACIT

CTGTAAGTACTTTCTGAGCAAGTATCCCAAGACCACACTGTTCAACTACTCTTTTAAGGAGA

GCGAGAATTATAACTCCCTGGACGAGTTCTACCGGGACGTGGATATCTGTTCTTACAAGCTG

AATATCAACACCACAATCAATAAGAGCATCCTGGATAGACTGGTGGAGGAGGGCAAGCTGT

ACCTGTTTGAGATCAAGAATCAGGACAGCAACGATGGCAAGTCCATCGGCCACAAGAATAA

CCTGCACACCATCTACTGGAACGCCATCTTCGAGAATTTTGACAACAGGCCTAAGCTGAATG

GCGAGGCCGAGATCTTCTATCGCAAGGCCATCTCCAAGGATAAGCTGGGCATCGTGAAGGG

CAAGAAAACCAAGAACGGCACCGAGATCATCAAGAATTACAGATTCAGCAAGGAGAAGTTT

ATCCTGCACGTGCCAATCACCCTGAACTTCTGCTCCAATAACGAGTATGTGAATGACATCGT

GAACACAAAGTTCTACAATTTTTCCAACCTGCACTTTCTGGGCATCGATAGGGGCGAGAAGC

ACCTGGCCIACTA IT C TCFGG ITjAATAAGAACGGCGAGATCGTGGACCAGGGCACAC IGAA

CCTGCCTTTCACCGACAAGGATGGCAATCAGCGCAGCATCA

ACAAGCAGGAGGACAAGTGGGAGGCCAAGGAGGTGGATTGTTGGAATTATAACGACCTGCT

GGATGCCATGGCCTCTAACCGGGACATGGCCAGAAAGAATTGGCAGAGGATCGGCACCATC

AAGGAGGCCAAGAACGGCTACGTGAGCCTGGTCATCAGGAAGATCGCCGATCTGGCCGTGA

ATAACGAGCGCCCCGCCTTCATCGTGCTGGAGGACCTGAATACAGGCTTTAAGCGGTCCAGA

CAGAAGATCGATAAGAGCGTGTACCAGAAGTTCGAGCTGGCCCTGGCCAAGAAGCTGAACT

TTCTGGTGGACAAGAATGCCAAGCGCGATGAGATCGGCTCCCCTACAAAGGCCCTGCAGCT

GACCCCCCCTGTGAATAACTACGGCGACATTGAGAACAAGAAGCAGGCCGGCATCATGCTG

IATACCCGGGCCAAITATACCTCT CAGACAGATCCAGCCACAGGCT GGAGAAAGACCATCTA

TCTGAAGGCCGGCCCCGAGGAGACAACATACAAGAAGGACGGCAAGATCAAGAACAAGAG

CGTGAAGGACCAGATCATCGAGACATTCACCGATATCGGCTTTGACGGCAAGGATTACTATT

TCGAGTACGACAAGGGCGAGITTGTGGATGAGAAAACCGGCGAGATCAAGCCCAAGAAGTG

614

WO 2016/205711

PCT/US2016/038181

GCGGCTGrACTCCGGCGAGAATGGCAAGTCCCTGGACAGGTTCCGCGGAGAGAGGGAGAAG

GATAAGTATGAGTGGAAGATCGACAAGATCGATATCGTGAAGATCCTGGACGATCTGTTCGT

GAATTTTGACAAGAACATCAGCCTGCTGAAGCAGCTGAAGGAGGGCGTGGAGCTGACCCGG

AATAACGAGCACGGCACAGGCGAGTCCCTGAGATTCGCCATCAACCTGATCCAGCAGATCC

GGAATACCGGCAA TAACGAGAGAGACAACGAITICATCCTG FCCCCAG1GAGGGACGAGAA

TGGCAAGCACTTTGACTCTCGCGAGTACTGGGATAAGGAGACAAAGGGCGAGAAGATCAGC

ATGCCCAGCTCCGGCGATGCCAATGGCGCCTTCAACATCGCCCGGAAGGGCATCATCATGAA

CGCCCACATCCTGGCCAATAGCGACTCCAAGGATCTGTCCCTGTTCGTGTCTGACGAGGAGT

GGGATCTGCACCTGAATAACAAGACCGAGTGGAAGAAGCAGCTGAACATCTTTTCTAGCAG

GAAGGCCAAGGCCAAGCGCAAGAAGAAAAGGCCGGCGGCCACGAAAAAGGCCCXXCAGGGAA

4rfA4G4/iA/MGGGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGC

CTGATTATGCATACCCATATGATGTCCCCGACTATGCCTAAGAATTC (SEQ ID NO: 217) [001678] 6- Parcubacteria bacterium GWC2011 _GWC2.. 44 _ 17 (PbCpfl) [001679] ATGGAGAACATCTTCGACCAGTTTATCGGCAAGTACAGCCTGTCCAAGACCCTGA

GATTCGAGCTGAAGCCCGTGGGCAAGACAGAGGACTTCCTGAAGATCAACAAGGTGTITGA

GAAGGATCAGACCATCGACGATAGCTACAATCAGGCCAAGTTCTATTTTGATTCCCTGCACC

AGAAGTTTATCGACGCCGCCCTGGCCTCCGATAAGACATCCGAGCTGTCTTTCCAGAACTTT

GCCGACGTGCTGGAGAAGCAGAATAAGATCATCCTGGATAAGAAGAGAGAGATGGGCGCCC

TGAGGAAGCGCGACAAGAACGCCGTGGGCATCGATAGGCTGCAGAAGGAGATCAATGACG

CCGAGGATATCATCCAGAAGGAGAAGGAGAAGATCTACAAGGACGTGCGCACCCTGTTCGA

TAACGAGGCCGAGTCTTGGAAAACCTACTATCAGGAGCGGGAGGTGGACGGCAAGAAGATC

ACCTTCAGCAAGGCCGACCTGAAGCAGAAGGGCGCCGATTTTCTGACAGCCGCCGGCATCCT

GAAGGTGCTGAAGTATGAGTTCCCCGAGGAGAAGGAGAAGGAGTTTCAGGCCAAGAACCAG

CCCTCCCTGTTCGTGGAGGAGAAGGAGAATCCTGGCCAGAAGAGGTACATCTTCGACTCTTT

TGATAAGITCGCCGGCTATCTGACCAAGTTTCAGCAGACAAAGAAGAATCTGTACGCAGCA

GACGGCACCAGCACAGCAGTGGCCACCCGCATCGCCGATAACTTTATCATCTTCCACCAGAA

TACCAAGGTGTTCCGGGACAAGTACAAGAACAATCACACAGACCTGGGCTTCGATGAGGAG

AACATCTTTGAGATCGAGAGGTATAAGAATTGCCTGCTGCAGCGCGAGATCGAGCACATCA

AGAATGAGAATAGCTACAACAAGATCATCGGCCGGATCAATAAGAAGATCAAGGAGTATCG

GGACCAGAAGGCCAAGGATACCAAGCTGACAAAGTCCGACTTCCCTTTCTTTAAGAACCTGG

ATAAGCAGATCCTGGGCGAGGTGGAGAAGGAGAAGCAGCTGATCGAGAAAACCCGGGAGA

AAACCGAGGAGGACGTGCTGATCGAGCGGTTCAAGGAGTTCATCGAGAACAATGAGGAGAG

GTTCACCGCCGCCAAGAAGCTGATGAATGCCTTCTGTAACGGCGAGTTTGAGTCCGAGTACG

615

WO 2016/205711

PCT/US2016/038181

AGGGCATCTATCTGAAGAATAAGGCCATCAACACAATCTCCCGGAGATGGTTCGTGTCTGAC

CAAAGGTGAAGAAGTTCATCTCCATCGCCGAGATCAAGAACGCCGTGGAGGAGCTGGACGG

CGATATCTTTAAGGCCGTGTTCTACGACAAGAAGATCATCGCCCAGGGCGGCTCTAAGCTGG

AGCAGTTCCTGGTCATCTGGAAGTACGAGTTTGAGTATCTGTTCCGGGACATCGAGAGAGAG

AACGGCGAGAAGCT GC 1GGGCIATGATAGCIGCC TGAAGAT CGCCAAGCAGCT GGGCAT CI

TCCCACAGGAGAAGGAGGCCCGCGAGAAGGCAACCGCCGTGATCAAGAATTACGCCGACGC

CGGCCTGGGCATCTTCCAGATGATGAAGTATTTTTCTCTGGACGATAAGGATCGGAAGAACA

CCCCCGGCCAGCTGAGCACAAATTTCTACGCCGAGTATGACGGCTACTACAAGGATTTCGAG

TTTATCAAGTACTACAACGAGTTTAGGAACTTCATCACCAAGAAGCCTTTCGACGAGGATAA

GATCAAGCTGAACTTTGAGAATGGCGCCCTGCTGAAGGGCTGGGACGAGAACAAGGAGTAC

GATTTCATGGGCGTGATCCTGAAGAAGGAGGGCCGCCTGTATCTGGGCATCATGCACAAGA

ACCACCGGAAGCTGTTTCAGTCCATGGGCAATGCCAAGGGCGACAACGCCAATAGATACCA

GAAGATGATCTATAAGCAGATCGCCGACGCCTCTAAGGATGTGCCCAGGCTGCTGCTGACCA

GCAAGAAGGCCATGGAGAAGTTCAAGCCTTCCCAGGAGATCCTGAGAATCAAGAAGGAGAA

AACCTTCAAGCGGGAGAGCAAGAACTTTTCCCTGAGAGATCTGCACGCCCTGATCGAGTACT

ATAGGAACTGCATCCCTCAGTACAGCAATTGGTCCTTTTATGACTTCCAGTTTCAGGATACCG

GCAAGTACCAGAATATCAAGGAGTTCACAGACGATGTGCAGAAGTACGGCTATAAGATCTC

CTTTCGCGACATCGACGATGAGTATATCAATCAGGCCCTGAACGAGGGCAAGATGTACCTGT

TCGAGGTGGTGAACAAGGATATCTATAACACCAAGAATGGCTCCAAGAATCTGCACACACT

GTACTTTGAGCACATCCTGTCTGCCGAGAACCTGAATGACCCAGTGTTCAAGCTGTCTGGCA

TGGCCGAGATCTTTCAGCGGCAGCCCAGCGTGAACGAAAGAGAGAAGATCACCACACAGAA

GAATCAGTGTATCCTGGACAAGGGCGATAGAGCCTACAAGTATAGGCGCTACACCGAGAAG

AAGATCATGTTCCACATGAGCCTGGTGCTGAACACAGGCAAGGGCGAGATCAAGCAGGTGC

AGTTTAATAAGATCATCAACCAGAGGATCAGCTCCTCTGACAACGAGATGAGGGTGAATGT

GATCGGCATCGATCGCGGCGAGAAGAACCTGCTGTACTATAGCGTGGTGAAGCAGAATGGC

GAGATCATCGAGCAGGCCTCCCTGAACGAGATCAATGGCGTGAACTACCGGGACAAGCTGA

TCGAGAGGGAGAAGGAGCGCCTGAAGAACCGGCAGAGCTGGAAGCCTGTGGTGAAGATCA

AGGATCTGAAGAAGGGCTACATCTCCCACGTGATCCACAAGATCTGCCAGCTGATCGAGAA

GTATTCTGCCATCGTGGTGCTGGAGGACCTGAATATGAGATTCAAGCAGATCAGGGGAGGA

A TCG A GCGGAGCG TGT AC C AGC AG TT C GAG A A .GGCCCTGA' f CGAIAAGCTGGGC TA IC TGG

TGTTTAAGGACAACAGGGATCTGAGGGCACCAGGAGGCGTGCTGAATGGCTACCAGCTGTC

TGCCCCCTTTGTGAGCTTCGAGAAGATGCGCAAGCAGACCGGCATCCTGTTCTACACACAGG

CCGAGTATACCAGCAAGACAGACCCAATCACCGGCTTTCGGAAGAACGTGTATATCTCTAAT

616

WO 2016/205711

PCT/US2016/038181

AGCGCCTCCCTGGATAAGATCAAGGAGGCCGTGAAGAAGTTCGACGCCATCGGCTGGGATG

GCAAGGAGCAGTCTTACTTCTTTAAGTACAACCCTTACAACCTGGCCGACGAGAAGTATAAG

AACTCTACCGTGAGCAAGGAGTGGGCCATCTTTGCCAGCGCCCCAAGAATCCGGAGACAGA

AGGGCGAGGACGGCTACTGGAAGTATGATAGGGTGAAAGTGAATGAGGAGTTCGAGAAGCT

GCTGAAGGTCTGGAATTTTGTGAACCCAAAGGCCACAGATATCAAGCAGGAGATCATCAAG AAGGAGAAGGC AGGCGACC rGCAGGGAGAGAAGGAGCT GGATGGCCGGCIGAGAAAC IT f TGGCACTCTTTCATCTACCTGTTTAACCTGGTGCTGGAGCTGCGCAATTCTTTCAGCCTGCAG

ATCAAGATCAAGGCAGGAGAAGTGATCGCAGTGGACGAGGGCGTGGACTTCATCGCCAGCC CAGTGAAGCCCTTCTTTACCACACCCAACCCTTACATCCCCTCCAACCTGTGCTGGCTGGCCG TGGAGAAT GCAGACGCAAACGGAGCCT ATAA FAT CGCCAGGAAGGGCGI GAT GATCCT G AA GAAGATCCGCGAGCACGCCAAGAAGGACCCCGAGTTCAAGAAGCTGCCAAACCTGTTTATC

AGCAATGCAGAGTGGGACGAGGCAGCCCGGGATTGGGGCAAGTACGCAGGCACCACAGCC

CIGAACCTGGACCACAAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAG

GGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGC

ATACCCATATGATGTCCCCGACTATGCCTAAGAATTC (SEQ ID NO: 218) [001680] 7- Smithella sp. SCJK08D17 (SsCpfl) [001681] ATGCAGACCCTGTTTGAGAACTTC AC AAATCAGTACCC AGTGTCC AAGACCCTGC GCTTTGAGCTGATCCCCCAGGGCAAGACAAAGGACTTCATCGAGCAGAAGGGCCTGCTGAA

GAAGGATGAGGACCGGGCCGAGAAGTATAAGAAGGTGAAGAACATCATCGATGAGTACCA

CAAGGACTTCATCGAGAAGTCTCTGAATGGCCTGAAGCTGGACGGCCTGGAGAAGTACAAG

ACCCTGTATCTGAAGCAGGAGAAGGACGATAAGGATAAGAAGGCCTTTGACAAGGAGAAG

GAGAACCTGCGCAAGCAGATCGCCAATGCCTTCCGGAACAATGAGAAGTTTAAGACACTGT

TCGCCAAGGAGCTGATCAAGAACGATCTGATGTCTTTCGCCTGCGAGGAGGACAAGAAGAA

TGTGAAGGAGTITGAGGCCTTCACCACATACTTCACCGGCITCCACCAGAACCGCGCCAATA

TGTACGTGGCCGATGAGAAGAGAACAGCCATCGCCAGCAGGCTGATCCACGAGAACCTGCC

AAAGTTTATCGACAATATCAAGATCTTCGAGAAGATGAAGAAGGAGGCCCCCGAGCTGCTG

TCTCCITTCAACCAGACCCTGAAGGATATGAAGGACGTGATCAAGGGCACCACACTGGAGG

AGATCTTTAGCCTGGAITATTTCAACAAGACCCTGACACAGAGCGGCATCGACATCTACAAT

TCCGTGATCGGCGGCAGAACCCCTGAGGAGGGCAAGACAAAGA fCAAGGGCCT GAACGAGI ACATCAATACCGACTTCAACCAGAAGCAGACAGACAAGAAGAAGCGGCAGCCAAAGTTCAA

GCAGCTGTATAAGCAGATCCTGAGCGATAGGCAGAGCCTGTCCTTTATCGCCGAGGCCTTCA

AGAACGACACCGAGATCCTGGAGGCCATCGAGAAGTITTACGTGAATGAGCTGCTGCACITC

AGCAATGAGGGCAAGTCCACAAACGTGCTGGACGCCATCAAGAATGCCGTGTCTAACCTGG

617

WO 2016/205711

PCT/US2016/038181

AGAGCTTTAACCTGACCAAGATGTATTTCCGCTCCGGCGCCTCTCTGACAGACGTGAGCCGG

AAGGTGTTTGGCGAGTGGAGCATCATCAATAGAGCCCTGGACAACTACTATGCCACCACATA

TCCAATCAAGCCCAGAGAGAAGTCTGAGAAGTACGAGGAGAGGAAGGAGAAGTGGCTGAA

GCAGGACTTCAACGTGAGCCTGATCCAGACCGCCATCGATGAGTACGACAACGAGACAGTG

A AGGGC A A GAAC AGCGGC A AAGT GATCGCCGAT TA ITITGCCA AG TTCI GCG A CG A I AAGG

AGAC AGA CC fGA ICC AG A AGG IG A ACGAGGGC TAC AT CGCCG TGAAGGA' TCT GC TGA AI AC

ACCCTGTCCTGAGAACGAGAAGCTGGGCAGCAATAAGGACCAGGTGAAGCAGATCAAGGCC

TTTATGGATTCTATCATGGACATCATGCACTTCGTGCGCCCCCTGAGCCTGAAGGATACCGA

CAAGGAGAAGGATGAGACATTCTACTCCCTGTTCACACCTCTGTACGACCACCTGACCCAGA

CAATCGCCCTGTATAACAAGGTGCGGAACTATCTGACCC AGAAGCC TTACAGCACAGAGAA.

GATCAAGCTGAACTTCGAGAACAGCACCCTGCTGGGCGGCTGGGATCTGAATAAGGAGACA

GACAACACAGCCATCATCCTGAGGAAGGATAACCTGTACTATCTGGGCATCATGGACAAGA

GGCACAATCGCATCTTTCGGAACGTGCCCAAGGCCGATAAGAAGGACTTCTGCTACGAGAA

GATGGTGTATAAGCTGCTGCCTGGCGCCAACAAGATGCTGCCAAAGGTGTTCTTTTCTCAGA

GCAGAATCCAGGAGTTTACCCCTTCCGCCAAGCTGCTGGAGAACTACGCCAATGAGACACA

CAAGAAGGGCGATAATTTCAACCTGAATCACTGTCACAAGCTGATCGATTTCTTTAAGGACT

CTATCAACAAGCACGAGGATTGGAAGAATTTCGACTTTAGGTTCAGCGCCACCTCCACCTAC

GCCGACC TGAGCGGCITITACCACGAGG f GGAGC ACC AGGGC TACA.AGA TCTCIT TTCAGAG

CGTGGCCGATTCCTTCATCGACGATCTGGTGAACGAGGGCAAGCTGTACCTGTTCCAGATCT

ATAATAAGGACTTTTCCCCATTCTCTAAGGGCAAGCCCAACCTGCACACCCTGTACTGGAAG

ATGCTGTTTGATGAGAACAATCTGAAGGACGTGGTGTATAAGCTGAATGGCGAGGCCGAGG

TGTTCTACCGCAAGAAGAGCATTGCCGAGAAGAACACCACAATCCACAAGGCCAATGAGTC

CATCATCAACAAGAATCCTGATAACCCAAAGGCCACCAGCACCTTCAACTATGATATCGTGA

AGGACAAGAGATACACCATCGACAAGTTTCAGTTCCACATCCCAATCACAATGAACTTTAAG

GCCGAGGGCATCTTCAACATGAATCAGAGGGTGAATCAGTTCCTGAAGGCCAATCCCGATAT

CAACATCATCGGCATCGACAGAGGCGAGAGGCACCTGCTGTACTATGCCCTGATCAACCAG

AAGGGCAAGATCCTGAAGCAGGATACCCTGAATGTGATCGCCAACGAGAAGCAGAAGGTGG

ACTACCACAATCTGCTGGATAAGAAGGAGGGCGACCGCGCAACCGCAAGGCAGGAGTGGG

GCGTGATCGAGACAATCAAGGAGCTGAAGGAGGGCTATCTGTCCCAGGTCATCCACAAGCT

GACCGATCTGATGATCGAGAACAATGCCATCATCGTGATGGAGGACCTGAACTTTGGCTTCA

AGCGGGGCAGACAGA AGGTGGAGAAGCAGGTGT ATCAGAAGTI TG AGAA GAT GC TGA TCG

ATAAGCTGAATTACCTGGTGGACAAGAATAAGAAGGCAAACGAGCTGGGAGGCCTGCTGAA

CGCATTCCAGCTGGCCAATAAGTITGAGTCCITCCAGAAGATGGGCAAGCAGAACGGCITTA

TCTTCTACGTGCCCGCCTGGAATACCTCTAAGACAGATCCTGCCACCGGCTTTATCGACTTCC

618

WO 2016/205711

PCT/US2016/038181

TGAAGCCCCGCTATGAGAACCTGAATCAGGCCAAGGATTTCTTTGAGAAGTTTGACTCTATC

CGGCTGAACAGCAAGGCCGATTACTTTGAGTTCGCCTTTGACTTCAAGAATTTCACCGAGAA

GGCCGATGGCGGCAGAACCAAGTGGACAGTGTGCACCACAAACGAGGACAGATATGCCTGG

AATAGGGCCCTGAACAATAACAGGGGCAGCCAGGAGAAGTACGACATCACAGCCGAGCTG

AAGTCCCTGTTCGATGGCAAGGTGGACTATAAGTCTGGGAAGGATCTGAAGCAGCAGATCG

CCAGCCAGGAGTCCGCCGACTTCTTTAAGGCCCTGATGAAGAACCTGTCCATCACCCTGTCT

CTGAGACACAATAACGGCGAGAAGGGCGATAATGAGCAGGACTACATCCTGTCCCCTGTGG

CCGATTCTAAGGGCCGCITCTITGACTCCCGGAAGGCCGACGATGACATGCCAAAGAATGCC

GACGCCAACGGCGCCTATCACATCGCCCTGAAGGGCCTGTGGTGTCTGGAGCAGATCAGCA

AGACCGATGACCTGAAGAAGGTGAAGCTGGCCATCTCCAACAAGGAGTGGCTGGAGTTCGT

GCAG ACACTGAAGGGCA4A4 GGCCGGCGGCCACGAAAAA GGCCGGCCA GGCAAAAAA GAAAAA

GGGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATG

CATACCCATATGATGTCCCCGACTATGCCTAAGAATTC (SEQ ID NO: 219) [001682] 8~ Acidaminococcus sp. BV3L6 (AsCpfl) [001683] ATGACACAGTTCGAGGGCTTTACCAACCTGTATCAGGTGAGCAAGACACT

GCGGTTTGAGCTGATCCCACAGGGCAAGACCCTGAAGCACATCCAGGAGCAGGGCT

TCATCGAGGAGGACAAGGCCCGCAATGATCACTACAAGGAGCTGAAGCCCATCATC

GATCGGATCTACAAGACCTATGCCGACCAGTGCCTGCAGCTGGTGCAGCTGGATTGG

GAGAACCTGAGCGCCGCCATCGACTCCTATAGAAAGGAGAAAACCGAGGAGACAA

GGAACGCCCTGATCGAGGAGCAGGCCACATATCGCAATGCCATCCACGACTACTTC

ATCGGCCGGACAGACAACCTGACCGATGCCATCAATAAGAGACACGCCGAGATCTA

CAAGGGCCTGTTCAAGGCCGAGCTGTTTAATGGCAAGGTGCTGAAGCAGCTGGGCA

CCGTGACCACAACCGAGCACGAGAACGCCCTGCTGCGGAGCTTCGACAAGTTTACA

ACCTACTTCTCCGGCTTTTATGAGAACAGGAAGAACGTGTTCAGCGCCGAGGATATC

AGCACAGCCATCCCACACCGCATCGTGCAGGACAACTTCCCCAAGTTTAAGGAGAA

TTGTCACATCTTCACACGCCTGATCACCGCCGTGCCCAGCCTGCGGGAGCACTTTGA

GAACGTGAAGAAGGCCATCGGCATCTTCGTGAGCACCTCCATCGAGGAGGTGTTTTC

CTTCCCTTTTTATAACCAGCTGCTGACACAGACCCAGATCGACCTGTATAACCAGCT

GCTGGGAGGAATCTCTCGGGAGGCAGGCACCGAGAAGATCAAGGGCCTGAACGAG

GTGCTGAATCTGGCCATCCAGAAGAATGATGAGACAGCCCACATCATCGCCTCCCTG

CCACACAGATTCATCCCCCTGTTTAAGCAGATCCTGTCCGATAGGAACACCCTGTCT

TTCATCCTGGAGGAGTTTAAGAGCGACGAGGAAGTGATCCAGTCCTTCTGCAAGTAC

619

WO 2016/205711

PCT/US2016/038181

AAGACACTGCTGAGAAACGAGAACGTGCTGGAGACAGCCGAGGCCCTGTTTAACGA

GCTGAACAGCATCGACCTGACACACATCTTCATCAGCCACAAGAAGCTGGAGACAA

TCAGCAGCGCCCTGTGCGACCACTGGGATACACTGAGGAATGCCCTGTATGAGCGG

AGAATCTCCGAGCTGACAGGCAAGATCACCAAGTCTGCCAAGGAGAAGGTGCAGCG

CAGCCTGAAGCACGAGGATATCAACCTGCAGGAGATCATCTCTGCCGCAGGCAAGG

AGCTGAGCGAGGCCTTCAAGCAGAAAACCAGCGAGATCCTGTCCCACGCACACGCC

GCCCTGGATCAGCCACTGCCTACAACCCTGAAGAAGCAGGAGGAGAAGGAGATCCT

GAAGTCTCAGCTGGACAGCCTGCTGGGCCTGTACCACCTGCTGGACTGGTTTGCCGT

GGATGAGTCCAACGAGGTGGACCCCGAGTTCTCTGCCCGGCTGACCGGCATCAAGC

TGGAGATGGAGCCTTCTCTGAGCTTCTACAACAAGGCCAGAAATTATGCCACCAAG

AAGCCCTACTCCGTGGAGAAGTTCAAGCTGAACTTTCAGATGCCTACACTGGCCTCT

GGCTGGGACGTGAATAAGGAGAAGAACAATGGCGCCATCCTGTTTGTGAAGAACGG

CCTGTACTATCTGGGCATCATGCCAAAGCAGAAGGGCAGGTATAAGGCCCTGAGCT

TCGAGCCCACAGAGAAAACCAGCGAGGGCTTTGATAAGATGTACTATGACTACTTC

CCTGATGCCGCCAAGATGATCCCAAAGTGCAGCACCCAGCTGAAGGCCGTGACAGC

CCACTTTCAGACCCACACAACCCCCATCCTGCTGTCCAACAATTTCATCGAGCCTCT

GGAGATCACAAAGGAGATCTACGACCTGAACAATCCTGAGAAGGAGCCAAAGAAG

TTTCAGACAGCCTACGCCAAGAAAACCGGCGACCAGAAGGGCTACAGAGAGGCCCT

GTGCAAGTGGATCGACTTCACAAGGGATTTTCTGTCCAAGTATACCAAGACAACCTC

TATCGATCTGTCTAGCCTGCGGC’CATCCTCTCAGTATAAGGACCTGGGCGAGTACTA

TGCCGAGCTGAATCCCCTGCTGTACCACATCAGCTTCCAGAGAATCGCCGAGAAGG

AGATCATGGATGCCGTGGAGACAGGCAAGCTGTACCTGTTCCAGATCTATAACAAG

GACTTTGCCAAGGGCCACCACGGCAAGCCTAATCTGCACACACTGTATTGGACCGG

CCTGTTTTCTCCAGAGAACCTGGCCAAGACAAGCATCAAGCTGAATGGCCAGGCCG

AGCTGTTCTACCGCCCTAAGTCCAGGATGAAGAGGATGGCACACCGGCTGGGAGAG

AAGATGCTGAACAAGAAGCTGAAGGATCAGAAAACCCCAATCCCCGACACCCTGTA

CCAGGAGCTGTACGACTATGTGAATCACAGACTGTCCCACGACCTGTCTGATGAGGC

CAGGGCCCTGCTGCCCAACGTGATCACCAAGGAGGTGTCTCACGAGATCATCAAGG

ATAGGCGCTTTACCAGCGACAAGTTCTTTTTCCACGTGCCTATCACACTGAACTATC

AGGCCGCCAATTCCCCATCTAAGTTCAACCAGAGGGTGAATGCCTACCTGAAGGAG

CACCCCGAGACACCTATCATCGGCATCGATCGGGGCGAGAGAAACCTGATCTATAT

620

WO 2016/205711

PCT/US2016/038181

CACAGTGATCGACTCCACCGGCAAGATCCTGGAGCAGCGGAGCCTGAACACCATCC

AGCAGTTTGATTACCAGAAGAAGCTGGACAACAGGGAGAAGGAGAGGGTGGCAGC

AAGGCAGGCCTGGTCTGTGGTGGGCACAATCAAGGATCTGAAGCAGGGCTATCTGA

GCCAGGTCATCCACGAGATCGTGGACCTGATGATCCACTACCAGGCCCTGGTGGTG

CTGGAGAACCTGAATTTCGGCTTTAAGAGCAAGAGGACCGGCATCGCCGAGAAGGC

CGTGTACCAGCAGTTCGAGAAGATGCTGATCGATAAGCTGAATTGCCTGGTGCTGAA

GGACTATCCAGCAGAGAAAGTGGGAGGCGTGCTGAACCCATACCAGCTGACAGACC

AGTTCACCTCCTTTGCCAAGATGGGCACCCAGTCTGGCTTCCTGTTTTACGTGCCTGC

CCCATATACATCTAAGATCGATCCCCTGACCGGCTTCGTGGACCCCTTCGTGTGGAA

AACCATCAAGAATCACGAGAGCCGCAAGCACTTCCTGGAGGGCTTCGACTTTCTGC

ACTACGACGTGAAAACCGGCGACTTCATCCTGCACTTTAAGATGAACAGAAATCTGT

CCTTCCAGAGGGGCCTGCCCGGCTTTATGCCTGCATGGGATATCGTGTTCGAGAAGA

ACGAGACACAGTTTGACGCCAAGGGCACCCCTTTCATCGCCGGCAAGAGAATCGTG

CCAGTGATCGAGAATCACAGATTCACCGGCAGATACCGGGACCTGTATCCTGCCAA

CGAGCTGATCGCCCTGCTGGAGGAGAAGGGCATCGTGTTCAGGGATGGCTCCAACA

TCCTGCCAAAGCTGCTGGAGAATGACGATTCTCACGCCATCGACACCATGGTGGCCC

TGATCCGCAGCGTGCTGCAGATGCGGAACTCCAATGCCGCCACAGGCGAGGACTAT

ATCAACAGCCCCGTGCGCGATCTGAATGGCGTGTGCTTCGACTCCCGGTTTCAGAAC

CCAGAGTGGCCCATGGACGCCGATGCCAATGGCGCCTACCACATCGCCCTGAAGGG

CCAGCTGCTGCTGAATCACCTGAAGGAGAGCAAGGATCTGAAGCTGCAGAACGGCA

TCTCCAATCAGGACTGGCTGGCCTACATCCAGGAGCTGCGCAACA4AAGGCCGGCGG

CCzlCG.4yGG£4GGCCGGCC?lGGC7GG1..4.4JG,4.4/GGlGGGATCCTACCCATACGATGTTC [001684] 9[001685] ATGTACTATGAGTCCCTGACCAAGCAGTACCCCGTGTCTAAGACAATCCGGAATG

AGCTGATCCCTATCGGCAAGACACTGGATAACATCCGCCAGAACAATATCCTGGAGAGCGA

CGTGAAGCGGAAGCAGAACTACGAGCACGTGAAGGGCATCCTGGATGAGTATCACAAGCAG

CTGATCAACGAGGCCCTGGACAATTGCACCCTGCCATCCCTGAAGATCGCCGCCGAGATCTA

CCTGAAGAATCAGAAGGAGGTGTCTGACAGAGAGGATTTCAACAAGACACAGGACCTGCTG

AGGAAGGAGGTGGTGGAGAAGCTGAAGGCCCACGAGAACTTTACCAAGATCGGCAAGAAG

621

WO 2016/205711

PCT/US2016/038181

GACATCCTGGATCTGCTGGAGAAGCTGCCTTCCATCTCTGAGGACGATTACAATGCCCTGGA

GAGCTTCCGCAACTTTTACACCTATTTCACATCCTACAACAAGGTGCGGGAGAATCTGTATT

CTGATAAGGAGAAGAGCTCCACAGTGGCCTACAGACTGATCAACGAGAATTTCCCAAAGTT

TCTGGACAATGTGAAGAGCTATAGGTTTGTGAAAACCGCAGGCATCCTGGCAGATGGCCTG

GGAGAGGAGGAGCAGGACT CCCT GIT CAT CGT GGAGACATT CA ACAAGACCCT GACACAGG

ACGGCATCGATACCTACAATTCTCAAGTGGGCAAGATCAACTCTAGCATCAATCTGTATAAC

CAGAAGAATCAGAAGGCCAATGGCTTCAGAAAGATCCCCAAGATGAAGATGCTGTATAAGC

AGATCCTGTCCGATAGGGAGGAGTCTITCATCGACGAGTITCAGAGCGATGAGGTGCTGATC

GACAACGTGGAGTCTTATGGCAGCGTGCTGATCGAGTCTCTGAAGTCCTCTAAGGTGAGCGC

CTTCTTTGATGCCCTGAGAGAGTCTAAGGGCAAGAACGTGTACGTGAAGAATGACCTGGCCA

AGACAGCCATGAGCAACATCGTGTTCGAGAATTGGAGGACCTTTGACGATCTGCTGAACCA

GGAGTACGACCTGGCCAACGAGAACAAGAAGAAGGACGATAAGTATTTCGAGAAGCGCCA

GAAGGAGCTGAAGAAGAATAAGAGCTACTCCCTGGAGCACCTGTGCAACCTGTCCGAGGAT

TCTTGTAACCTGATCGAGAATTATATCCACCAGATCTCCGACGATATCGAGAATATCATCAT

CAACAATGAGACATTCCTGCGCATCGTGATCAATGAGCACGACAGGTCCCGCAAGCTGGCC

AAGAACCGGAAGGCCGTGAAGGCCATCAAGGACTTTCTGGATTCTATCAAGGTGCTGGAGC

GGGAGCTGAAGCTGATCAACAGCTCCGGCCAGGAGCTGGAGAAGGATCTGATCGTGTACTC

TGCCCACGAGGAGC TGCTGGTGGAGC F GAAGC AGGTGGAC AGCC TGT ATAACA TGACCAGA

AATTATCTGACAAAGAAGCCTTTCTCTACCGAGAAGGTGAAGCTGAACTTTAATCGCAGCAC

ACTGCTGAACGGCTGGGATCGGAATAAGGAGACAGACAACCTGGGCGTGCTGCTGCTGAAG

GACGGCAAGTACTATCTGGGCATCATGAACACAAGCGCCAATAAGGCCTTCGTGAATCCCCC

TGTGGCCAAGACCGAGAAGGTGTTTAAGAAGGTGGATTACAAGCTGCTGCCAGTGCCCAAC

CAGATGCTGCCAAAGGTGTTCTTTGCCAAGAGCAATATCGACTTCTATAACCCCTCTAGCGA

GATCTACTCCAATTATAAGAAGGGCACCCACA

GTCACAACCTGATCGACTTCTITAAGGAGTCTATCAGCAAGCACGAGGACTGGAGCAAGTTC

GGCTTTAAGTTCAGCGATACAGCCTCCTACAACGACATCTCCGAGTTCTATCGCGAGGTGGA

GAAGCAGGGCTACAAGCTGACCTATACAGACATCGATGAGACATACATCAATGATCTGATC

GAGCGGAACGAGCTGTACCTGTTCCAGATCTATAATAAGGACTTTAGCATGTACTCCAAGGG

CAAGCTGAACCTGCACACACTGTATTTCATGATGCTGTTTGATCAGCGCAATATCGACGACG

TGGTGTATAAGCTGAACGGAGAGGCAGAGGTGTTCTATAGGCCAGCCTCCATCTCTGAGGAC

GAGCTGATCATCCACAAGGCCGGCGAGGAGATCAAGAACAAGAATCCTAACCGGGCCAGAA

CCAAGGAGACAAGCACCTTCAGCTACGACATCGTGAAGGATAAGCGGTATAGCAAGGATAA

GTTTACCGTGCACATCCCCATCACAATGAACTTCGGCGTGGATGAGGTGAAGCGGTTCAACG

ACGCCGTGAACAGCGCCATCCGGATCGATGAGAATGTGAACGTGATCGGCATCGACCGGGG

622

WO 2016/205711

PCT/US2016/038181

CGAGAGAAATCTGC TGTACGTGGTGGT CATCGACT C TAAGGGCAACA fCCTGGAGCAGATC I

CCCTGAACTCTATCATCAATAAGGAGTACGACATCGAGACAGATTATCACGCACTGCTGGAT

GAGAGGGAGGGCGGCAGAGATAAGGCCCGGAAGGACTGGAACACCGTGGAGAATATCAGG

GACCTGAAGGCCGGCTACCTGAGCCAGGTGGTGAACGTGGTGGCCAAGCTGGTGCTGAAGT

ATAAIGCCA fCAT C TGCCTGGAGGACC TGA AC TTT GGCT TCAAGAGGGGCCGCCAGAAGGTG

GAGAAGCAGGIGTACCAGAAGTTCGAGAAGATGCI G AT CGA f AAGCI GAATf ACCTGGTCA

TCGACAAGAGCCGCGAGCAGACATCCCCTAAGGAGCTGGGAGGCGCCCTGAACGCACTGCA

GCTGACCTCTAAGTTCAAGAGCTTTAAGGAGCTGGGCAAGCAGTCCGGCGTGATCTACTATG

TGCCTGCCTACCTGACCTCTAAGATCGATCCAACCACAGGCTTCGCCAATCTGTTTTATATGA

AGTGTGAGAACGTGGAGAAGTCCAAGAGATTCTTTGACGGCTTTGATTTCATCAGGTTCAAC

GCCCTGGAGAACGTGTTCGAGTTCGGCTTTGACTACCGGAGCTTCACCCAGAGGGCCTGCGG

CATCAATTCCAAGTGGACCGTGTGCACCAACGGCGAGCGCATCATCAAGTATCGGAATCCA

GATAAGAACAATATGTTCGACGAGAAGGTGGTGGTGGTGACCGATGAGATGAAGAACCTGT

TTGAGCAGTACAAGATCCCCTATGAGGATGGCAGAAATGTGAAGGACATGATCATCAGCAA

CGAGGAGGCCGAGTTCTACCGGAGACTGTATAGGCTGCTGCAGCAGACCCTGCAGATGAGA

AACAGCACCTCCGACGGCACAAGGGATTACATCATCTCCCCTGTGAAGAATAAGAGAGAGG

CCTACITCAACAGCGAGCTGTCCGACGGCTCTGTGCCAAAGGACGCCGATGCCAACGGCGCC

TACAATATCGCCAGAAAGGGCCTGTGGGTGCTGGAGCAGATCAGGCAGAAGAGCGAGGGCG

AGAAGATCAATCTGGCCATGACCAACGCCGAGTGGCTGGAGTATGCCCAGACACACCTGCT

GLiLlGYTCCGYJCGYTCCTCGzWWlGYJCCGG’CCTGGQl/Ll/LlTGzWWlGGGATCCTACCCATA

CGATGTTC

ATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGATG [001686] 10[001687] ATGAACAATTACGACGAGTTCACCAAGCTGTATCCTATCCAGAAAACCATCCGGT TTGAGCTGAAGCCACAGGGCAGAACCATGGAGCACCTGGAGACATTCAACTTCTTTGAGGA

GGACCGGGATAGAGCCGAGAAGTATAAGATCCTGAAGGAGGCCATCGACGAGTACCACAA

GAAGTTTATCGATGAGCACCTGACCAATATGTCCCTGGATTGGAACTCTCTGAAGCAGATCA

GCGAGAAGTACTATAAGAGCAGGGAGGAGAAGGACAAGAAGGTGITCCTGTCCGAGCAGA

AGAGGA TGCGCCAGGAGATCGTGTCTGAGT TTAAGAAGGACGA TCGCTTCAAGGACCTGTT T

TCCAAGAAGCTGTTCTCTGAGCTGCTGAAGGAGGAGATCTACAAGAAGGGCAACCACCAGG

AGATCGACGCCCTGAAGAGCTTCGATAAGTTTTCCGGCTATTTCATCGGCCTGCACGAGAAT

AGGAAGAACATGTACTCCGACGGCGATGAGATCACCGCCATCTCCAATCGCATCGTGAATG

AGAACTTCCCCAAGTTTCTGGATAACCTGCAGAAGTACCAGGAGGCCAGGAAGAAGTATCC

623

WO 2016/205711

PCT/US2016/038181

TGAGTGGATCATCAAGGCCGAGAGCGCCCTGGTGGCCCACAATATCAAGATGGACGAGGTG

TTCTCCCTGGAGTACTTTAATAAGGTGCTGAACCAGGAGGGCATCCAGCGGTACAACCTGGC

CCTGGGCGGCTATGTGACCAAGAGCGGCGAGAAGATGATGGGCCTGAATGATGCCCTGAAC

CTGGCCCACCAGTCCGAGAAGAGCTCCAAGGGCAGAATCCACATGACCCCCCTGTTCAAGC

AGATCCTGTCCGAGAAGGAGTCCTTCTCTTACATCCCCGACGTGTTTACAGAGGATTCTCAG

CTGCTGCCTAGCATCGGCGGCTTCTTTGCCCAGATCGAGAATGACAAGGATGGCAACATCTT

CGACCGGGCCCTGGAGCTGATCTCTAGCTACGCCGAGTATGATACCGAGCGGATCTATATCA

GACAGGCCGACATCAATAGAGTGTCCAACGTGATCTTTGGAGAGTGGGGCACCCTGGGAGG

CCTGATGAGGGAGTACAAGGCCGACTCTATCAATGATATCAACCTGGAGCGCACATGCAAG

AAGGIGGACAAGTGGCT GGAT FCTAAGGAGT FT GCCCT GAGCGAT GTGCIGGAGGCCAT CA

AGAGGACCGGCAACAATGACGCCTTCAACGAGTATATCTCCAAGATGCGGACAGCCAGAGA

GAAGATCGATGCCGCCCGCAAGGAGATGAAGTTCATCAGCGAGAAGATCTCCGGCGATGAG

GAGTCTATCCACATCATCAAGACCCTGCTGGACAGCGTGCAGCAGTTCCTGCACITCTTTAA

TCTGITTAAGGCAAGGCAGGACATCCCACTGGATGGAGCCTTCTACGCCGAGTTTGACGAGG

TGCACAGCAAGCTGTTTGCCATCGTGCCCCTGTATAACAAGGTGCGGAACTATCTGACCAAG

AACAATCTGAACACAAAGAAGATCAAGCTGAAITTCAAGAACCCTACACTGGCCAATGGCT

GGGACCAGAACAAGGTGTACGATTATGCCTCCCTGATCTTTCTGCGGGACGGCAATTACTAT

CTGGGCATCATCAATCCTAAGAGAAAGAAGAACATCAAGTTCGAGCAGGGCTCTGGCAACG

GCCCCTTCTACCGGAAGATGGTGTATAAGCAGATCCCCGGCCCTAATAAGAACCTGCCAAGA

GTGTTCCTGACCTCCACAAAGGGCAAGAAGGAGTATAAGCCCTCTAAGGAGATCATCGAGG

GCTACGAGGCCGACAAGCACATCAGGGGCGATAAGTTCGACCTGGAITITTGTCACAAGCTG

ATCGATTTCTTTAAGGAGTCCATCGAGAAGCACAAGGACTGGTCTAAGTTCAACTTCTACTT

CAGCCCAACCGAGAGCTATGGCGACATCTCTGAGTTCTACCTGGATGTGGAGAAGCAGGGC

TATCGCATGCACTTTGAGAATATCAGCGCCGAGACAATCGACGAGTATGTGGAGAAGGGCG

ATCTGTTTCTGTTCCAGATCTACAACAAGGATTTTGTGAAGGCCGCCACCGGCAAGAAGGAC

ATGCACACAATCTACTGGAATGCCGCCTTCAGCCCCGAGAACCTGCAGGACGTGGTGGTGA

AGCTGAACGGCGAGGCCGAGCTGTTTTATAGGGACAAGTCCGATATCAAGGAGATCGTGCA

CCGCGAGGGCGAGATCCTGGTGAATAGGACCTACAACGGCCGCACACCAGTGCCCGACAAG

ATCCACAAGAAGCTGACCGATTATCACAATGGCCGGACAAAGGACCTGGGCGAGGCCAAGG

AGTACCTGGATAAGGTGAGATACTTCAAGGCCCACTATGACATCACCAAGGATCGGAGATA

CCTGAACGACAAGATCTATTTCCACGTGCCTCTGACCCTGAACTTCAAGGCCAACGGCAAGA

AGAATCTGAACAAGATGGTCATCGAGAAGTTCCTGTCCGATGAGAAGGCCCACATCATCGG

CATCGACAGGGGCGAGCGCAATCTGCTGTACTATTCCATCATCGACAGGTCTGGCAAGATCA

TCGATCAGCAGAGCCTGAATGTGATCGACGGCTTTGATTATCGGGAGAAGCTGAACCAGAG

624

WO 2016/205711

PCT/US2016/038181

AGAGATCGAGATGAAGGATGCCCGCCAGTCT'fGGAACGCCATCGGCAAGATCAAGGACCTG

AAGGAGGGCTACCTGAGCAAGGCCGTGCACGAGATCACCAAGATGGCCATCCAGTATAATG

CCATCGTGGTCATGGAGGAGCTGAACTACGGCTTCAAGCGGGGCCGGITCAAGGTGGAGAA

GCAGATCTATCAGAAGTTCGAGAATATGCTGATCGATAAGATGAACTACCTGGTGITTAAGG

ACGCACCTGATGAGT CCCC AGGAGGCGT GC TGAA FGCCTACCAGCIGACAAACCCAC FGGA GTCTTTCGCCAAGCTGGGCAAGCAGACCGGCATCCTGTTTTACGTGCCAGCCGCCTATACAT CCAAGATCGACCCCACCACAGGCTTCGTGAATCTGTTTAACACCTCCTCTAAGACAAACGCC CAGGAGCGGAAGGAGTTCCTGCAGAAGTTTGAGAGCATCTCCTATTCTGCCAAGGATGGCG

GCATCTTTGCCTTCGCCTTTGACTACAGAAAGITCGGCACCAGCAAGACAGATCACAAGAAC

GTG FGGACCGCCTA FACAAACGGCGAGAGGAT GCGCTACAT CAAGGAGAAGAAGCGGAATG AGCTGTTTGACCCTTCTAAGGAGATCAAGGAGGCCCTGACCAGCTCCGGCATCAAGTACGAT GGCGGCCAGAACATCCTGCCAGACATCCTGAGGAGCAACAATAACGGCCTGATCTACACAA

TGTATTCTAGCTTCATCGCCGCCATCCAGA'IGCGCGTGTACGACGGCAAGGAGGATTATAIX’

ATCAGCCCCATCAAGAACTCCAAGGGCGAGTTCTTTAGGACCGACCCCAAGAGGCGCGAGC

TGCCTATCGACGCCGATGCCAATGGCGCCTACAACATCGCCCTGAGGGGAGAGCTGACAAT

GAGGGCAATCGCAGAGAAGITCGACCCTGATAGCGAGAAGATGGCCAAGCTGGAGCTGAAG

CACAAGGATTGGTTCGAGTTTATGCAGACCAGAGGCGACA4A4GGCCGGCGGCC4CG4A4A4

GGCCGGCC4GGCATX4A4GArirf4AGGGATCCTACCCATACGATGTTCCAGATTACGCTTAT

CCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTATGCCTAAGAATT C (SEQ ID NO: 222) [001688] 11 [001689] ATGAACGGCAATAGGTCCATCGTGTACCGCGAGTTCGTGGGCGTGATCCCCGTGG CCAAGACCCTGAGGAATGAGCTGCGCCCTGTGGGCCACACACAGGAGCACATCATCCAGAA

CGGCCTGATCCAGGAGGACGAGCTGCGGCAGGAGAAGAGCACCGAGCTGAAGAACATCAT

GGACGATTACTATAGAGAGTACATCGATAAGTCTCTGAGCGGCGTGACCGACCTGGACTTCA

CCCTGCTGTTCGAGCTGATGAACCTGGTGCAGAGCTCCCCCTCCAAGGACAATAAGAAGGCC

CTGGAGAAGGAGCAGTCTAAGATGAGGGAGCAGATCTGCACCCACCTGCAGTCCGACTCTA

ACTACAAGAATATCT'ITAACGCCAAGCTGCTGAAGGAGATCCTGCCTGATTTCATCAAGAAC

TACAA rCAGTATGACGTGAAGGATAAGGCCGGCAAGCTGGAGACACTGGCCCTGTT FAAIG GCTTCAGCACATACTTTACCGACTTCTTTGAGAAGAGGAAGAACGTGTTCACCAAGGAGGCC

GTGAGCACATCCATCGCCTACCGCATCGTGCACGAGAACTCCCTGATCTTCCTGGCCAATAT

GACCTCTTATAAGAAGATCAGCGAGAAGGCCCTGGATGAGATCGAAGTGATCGAGAAGAAC

AATCAGGACAAGATGGGCGATTGGGAGCTGAATCAGATCTTTAACCCTGACTTCTACAATAT

625

WO 2016/205711

PCT/US2016/038181

GGTGCTGATCCAGTCCGGCATCGACTTCTACAACGAGATCTGCGGCGTGGTGAATGCCCACA

TGAACCTGTACTGTCAGCAGACCAAGAACAATTATAACCTGTTCAAGATGCGGAAGCTGCAC

AAGCAGATCCTGGCCTACACCAGCACCAGCTTCGAGGTGCCCAAGATGTTCGAGGACGATA

TGAGCGTGTATAACGCCGTGAACGCCTTCATCGACGAGACAGAGAAGGGCAACATCATCGG

CAAGCIGAAGGA f AICGTGAATAAG f ACGACGAGCI GGA IGAGAAGAGAAT C ΓΑΤ ATCAGC AAGGACTTTTACGAGACACTGAGCTGCTTCATGTCCGGCAACTGGAATCTGATCACAGGCTG CGTGGAGAACTTCTACGATGAGAACATCCACGCCAAGGGCAAGTCCAAGGAGGAGAAGGTG AAGAAGGCCGTGAAGGAGGACAAGTACAAGTCTATCAATGACGTGAACGATCTGGTGGAGA AGTATATCGATGAGAAGGAGAGGAATGAGTTCAAGAACAGCAATGCCAAGCAGTACATCCG

CGAGATCTCCAACATCATCACCGACACAGAGACAGCCCACCTGGAGTATGACGATCACATCT

CTCTGATCGAGAGCGAGGAGAAGGCCGACGAGATGAAGAAGCGGCTGGATATGTATATGAA

CATGTACCACTGGGCCAAGGCCITTATCGTGGACGAGGTGCTGGACAGAGATGAGATGTTCT

ACAGCGATATCGACGATATCTATAATATCCTGGAGAACATCGTGCCACTGTATAATCGGGTG

AGAAACTACGTGACCCAGAAGCCCTACAACTCTAAGAAGATCAAGCTGAATTTCCAGAGCC

CTACACTGGCCAATGGCTGGTCCCAGTCTAAGGAGTTCGACAACAATGCCATCATCCTGATC

AGAGATAACAAGTACTATCTGGCCATCITCAATGCCAAGAACAAGCCAGACAAGAAGATCA

TCCAGGGCAACTCCGATAAGAAGAACGACAACGATTACAAGAAGATGGTGTATAACCTGCT

GCCAGGCGCCAACAAGATGCTGCCCAAGGTGTTTCTGTCTAAGAAGGGCATCGAGACATTC

AAGCCCTCCGACTATATCATCTCTGGCTACAACGCCCACAAGCACATCAAGACAAGCGAGA

ATITTGATATCTCCITCTGTCGGGACCTGATCGAITACITCAAGAACAGCATCGAGAAGCAC

GCCGAGTGGAGAAAGTATGAGTTCAAGTTTTCCGCCACCGACAGCTACTCCGATATCTCTGA

G TTCIATCGGGAGGT GGA GAT GC AGGGCTAC AGAATCGACI GGA CAT AT A TCAGCG AGGCC GACATCAACAAGCTGGATGAGGAGGGCAAGATCTATCTGTTTCAGATCTACAATAAGGATTT

CGCCGAGAACAGCACCGGCAAGGAGAATCTGCACACAATGTACTTTAAGAACATCTTCTCC

GAGGAGAAT’CTGAAGGACATCATCATCAAGCTGAACGGCCAGGCCGAGCTGTTTTATCGGA

GAGCCTCTGTGAAGAATCCCGTGAAGCACAAGAAGGATAGCGTGCTGGTGAACAAGACCTA

CAAGAATCAGCTGGACAACGGCGACGTGGTGAGAATCCCCATCCCTGACGATATCTATAAC

GAGATCTACAAGATGTATAATGGCTACATCAAGGAGTCCGACCTGTCTGAGGCCGCCAAGG

AGTACCTGGATAAGGTGGAGGTGAGGACCGCCCAGAAGGACATCGTGAAGGATTACCGCTA

TACAGTGGACAAGTACTTCATCCACACACCTATCACCATCAACTATAAGGTGACCGCCCGCA

ACAATGTGAATGATATGGTGGTGAAGTACATCGCCCAGAACGACGATATCCACGTGATCGG

CATCGACCGGGGCGAGAGAAACCTGATCTACATCTCCGTGATCGATTCTCACGGCAACATCG

TGAAGCAGAAATCCTACAACATCCTGAACAACTACGACTACAAGAAGAAGCTGGTGGAGAA

GGAGAAAACCCGGGAGTACGCCAGAAAGAACTGGAAGAGCATCGGCAATATCAAGGAGCT

626

WO 2016/205711

PCT/US2016/038181

G AAGGAGGGCTA TAT C TCCGGCGTGG fGCACGAGATCGCCATGCT GATCGTGGAGTACAAC

GCCATCATCGCCATGGAGGACCTGAATTATGGCTTTAAGAGGGGCCGCTTCAAGGTGGAGC

GGCAGGTGTACCAGAAGnTGAGAGCATGCTGATCAATAAGCTGAACTATTTCGCCAGCAA

GGAGAAGTCCGTGGACGAGCCAGGAGGCCTGCTGAAGGGCTATCAGCTGACCTACGTGCCC

GA f AATATCAAGAACC FGGGCAAGCAGTGCGGCGTGAIC FT ITACG TGCCTGCCGCCTTCAC

CAGCAAGATCGACCCATCCACAGGCTTTATCTCTGCCTTCAACTTTAAGTCTATCAGCACAA

ATGCCTCTCGGAAGCAGTTCTTTATGCAGTTTGACGAGATCAGATACTGTGCCGAGAAGGAT

ATGTTCAGCTTTGGCTTCGACTACAACAACTTCGATACCTACAACATCACAATGGGCAAGAC

ACAGTGGACCGTGTATACAAACGGCGAGAGACTGCAGTCTGAGTTCAACAATGCCAGGCGC

ACCGGCAAGACA AAGAGCATCAA TCTGACAGAGACAAT C AAGC 1 GC T GC TGGAGGACAATG AGATCAACTACGCCGACGGCCACGATATCAGGATCGATATGGAGAAGATGGACGAGGATAA GAAGAGCGAGTTCTTTGCCCAGCTGCTGAGCCTGTATAAGCTGACCGTGCAGATGCGCAATT

CCTATACAGAGGCCGAGGAGCAGGAGAACGGCATCTCTTACGACAAGATCATCAGCCCTGT

GATCAATGATGAGGGCGAGTTCTTTGACTCCGATAACTATAAGGAGTCTGACGATAAGGAGT

GCAAGATGCCAAAGGACGCCGATGCCAACGGCGCCTACTGTATCGCCCTGAAGGGCCTGTA

TGAGGTGCTGAAGATCAAGAGCGAGTGGACCGAGGACGGCITTGATAGGAATTGCCTGAAG

CTGCCACACGCAGAGTGGCTGGACTTCATCCAGAACAAGCGGTACGAGfoTUlGGCCGGCGG

CCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGMCCTACCCATACGATGTTCCAGAT TACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTATGC CTAAGAATTC (SEQ ID NO: 223) [001690] 12- Moraxella bovocuii 237 (MbCpfl) [001691 ] ATGCTGTTCCAGGACTITACCCACCTGTATCCACTGTCCAAGACAGTGAGATITG AGCTGAAGCCCATCGATAGGACCCTGGAGCACATCCACGCCAAGAACTTCCTGTCTCAGGAC

GAGACAATGGCCGATATGCACCAGAAGGTGAAAGTGATCCTGGACGATTACCACCGCGACT

ICATCGCCGATATGA FGGGCGAGGTGAAGCTGACCAAGCT GGCCGAGTTCTATGACGIGTAC

CTGAAGTTTCGGAAGAACCCAAAGGACGATGAGCTGCAGAAGCAGCTGAAGGATCTGCAGG

CCGTGCTGAGAAAGGAGATCGTGAAGCCCATCGGCAATGGCGGCAAGTATAAGGCCGGCTA

CGACAGGCTGTTCGGCGCCAAGCTGTTTAAGGACGGCAAGGAGCTGGGCGATCTGGCCAAG

TTCGTGATCGCACAGGAGGGAGAGAGCTCCCCAAAGCTGGCCCACCTGGCCCACTTCGAGA

AAGCACACCGCCATCGCCTACCGCCTGATCCACGAGAACCTGCCCCGGITTATCGACAATCT

GCAGATCCTGACCACAATCAAGCAGAAGCACTCTGCCCTGTACGATCAGATCATCAACGAG

CTGACCGCCAGCGGCCTGGACGTGTCTCTGGCCAGCCACCTGGATGGCTATCACAAGCTGCT

627

WO 2016/205711

PCT/US2016/038181

GACACAGGAGGGCATCACCGCCTACAATACACTGCTGGGAGGAATCTCCGGAGAGGCAGGC

TCTCCTAAGATCCAGGGCATCAACGAGCTGATCAATTCTCACCACAACCAGCACTGCCACAA

GAGCGAGAGAATCGCCAAGCTGAGGCCACTGCACAAGCAGATCCTGTCCGACGGCATGAGC

GTGTCCTTCCTGCCCTCTAAGTTTGCCGACGATAGCGAGATGTGCCAGGCCGTGAACGAGTT

CTATCGCCACTACGCCGACGTGTTCGCCAAGGTGCAGAGCCTGTTCGACGGCTTTGACGATC

ACCAGAAGGATGGCATCTACGTGGAGCACAAGAACCTGAATGAGC TGTCCAAGCAGGCC TT

CGGCGACTTTGCACTGCTGGGACGCGTGCTGGACGGATACTATGTGGATGTGGTGAATCCAG

AGTTCAACGAGCGGTTTGCCAAGGCCAAGACCGACAATGCCAAGGCCAAGCTGACAAAGGA

GAAGGATAAGTTCATCAAGGGCGTGCACTCCCTGGCCTCTCTGGAGCAGGCCATCGAGCACT

ATACCGCAAGGCACGACGATGAGAGCGTGCAGGCAGGCAAGCTGGGACAGTACTTCAAGCA

CGGCCTGGCCGGAGTGGACAACCCCATCCAGAAGATCCACAACAATCACAGCACCATCAAG

GGCTTTCTGGAGAGGGAGCGCCCTGCAGGAGAGAGAGCCCTGCCAAAGATCAAGTCCGGCA

AGAATCCTGAGATGACACAGCTGAGGCAGCTGAAGGAGCTGCTGGATAACGCCCTGAATGT

GGCCCACTTCGCCAAGCTGCTGACCACAAAGACCACACTGGACAATCAGGATGGCAACTTCT

ATGGCGAGTTTGGCGTGCTGTACGACGAGCTGGCCAAGATCCCCACCCTGTATAACAAGGTG

AGAGATTACCTGAGCCAGAAGCCTTTCTCCACCGAGAAGTACAAGCTGAACTTTGGCAATCC

AACACTGCTGAATGGCTGGGACCTGAACAAGGAGAAGGATAATTTCGGCGTGATCCTGCAG

AAGGACGGCTGCTACTATCTGGCCCTGCTGGACAAGGCCCACAAGAAGGTGTTTGATAACG

CCCCTAATACAGGCAAGAGCATCTATCAGAAGATGATCTATAAGTACCTGGAGGTGAGGAA

GCAGTTCCCCAAGGTGTTCTTTTCCAAGGAGGCCATCGCCATCAACTACCACCCTTCTAAGG

AGCTGGTGGAGATCAAGGACAAGGGCCGGCAGAGATCCGACGATGAGCGCCTGAAGCTGTA

TCGGTTTATCCTGGAGTGTCTGAAGATCCACCCTAAGTACGATAAGAAGTTCGAGGGCGCCA

TCGGCGACATCCAGCTGTTTAAGAAGGATAAGAAGGGCAGAGAGGTGCCAATCAGCGAGAA

TCTTTATCGGCGAGTTCAAGAGGTATAACCCAAGCCAGGACCTGGTGGATCAGTATAATATC

TACAAGAAGATCGACTCCAACGATAATCGCAAGAAGGAGAATTTCTACAACAATCACCCCA

A GT ΓΤ AAGAAGGA f CTGGTGCGG TACT A IT ACGAGTCIATG fGCAAGCACGAGGAGTGGGA

GGAGAGCTTCGAGTTTTCCAAGAAGCTGCAGGACATCGGCTGTTACGTGGATGTGAACGAG

CTGTTTACCGAGATCGAGACACGGAGACTGAATTATAAGATCTCCTTCTGCAACATCAATGC

CGACTACATCGATGAGCTGGTGGAGCAGGGCCAGCTGTATCTGTTCCAGATCTACAACAAGG

ACTnTCCCCAAAGGCCCACGGCAAGCCCAATCTGCACACCCTGTACTTCAAGGCCCTGTTTT

CTGAGGACAACCTGGCCGATCCTATCTATAAGCTGAATGGCGAGGCCCAGATCTTCTACAGA

AAGGCCTCCCTGGACATGAACGAGACAACAATCCACAGGGCCGGCGAGGTGCTGGAGAACA

AGAATCCCGATAATCCTAAGAAGAGACAGTTCGTGTACGACATCATCAAGGATAAGAGGTA

628

WO 2016/205711

PCT/US2016/038181

CACACAGGACAAGTTCATGCTGCACGTGCCAATCACCATGAACTTTGGCGTGCAGGGCATGA

CAATCAAGGAGTTCAATAAGAAGGTGAACCAGTCTATCCAGCAGTATGACGAGGTGAACGT

GATCGGCATCGATCGGGGCGAGAGACACCTGCTGTACCTGACCGTGATCAATAGCAAGGGC

GAGATCCTGGAGCAGTGTTCCCTGAACGACATCACCACAGCCTCTGCCAATGGCACACAGAT

GACCACACCTTACCACAAGATCCTGGATAAGAGGGAGATCGAGCGCCTGAACGCCCGGGTG

GGAT GGGGCGAGAT CGAGACAAT CAAGGAGCT GAA GT C TGGCT AT CTGAGCC ACG IGG I GC

ACCAGATCAGCCAGCTGATGCTGAAGTACAACGCCATCGTGGTGCTGGAGGACCTGAATTTC

GGCTTTAAGAGGGGCCGCTTTAAGGTGGAGAAGCAGATCTATCAGAACTTCGAGAATGCCC

TGATCAAGAAGCTGAACCACCTGGTGCTGAAGGACAAGGCCGACGATGAGATCGGCTCTTA

CAAGAATGCCCTGCAGCTGACCAACAATTTCACAGATCTGAAGAGCATCGGCAAGCAGACC

GGCTTCCTGTTTTATGTGCCCGCCTGGAACACCTCTAAGATCGACCCTGAGACAGGCTTTGTG

GATCTGCTGAAGCCAAGATACGAGAACATCGCCCAGAGCCAGGCCTTCTTTGGCAAGTTCGA

CAAGATCTGCTATAATGCCGACAAGGATTACTTCGAGTTTCACATCGACTACGCCAAGTTTA

CCGATAAGGCCAAGAATAGCCGCCAGATCTGGACAATCTGTTCCCACGGCGACAAGCGGTA

CGTGTACGATAAGACAGCCAACCAGAATAAGGGCGCCGCCAAGGGCATCAACGTGAATGAT

GAGCTGAAGTCCCTGTTCGCCCGCCACCACATCAACGAGAAGCAGCCCAACCTGGTCATGG

ACATCTGCCAGAACAATGATAAGGAGTTTCACAAGTCTCTGATGTACCTGCTGAAAACCCTG

CTGGCCCTGCGGTACAGCAACGCCTCCT C TGACGAGGATTT CAT CCIGTCCCCCGT GGCAAA

CGACGAGGGCGTGTTCTTTAATAGCGCCCTGGCCGACGATACACAGCCTCAGAATGCCGATG

CCAACGGCGCCTACCACATCGCCCTGAAGGGCCTGTGGCTGCTGAATGAGCTGAAGAACTCC

GACGATCTGAACAAGGTGAAGCTGGCCATCGACAATCAGACCTGGCTGAATTTCGCCCAGA

ACAGGAAAAGGCCCXXGGCCACGAAAAACXXCGCXCAGGCAAAAAAGAAAAAGGGAA'CCAACC CATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATAT GATGTCCCCGACTATGCCTAAGAATTC (SEQ Π [001692] 13- Leptospira inadai (LiCpfl) [001693] ATGGAGGACTATTCCGGCTTTGTGAACATCTACTCTATCCAGAAAACCCTGAGGT

TCGAGCTGAAGCCAGTGGGCAAGACACTGGAGCACATCGAGAAGAAGGGCTTCCTGAAGAA

GGACAAGATCCGGGCCGAGGATTACAAGGCCGTGAAGAAGATCATCGATAAGTACCACAGA

GCCTATATCGAGGAGGTGTTTGATTCCGTGCTGCACCAGAAGAAGAAGAAGGACAAGACCC

GCTTTTCTACACAGTTCATCAAGGAGATCAAGGAGTTCAGCGAGCTGTACTATAAGACCGAG

AAGAACATCCCCGACAAGGAGAGGCTGGAGGCCCTGAGCGAGAAGCTGCGCAAGATGCTG

GTGGGCGCCTTTAAGGGCGAGITCTCCGAGGAGGTGGCCGAGAAGTATAAGAACCTGTTTTC

TAAGGAGCTGATCAGGAATGAGATCGAGAAGITCTGCGAGACAGACGAGGAGCGCAAGCA

GGTGTCTAACTTCAAGAGCTTCACCACATACTTTACCGGCTTCCACTCCAACAGGCAGAATA

629

WO 2016/205711

PCT/US2016/038181

TCTATTCCGACGAGAAGAAGTCTACAGCCATCGGCTACCGCATCATCCACCAGAACCTGCCT

AAGTTCCTGGATAATCTGAAGATCATCGAGTCCATCCAGCGGCGGTTCAAGGACTTCCCATG

GTCTGATCTGAAGAAGAACCTGAAGAAGATCGATAAGAATATCAAGCTGACCGAGTACTTC

AGCATCGACGGCTTCGTGAACGTGCTGAATCAGAAGGGCATCGATGCCTACAACACAATCCT

GGGCGGCAAGTCCGAGGAGTCIGGCGAGAAGATCCAGGGCCIGAACGAGTACA! C AAT CTG

TATCGGCAGAAGAACAATATCGACAGAAAGAACCTGCCCAATGTGAAGATCCTGTTTAAGC

AGATCCTGGGCGATAGGGAGACAAAGAGCTTTATCCCTGAGGCCTTCCCAGACGATCAGTCC

GTGCTGAACTCTATCACAGAGTTCGCCAAGTACCTGAAGCTGGATAAGAAGAAGAAGAGCA

TCATCGCCGAGCTGAAGAAGTTTCTGAGCTCCTTCAATCGCTACGAGCTGGACGGCATCTAT

CTGGCCAACGATAATAGCCTGGCCTCTATCAGCACCTTCCTGTTTGACGATTGGTCCTTTATC

AAGAAGTCCGTGTCTTTCAAGTATGACGAGTCCGTGGGCGACCCCAAGAAGAAGATCAAGT

CTCCCCTGAAGTACGAGAAGGAGAAGGAGAAGTGGCTGAAGCAGAAGTACTATACAATCTC

TTTCCTGAACGATGCCATCGAGAGCTATTCCAAGTCTCAGGACGAGAAGAGGGTGAAGATC

CGCCTGGAGGCCTACTTTGCCGAGTTCAAGAGCAAGGACGATGCCAAGAAGCAGTTCGACC

TGCTGGAGAGGATCGAGGAGGCCTATGCCATCGTGGAGCCTCTGCTGGGAGCAGAGTAC.ee

AAGGGACCGCAACCTGAAGGCCGATAAGAAGGAAGTGGGCAAGATCAAGGACTTCCTGGAT

AGCATCAAGTCCCTGCAGTTCTTTCTGAAGCCTCTGCTGTCCGCCGAGATCTTTGACGAGAA

GGAT C1GGGCITCT ACAATCAGCT GGAGGGCI ACTA TGAGGAGATCGA IT CIATCGGCCACC

TGTATAACAAGGTGCGGAATTATCTGACCGGCAAGATCTACAGCAAGGAGAAGTTTAAGCT

GAACTTCGAGAACAGCACCCTGCTGAAGGGCTGGGACGAGAACCGGGAGGTGGCCAATCTG

TGCGTGATCTTCAGAGAGGACCAGAAGTACTATCTGGGCGTGATGGATAAGGAGAACAATA

CCATCCTGTCCGACATCCCCAAGGTGAAGCCTAACGAGCTGTTTTACGAGAAGATGGTGTAT

AAGCTGATCCCCACACCTCACATGCAGCTGCCCCGGATCATCTTCTCTAGCGACAACCTGTC

TATCTATAATCCTAGCAAGTCCATCCTGAAGATCAGAGAGGCCAAGAGCTTTAAGGAGGGC

AAGAACTTCAAGCTGAAGGACTGTCACAAGTTTATCGATTTCTACAAGGAGTCTATCAGCAA

GAATGAGGACTGGAGCAGATTCGACTTCAAGTTCAGCAAGACCAGCAGCTACGAGAACATC

AGCGAGITITACCGGGAGGTGGAGAGACAGGGC TAT AACC FGGACITCAAGAAGGT GT CI A AGTTCTACATCGACAGCCTGGTGGAGGATGGCAAGCTGTACCTGTTCCAGATCTATAACAAG

GACTTTTCTATCTTCAGCAAGGGCAAGCCCAATCTGCACACCATCTATTTTCGGTCCCTGTTC

TCTAAGGAGAACCTGAAGGACGTGTGCCTGAAGCTGAATGGCGAGGCCGAGATGTTCTTTC

GGAAGAAGTCCATCAACTACGATGAGAAGAAGAAGCGGGAGGGCCACCACCCCGAGCTGTT

TGAGAAGCTGAAGTATCCTATCCTGAAGGACAAGAGATACAGCGAGGATAAGTTTCAGTTC

CACCTGCCCATCAGCCTGAACTTCAAGTCCAAGGAGCGGCTGAACTTTAATCTGAAAGTGAA

TGAGTTCCTGAAGAGAAACAAGGACATCAATATCATCGGCATCGATCGGGGCGAGAGAAAC

630

WO 2016/205711

PCT/US2016/038181

CTGCTGTACCTGGTCATGATCAATCAGAAGGGCGAGATCCTGAAGCAGACCCTGCTGGACA gcatgcagtccggcaagggccggcctgagatcaactacaaggagaagctgcaggagaagg agatcgagagggataaggcccgcaagagctggggcacagtggagaatatcaaggagctga aggagggctatctgtctatcgtgatccaccagatcagcaagctgatggtggagaacaatgc catcgtggtgctggaggacctgaacatcggcittaagcggggcagacagaaggtggagcgg caggtgtaccagaagttcgagaagatgctgatcgataagctgaactttctggtgttcaagga gaataagccaaccgagccaggaggcgtgctgaaggcctatcagctgacagacgagtttcag tcittcgagaagctgagcaagcagaccggcittctgitctacgtgccaagctggaacacctc caagatcgaccccagaacaggctttatcgaittcctgcaccctgcctacgagaatatcgaga aggccaagcagtggatcaacaagtttgattccatcaggttcaattctaagatggactggttt gagttcaccgccgatacacgcaagitttccgagaacctgatgctgggcaagaatcgggtgtg ggtcatctgcaccacaaatgtggagcggtacitcaccagcaagaccgccaacagctccatcc agtacaatagcatccagatcaccgagaagctgaaggagctgtttgtggacatccctttcagc aacggccaggatctgaagccagagatcctgaggaagaatgacgccgtgttctttaagagcc tgctgttttacatcaagaccacactgtccctgcgccagaacaatggcaagaagggcgagga ggagaaggacitcatcctgagcccagtggtggaitccaagggccggttcittaactctctgg aggccagcgacgatgagcccaaggacgccgatgccaatggcgcctaccacatcgccctgaa gggcctgatgaacctgctggtgctgaatgagacaaaggaggagaacctgagcagaccaaag tggaagatcaagaataaggactggctggagttcgtgtgggagaggaaccgclwiggccgg

CGOXX^CGAU4A4GGCCGGCCL4GGC^A4AL4GA4AU4GGGATCCTACCCATACGATGTTCCA

GATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTA

TGCCTAAGAATTC (SEQ ID NO: 22S) [001694] 14- Lachnospiraceae bacterium ND2006 (LbCpfl) [001695] ATGAGCAAGCTGGAGAAGTTTACAAACTGCTACTCCCTGTCTAAGACCCTGAGGT

TCAAGGCCATCCCTGTGGGCAAGACCCAGGAGAACATCGACAATAAGCGGCTGCTGGTGGA

GGACGAGAAGAGAGCCGAGGATTATAAGGGCGTGAAGAAGCTGCTGGATCGCTACTATCTG

TCTTTTATCAACGACGTGCTGCACAGCATCAAGCTGAAGAATCTGAACAATTACATCAGCCT

GTTCCGGAAGAAAACCAGAACCGAGAAGGAGAATAAGGAGCTGGAGAACCTGGAGATCAA

TCTGCGGAAGGAGATCGCCAAGGCCTTCAAGGGCAACGAGGGCTACAAGTCCCTGTITAAG

AAGGATATCATCGAGACAATCCTGCCAGAGTTCCTGGACGATAAGGACGAGATCGCCCTGG

TGAACAGCTTCAATGGCTTTACCACAGCCTTCACCGGCTTCTTTGATAACAGAGAGAATATG mTCCGAGGAGGCCAAGAGCACATCCATCGCCITCAGGTGTATCAACGAGAATCTGACCCG

CTACATCTCTAATATGGACATCITCGAGAAGGTGGACGCCATCTTTGATAAGCACGAGGTGC

AGGAGATCAAGGAGAAGATCCTGAACAGCGACTATGATGTGGAGGATTTCTTTGAGGGCGA

631

WO 2016/205711

PCT/US2016/038181

GTTCTTTAACTTTGTGCTGACACAGGAGGGCATCGACGTGTATAACGCCATCATCGGCGGCT

TCGTGACCGAGAGCGGCGAGAAGATCAAGGGCCTGAACGAGTACATCAACCTGTATAATCA

GAAAACCAAGCAGAAGCTGCCTAAGTTTAAGCCACTGTATAAGCAGGTGCTGAGCGATCGG

GAGTCTCTGAGCTTCTACGGCGAGGGCTATACATCCGATGAGGAGGTGCTGGAGGTGTTTAG

A A AC ACCCT GAACAAGAACAGCGAGATCITCAGCT CCA TCAAGAAGC TGGAGAAGC TGTTC

AAGAATTTTGACGAGTACTCTAGCGCCGGCATCTTTGTGAAGAACGGCCCCGCCATCAGCAC

AATCTCCAAGGATATCTTCGGCGAGTGGAACGTGATCCGGGACAAGTGGAATGCCGAGTAT

GACGATATCCACCTGAAGAAGAAGGCCGTGGTGACCGAGAAGTACGAGGACGATCGGAGA

AAGTCCTTCAAGAAGATCGGCTCCTTTTCTCTGGAGCAGCTGCAGGAGTACGCCGACGCCGA

TCTGTCTGTGGTGGAGAAGCTGAAGGAGATCATCATCCAGAAGGTGGATGAGATCTACAAG

GAACGACGCCGTGGTGGCCATCATGAAGGACCTGCTGGATTCTGTGAAGAGCTTCGAGAAIT

ACATCAAGGCCTTCTTTGGCGAGGGCAAGGAGACAAACAGGGACGAGTCCITCTATGGCGA

TTTTGTGCTGGCCTACGACATCCTGCTGAAGGTGGACCACATCTACGATGCCATCCGCAATT

ATGTGACCCAGAAGCCCTACTCTAAGGATAAGTTCAAGCTGTATTTTCAGAACCCTCAGTTC

ATGGGCGGCTGGGACAAGGATAAGGAGACAGACTATCGGGCCACCATCCTGAGATACGGCT CCAAGTACTATCTGGCCATCATGGATAAGAAGTACGCCAAGTGCCTGCAGAAGATCGACAA GGACGAIGTGAACGGCAAT fACGAGAAGATCAACIATAAGCTGCTGCCCGGCCCTAATAAG

CCAGAAGATCTACAAGAATGGCACATTCAAGAAGGGCGATATGTTTAACCTGAATGACTGT

CACAAGCTGATCGACTTCTTTAAGGATAGCATCTCCCGGTATCCAAAGTGGTCCAATGCCTA

CGATTTCAACTTTTCTGAGACAGAGAAGTATAAGGACATCGCCGGCTTTTACAGAGAGGTGG

AGGAGCAGGGCTATAAGGTGAGCITCGAGTCTGCCAGCAAGAAGGAGGTGGATAAGCTGGT

GGAGGAGGGCAAGCTGTATATGTTCCAGATCTATAACAAGGACTTTTCCGATAAGTCTCACG

GCACACCCAATCTGCACACCATGTACTTCAAGCTGCTGTTTGACGAGAACAATCACGGACAG

ATCAGGCTGAGCGGAGGAGCAGAGCTGITCATGAGGCGCGCCTCCCTGAAGAAGGAGGAGC

TGGTGGTGCACCCAGCCAACTCCCCTATCGCCAACAAGAATCCAGATAATCCCAAGAAAAC

CACAACCCTGTCCTACGACGTGTATAAGGATAAGAGGTTTTCTGAGGACCAGTACGAGCTGC

ACATCCCAATCGCCATCAATAAGTGCCCCAAGAACATCITCAAGATCAATACAGAGGTGCGC

GTGCTGCTGAAGCACGACGATAACCCCTATGTGATCGGCATCGATAGGGGCGAGCGCAATC

IGCTGTATAT CGTGGTGGTGGACGGCAAGGGCAACAT CGTGGAGCAGTATTCCCTGAACGA

GATCATCAACAACTTCAACGGCATCAGGATCAAGACAGATTACCACTCTCTGCTGGACAAGA

AGGAGAAGGAGAGGTTCGAGGCCCGCCAGAACTGGACCTCCATCGAGAATATCAAGGAGCT

GAAGGCCGGCTATATCTCTCAGGTGGTGCACAAGATCTGCGAGCTGGTGGAGAAGTACGAT

632

WO 2016/205711

PCT/US2016/038181

GCCGTGATCGCCCTGGAGGACCTGAACTCTGGCTTTAAGAATAGCCGCGTGAAGGTGGAGA

AGCAGGTGTATCAGAAGTTCGAGAAGATGCTGATCGATAAGCTGAACTACATGGTGGACAA

GAAGTCTAATCCTTGTGCAACAGGCGGCGCCCTGAAGGGCTATCAGATCACCAATAAGTTCG

AGAGCTTTAAGTCCATGTCTACCCAGAACGGCTTCATCTITTACATCCCTGCCTGGCTGACAT

CCAAGATCGATCCATCTACCGGCTTTGTGAACCTGCTGAAAACCAAGTATACCAGCATCGCC

GATTCCAAGAAGTTCATCAGCTCCTTTGACAGGATCATGTACGTGCCCGAGGAGGATCTGTT

CGAGTTTGCCCTGGACTATAAGAACTTCTCTCGCACAGACGCCGATTACATCAAGAAGTGGA

AGCTGTACTCCTACGGCAACCGGATCAGAATCITCCGGAATCCTAAGAAGAACAACGTGITC

GACTGGGAGGAGGTGTGCCTGACCAGCGCCTATAAGGAGCTGTTCAACAAGTACGGCATCA

ATTATCAGCAGGGCGATATCAGAGCCCTGCTGTGCGAGCAGTCCGACAAGGCCTTCTACTCT

AGCTTTATGGCCCTGATGAGCCTGATGCTGCAGATGCGGAACAGCATCACAGGCCGCACCG

ACGTGGAinTCTGATCAGCCCTGTGAAGAACTCCGACGGCATCITCTACGATAGCCGGAAC

TATGAGGCCCAGGAGAATGCCATCCTGCCAAAGAACGCCGACGCCAATGGCGCCTATAACA

TCGCCAGAAAGGTGCTGTGGGCCATCGGCCAGTTCAAGAAGGCCGAGGACGAGAAGCTGGA

TAAGGTGAAGATCGCCATCTCTAACAAGGAGTGGCTGGAGTACGCCCAGACCAGCGTGAAG

CACA4rtAGGCCGGCGGCCNC’GA4A4AGGCCGGCCAGGCL4AA4A4Gffi4ffi4AGGGATCCTACCCA

TACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGA

TGTCCCCGACTATGCCTAAGAATTC (SEQ ID NO: 226) [001696] 15- Porpbyromonas crevioricanis (PcCpfl) [001697] ATGGACAGCCTGAAGGATTTCACCAACCTGTACCCCGTGTCCAAGACACTGCGGT

TTGAGCTGAAGCCTGTGGGCAAGACCCTGGAGAATATCGAGAAGGCCGGCATCCTGAAGGA

GGATGAGCACAGAGCCGAGAGCTACCGGAGAGTGAAGAAGATCATCGATACATATCACAAG

GTGTTCATCGACAGCTCCCTGGAGAACATGGCCAAGATGGGCATCGAGAATGAGATCAAGG

CCATGCTGCAGTCCTITTGCGAGCTGTATAAGAAGGACCACAGGACCGAGGGAGAGGACAA

GGCCCTGGATAAGATCAGGGCCGTGCTGAGGGGCCTGATCGTGGGAGCCTTCACCGGCGTG

TGCGGCCGGCGGGAGAACACAGTGCAGAATGAGAAGTATGAGAGCCTGTTTAAGGAGAAGC

TGATCAAGGAGATCCTGCCAGATTrCGTGCTGTCTACAGAGGCCGAGTCCCTGCCCmTCTG

TGGAGGAGGCCACCAGAAGCCTGAAGGAGTTCGACTCCTTTACATCTTACTTCGCCGGCTTT

TATGAGAACCGGAAGAATATCTACTCTACCAAGCCCCAGAGCACAGCCATCGCCTATAGACT

GATCCACGAGAACCTGCCTAAGTTCATCGATAATATCCTGGTGTTTCAGAAGATCAAGGAGC

CAATCGCCAAGGAGCTGGAGCACATCAGGGCAGACTTCAGCGCCGGCGGCTACATCAAGAA

GGATGAGCGCCTGGAGGACATCTTTTCCCTGAACTACTATATCCACGTGCTGTCTCAGGCCG

GCATCGAGAAGTACAATGCCCTGATCGGCAAGATCGTGACCGAGGGCGATGGCGAGATGAA

633

WO 2016/205711

PCT/US2016/038181

GGGCCTGAACGAGCACATCAACCTGTATAATCAGCAGAGGGGCCGCGAGGACCGGCTGCCA

CTGTTCAGACCCCTGTATAAGCAGATCCTGTCTGATAGGGAGCAGCTGTCCTATCTGCCAGA

GTCTTTCGAGAAGGACGAGGAGCTGCTGAGGGCCCTGAAGGAGTTTTACGATCACATCGCA

GAGGACATCCTGGGAAGGACCCAGCAGCTGATGACAAGCATCTCCGAGTACGATCTGTCCC

GGATCT ATG IGAGAAACGATAGCCAGCTGACCGACATCI CC AAGAAGAIGCTGGGCGATIG

GAA' TGCCAT C TAC AT GGCC CGGGAG AGAGCCT A' TG AC C ACGAGC AGGC CCCC A AGCGCAT C

ACAGCCAAGTACGAGAGGGACCGCATCAAGGCCCTGAAGGGCGAGGAGTCTATCAGCCTGG

CCAACCTGAACAGCTGCATCGCCTTCCTGGACAACGTGAGGGATTGTCGCGTGGACACCTAT

CTGTCTACACTGGGACAGAAGGAGGGACCTCACGGCCTGAGCAACCTGGTGGAGAACGTGT

TCGCCTCCTACCACGAGGCCGAGCAGCTGCTGTCTTTTCCCTATCCTGAGGAGAACAATCTG

ATCCAGGACAAGGATAACGTGGTGCTGATCAAGAACCTGCTGGATAATATCAGCGACCTGC

AGAGGTTCCTGAAGCCACTGTGGGGCATGGGCGATGAGCCCGACAAGGATGAGAGGmTA

CGGCGAGTACAATTATATCAGGGGCGCCCTGGACCAGGTCATCCCTCTGTATAACAAGGTGC

GGAATTATCIGACCCGCAAGCCA TACT CCACACGCAAGG TGAAGC TGAACTTCGGCAATAG CCAGCTGCTGTCCGGCTGGGATAGGAACAAGGAGAAGGACAATTCTTGCGTGATCCTGCGC AAGGGCCAGAACTTCTACCTGGCCATCATGAACAATCGGCACAAGCGGAGCTTCGAGAATA

AGATGCTGCCCGAGTATAAGGAGGGCGAGCCTTACTTCGAGAAGATGGATTATAAGTTTCTG

CCAGACCCCAACAAGATGCIGCCCAAGGTGTTCCTGTCTAAGAAGGGCA TCGAGATCTACA AGCCTAGCCCAAAGCTGCTGGAGCAGTATGGCCACGGCACCCACAAGAAGGGCGATACCTT

CAGCATGGACGATCTGCACGAGCTGATCGACTTCnTAAGCACTCCATCGAGGCCCACGAGG

ATTGGAAGCAGTTCGGCTTTAAGTTCAGCGACACCGCCACATACGAGAACGTGAGCAGCTTC

TACCGGGAGGTGGAGGACCAGGGCTACAAGCTGTCTTTTAGAAAGGTGTCCGAGTCTTACGT

GTATAGCCTGATCGATCAGGGCAAGCTGTACCTGTTCCAGATCTATAACAAGGACTTTAGCC

CTTGTTCCAAGGGCACCCCAAATCTGCACACACTGTACTGGCGGATGCTGTTCGATGAGAGA

AACCTGGCCGACGTGATCTATAAGCTGGATGGCAAGGCCGAGATCTTCTTTCGGGAGAAGTC

CCTGAAGAATGACCACCCAACCCACCCTGCAGGCAAGCCCATCAAGAAGAAGAGCCGGCAG

AAGAAGGGCGAGGAGAGCC TGT f CGAGIACGATCI GGT GAAGGACCGGAGA'f AIACCATGG

ATAAGTTTCAGTTCCACGTGCCAATCACAATGAACTTTAAGTGCTCTGCCGGCAGCAAGGTG

AACGACATGGTGAATGCCCACATCAGGGAGGCCAAGGACATGCACGTGATCGGCATCGATA

GGGGCGAGCGCAATCTGCTGTATATCTGCGTGATCGACAGCCGCGGCACCATCCTGGATCAG

ATCTCCCTGAACACAATCAATGACATCGATTATCACGATCTGCTGGAGTCCAGGGACAAGGA

TCGCCAGCAGGAGCACAGGAACTGGCAGACCATCGAGGGCATCAAGGAGCTGAAGCAGGG

CTACCTGTCTCAGGCCGTGCACCGCATCGCCGAGCTGATGGTGGCCTATAAGGCCGTGGTGG

CCCTGGAGGACCTGAACATGGGCTTCAAGCGGGGCAGACAGAAGGTGGAGAGCAGCGTGTA

634

WO 2016/205711

PCT/US2016/038181

CCAGCAGTITGAGAAGCAGCTGATCGACAAGC TGAATTA FCTGG fGGA FAAGAAGAAGCGG

CCCGAGGACATCGGAGGCCTGCTGAGAGCCTACCAGTTCACCGCCCCTTTCAAGAGCTTTAA

GGAGATGGGCAAGCAGAACGGCTTTCTGTTCTATATCCCTGCCTGGAACACATCCAATATCG

ACCCAACCACAGGCTTCGTGAACCTGTTTCACGTGCAGTACGAGAATGTGGATAAGGCCAA

GAGCTTCTTTCAGAAGTTCGACAGCATCTCCTACAACCCTAAGAAGGATTGGTTTGAGTTCG

CCTTTGACTATAAGAACTTCACCAAGAAGGCCGAGGGCTCTAGGAGCATGTGGATTCTGTGC

ACCCACGGCTCCCGGATCAAGAACTTCAGAAATTCTCAGAAGAATGGCCAGTGGGATAGCG

AGGAGTTTGCCCTGACCGAGGCCTTCAAGTCCCTGTTTGTGCGGTACGAGATCGATTATACC

GCCGACCTGAAAACCGCCATCGTGGACGAGAAGCAGAAGGATTTCTTTGTGGACCTGCTGA

AGCTG ΓΤ C AAGC TGACCGT GCAGATGAGAAACT CCT GGAAGGAGAAGGACCT GGAT1ACCT

GATCTCTCCAGTGGCCGGCGCCGATGGCAGGTTCTTTGACACACGCGAGGGCAATAAGAGC

CTGCCCAAGGACGCAGATGCAAACGGAGCCTATAATATCGCCCTGAAGGGCCTGTGGGCAC

TGAGGCAGATCAGACAGACCTCCGAGGGCGGCAAGCTGAAGCTGGCCATCTCTAACAAGGA

GTGGCTGCAGTTTGTGCAGGAGAGATCCTACGAGAAGGACAAAAGGCCGGCGGCCACGAA4

AAGGCCGGCCAGGCAAAAAAGAAAAAGGGNTCCJACCCNTACGAYGYYCCAGAYYACGCYYA

TCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTATGCCTAAGAAT [001698] 16~ Previ [001699] ATGGAGAACTATCAGGAGTTCACCAACCTGTTTCAGCTGAATAAGACACTGAGA TTCGAGCTGAAGCCCATCGGCAAGACCTGCGAGCTGCTGGAGGAGGGCAAGATCTTCGCCA GCGGCTCCTTTCIGGAGAAGGACAAGGIGAGGGCCGA TAACGT GAGCTACG FGAAGAAGGA GATCGACAAGAAGCACAAGATCTTTATCGAGGAGACACTGAGCTCCTTCTCTATCAGCAACG

ATCTGCTGAAGCAGTACITTGACTGCTATAATGAGCTGAAGGCCITCAAGAAGGACTGTAAG

AGCGATGAGGAGGAGGTGAAGAAAACCGCCCTGCGCAACAAGTGTACCTCCATCCAGAGGG

CCATGCGCGAGGCCATCTCTCAGGCCTTTCTGAAGAGCCCCCAGAAGAAGCTGCTGGCCATC

AAGAACCTGATCGAGAACGTGTTCAAGGCCGACGAGAATGTGCAGCACTTCTCCGAGTTTAC

CAGCTATTTCTCCGGCTTTGAGACAAACAGAGAGAATTTCTACTCTGACGAGGAGAAGTCCA

CATCTATCGCCTATAGGCTGGTGCACGATAACCTGCCTATCTTCATCAAGAACATCTACATCT TCGAGAAGCTGAAGGAGCAGITCGACGCCAAGACCCTGAGCGAGAT C IT CGAGAACTACAA

GCTGTATGTGGCCGGCTCTAGCCTGGATGAGGTGTTCTCCCTGGAGTACTTTAACAATACCCT

GACACAGAAGGGCATCGACAACTATAATGCCGTGATCGGCAAGATCGTGAAGGAGGATAAG

CAGGAGATCCAGGGCCTGAACGAGCACATCAACCTGTATAATCAGAAGCACAAGGACCGGA

GACTGCCCTTCTTTATCTCCCTGAAGAAGCAGATCCTGTCCGATCGGGAGGCCCTGTCTTGGC

635

WO 2016/205711

PCT/US2016/038181

TGCCTGACATGTTCAAGAATGATTCTGAAGTGATCAAGGCCCTGAAGGGCTTCTACATCGAG gac:ggctttgagaacaatgtgctgacacctctggccaccctgctgtcctctctggataagta

CAACCTGAATGGCATCTTTATCCGCAACAATGAGGCCCTGAGCTCCCTGTCCCAGAACGTGT

ATCGGAATTTTTCTATCGACGAGGCCATCGATGCCAACGCCGAGCTGCAGACCTTCAACAAT tacgagctgatcgccaatgccctgcgcgccaagatcaagaaggagacaaagcagggccgga AG FCTTTCGAGAAGTACGAGGAGT ATA FCGATAAGAAGG FGAAGGCCATCGACAGCCTG FC CATCCAGGAGATCAACGAGCTGGTGGAGAATTACGTGAGCGAGTTTAACTCTAATAGCGGC

AACATGCCAAGAAAGGTGGAGGACTACTTCAGCCTGATGAGGAAGGGCGACTTCGGCTCCA

ACGATCTGATCGAAAATATCAAGACCAAGCTGAGCGCCGCAGAGAAGCTGCTGGGCACAAA

GTACCAGGAGACAGCCAAGGACATCTTCAAGAAGGATGAGAACTCCAAGCTGATCAAGGAG

CTGCTGGACGCCACCAAGCAGTTCCAGCACTTTATCAAGCCACTGCTGGGCACAGGCGAGG

AGGCAGATCGGGACCTGGTGTTCTACGGCGATTTTCTGCCCCTGTATGAGAAGTTTGAGGAG

CTGACCCTGCTGTATAACAAGGTGCGGAATAGACTGACACAGAAGCCCTATTCCAAGGACA

AGATCCGCCTGTGCTTCAACAAGCCTAAGCTGATGACAGGCTGGGTGGATTCCAAGACCGA

GAAGTCTGACAACGGCACACAGTACGGCGGCTATCTGTTTCGGAAGAAGAATGAGATCGGC

GAGTACGATTATTTTCTGGGCATCTCTAGCAAGGCCCAGCTGTTCAGAAAGAACGAGGCCGT

GATCGGCGACTACGAGAGGCTGGATTACTATCAGCCAAAGGCCAATACCATCTACGGCTCTG

CC FAT GAGGGCGAGAACAGC FACAAGGAGGACAAGAAGCGGC TGAACAAAGTGATCAT CG

CCTATATCGAGCAGATCAAGCAGACAAACATCAAGAAGTCTATCATCGAGTCCATCTCTAAG

TATCCTAATATCAGCGACGATGACAAGGTGACCCCATCCTCTCTGCTGGAGAAGATCAAGAA

GGTGTCTATCGACAGCTACAACGGCATCCTGTCCTTCAAGTCITITCAGAGCGTGAACAAGG

AAGTGATCGATAACCTGCTGAAAACCATCAGCCCCCTGAAGAACAAGGCCGAGTTTCTGGA

CCTGATCAATAAGGATTATCAGATCTTCACCGAGGTGCAGGCCGTGATCGACGAGATCTGCA

AGCAGAAAACCTTCATCTACTTTCCAATCTCCAACGTGGAGCTGGAGAAGGAGATGGGCGA

TAAGGACAAGCCCCTGTGCCTGTTCCAGATCAGCAATAAGGATCTGTCCTTCGCCAAGACCT

TTAGCGCCAACCTGCGGAAGAAGAGAGGCGCCGAGAATCTGCACACAATGCTGTTTAAGGC

CCTGATGGAGGGCAACCAGGATAATCTGGACCTGGGCTCTGGCGCCATCTTCTACAGAGCCA

AGAGCCTGGACGGCAACAAGCCCACACACCCTGCCAATGAGGCCATCAAGTGTAGGAACGT

GGCCAATAAGGATAAGGTGTCCCTGTTCACCTACGACATCTATAAGAACAGGCGCTACATGG

AGAATAAGTTCCTGTTTCACCTGAGCATCGTGCAGAACTATAAGGCCGCCAATGACTCCGCC

CAGCTGAACAGCTCCGCCACCGAGTATATCAGAAAGGCCGATGACCTGCACA'FCATCGGCA

TCGATAGGGGCGAGCGCAATCTGCTGTACTATTCCGTGATCGATATGAAGGGCAACATCGTG

GAGCAGGACTCTCTGAATATCATCAGGAACAATGACCTGGAGACAGATTACCACGACCTGC

TGGATAAGAGGGAGAAGGAGCGCAAGGCCAACCGGCAGAATTGGGAGGCCGTGGAGGGCA

636

WO 2016/205711

PCT/US2016/038181

TCAAGGACCTGAAGAAGGGCTACCTGAGCCAGGCCGTGCACCAGATCGCCCAGCTGATGCT

GAAGTATAACGCCATCATCGCCCTGGAGGATCTGGGCCAGATGTTTGTGACCCGCGGCCAGA

AGATCGAGAAGGCCGTGTACCAGCAGTTCGAGAAGAGCCTGGTGGATAAGCTGTCCTACCT

GGTGGACAAGAAGCGGCCTTATAATGAGCTGGGCGGCATCCTGAAGGCCTACCAGCTGGCC

TCTAGCATCACCAAGAACAATTCTGACAAGCAGAACGGCTTCCTGTTTTATGTGCCAGCCTG GAATACAAGCAAGATCGA FCCCG TGACCGGCTITACAGACC FGCTGCGGCCCAAGGCCATG ACCATCAAGGAGGCCCAGGACTTCTTTGGCGCCTTCGATAACATCTCTTACAATGACAAGGG

CTATTTCGAGTTTGAGACAAACTACGACAAGTTTAAGATCAGAATGAAGAGCGCCCAGACC

AGGTGGACAATCTGCACCTTCGGCAATCGGATCAAGAGAAAGAAGGATAAGAACTACTGGA

ATTATGAGGAGGTGGAGCIGACCGAGGAGTTCAAGAAGCTG ITTAAGGACAGCAACATCGA TTACGAGAACTGTAATCTGAAGGAGGAGATCCAGAACAAGGACAATCGCAAGTTCTTTGAT

GACCTGATCAAGCTGCTGCAGCTGACACTGCAGATGCGGAACTCCGATGACAAGGGCAATG

ATTATATCATCTCTCCTGTGGCCAACGCCGAGGGCCAGTTCTTTGACTCCCGCAATGGCGAT

AAGAAGCTGCCACTGGATGCAGACGCAAACGGAGCCTACAATATCGCCCGCAAGGGCCTGT

GGAACATCCGGCAGATCAAGCAGACCAAGAACGACAAGAAGCTGAATCTGAGCATCTCCTC

TACAGAGTGGCTGGATTTCGTGCGGGAGAAGCCTTACCTGAAGA4A4GGC’CGGCGGCG4CG4

A4A4GGCCGGCC4GGCLWL4zlG^L4A4GGGATCCTACCCATACGATGTTCCAGATTACGCT

TATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTATGCCTAAGA

ATTC (SEQ ID NO: 228) [001700] 17- Porphyromonas macacae (PmCpfl) [001701] ATGAA AACCCAGCACTTCTTTGAGGACTTC AC AAGCCTGTACTCTCTGAGCAAGA

CCATCCGGTTTGAGCTGAAGCCAATCGGCAAGACCCTGGAGAACATCAAGAAGAATGGCCT

GATCCGGAGAGATGAGCAGAGACTGGACGATTACGAGAAGCTGAAGAAAGTGATCGACGA

GTATCACGAGGATTTCATCGCCAACATCCTGAGCTCCTTTTCCTTCTCTGAGGAGATCCTGCA

GTCCTACATCCAGAATCTGAGCGAGTCCGAGGCCAGGGCCAAGATCGAGAAAACCATGCGC

GACACACTGGCCAAGGCCTTCTCTGAGGATGAGAGGTACAAGAGCATCTTTAAGAAGGAGC

TGGTGAAGAAGGACATCCCCGTGTGGTGCCCTGCCTATAAGAGCCTGTGCAAGAAGTTCGAT

AACTTTACCACATCTCTGGTGCCCTTCCACGAGAACAGGAAGAACCTGTATACCAGCAATGA

GATCACAGCCTCTATCCCTTATCGCATCGTGCACGTGAACCTGCCAAAGTTTATCCAGAATA

TCGAGGCCCTGTGCGAGCTGCAGAAGAAGATGGGCGCCGACCTGTACCTGGAGATGATGGA

GAACCTGCGCAACGTGTGGCCCAGCTTCGTGAAAACCCCAGACGACCTGTGCAACCTGAAA

ACCTATAATCACCTGATGGTGCAGTCTAGCATCAGCGAGTACAACAGGTTTGTGGGCGGCTA

ITCCACCGAGGACGGCACAAAGCACCAGGGCATCAACGAGTGGATCAAT ATCT ACAGACAG

637

WO 2016/205711

PCT/US2016/038181

AGGAA TAAGGAGATGCGCCT GCC TGGCCTGGTGITCCTGCACAAGC AGATCCT GGCC AAGG

AGACAGITCAGGAAGCTGmTGGAATACCGTGTCCTCTAAGGAGGACGATGCCGCCTCCCT

GAAGGACCTGTTCTGTGGCCTGTCTGGCTATGACCCTGAGGCCATCTACGTGAGCGATGCCC

ACCTGGCCACAATCTCCAAGAACATCTTTGACAGATGGAATTACATCTCCGATGCCATCAGG

CGCAAGACCGAGGTGC I GAT GCC ACGGAAG AAGG AGA GCGTGGA GAGA ΓΑΤ GCCGAGAAG

ATCTCCAAGCAGATCAAGAAGAGACAGTCTTACAGCCTGGCCGAGCTGGACGATCTGCTGG

CCCACTATAGCGAGGAGTCCCTGCCCGCAGGCTTCTCTCTGCTGAGCTACTTTACATCTCTGG

GCGGCCAGAAGTATCTGGTGAGCGACGGCGAAGTGATCCTGTACGAGGAGGGCAGCAACAT

CTGGGACGAGGTGC TGAT CGCCITCAGGGATCT GCAGGT CA TCC f GGACAAGGACTICACCG

AGAAGAAGCTGGGCAAGGATGAGGAGGCCGTGTCTGTGATCAAGAAGGCCCTGGACAGCGC

CCTGCGCCTGCGGAAGITCITTGATCTGCTGTCCGGCACAGGCGCAGAGATCAGGAGAGACA

GCTCCTTCTATGCCCTGTATACCGACCGGATGGATAAGCTGAAGGGCCTGCTGAAGATGTAT

GATAAGGTGAGAAACTACCTGACCAAGAAGCCTTATTCCATCGAGAAGTTCAAGCTGCACTT

TGACAACCCATCCCTGCTGTCTGGCTGGGATAAGAATAAGGAGCTGAACAATCTGTCTGTGA

TCTTCCGGCAGAACGGCTACTATTACCTGGGCATCATGACACCCAAGGGCAAGAATCTGTTC

AAGACCCTGCCTAAGCTGGGCGCCGAGGAGATGITITATGAGAAGATGGAGTACAAGCAGA

TCGCCGAGCCTATGCTGATGCTGCCAAAGGTGTTCTTTCCCAAGAAAACCAAGCCAGCCTTC

GCCCCAGACCAGAGCGTGGTGGATATCTACAACAAGAAAACCTTCAAGACAGGCCAGAAGG

GCITTAATAAGAAGGACCTGTACCGGCTGATCGACTTCTACAAGGAGGCCCTGACAGTGCAC

GAGTGGAAGCTGTTTAACITCTCC'mTCTCCAACCGAGCAGTATCGGAATATCGGCGAGTT

CTTTGACGAGGTGAGAGAGCAGGCCTACAAGGTGTCCATGGTGAACGTGCCCGCCTCTTATA

TCGACGAGGCCGTGGAGAACGGCAAGCTGTATCTGTTCCAGATCTACAATAAGGACTTCAGC

CCCTACTCCAAGGGCATCCCTAACCTGCACACACTGTATTGGAAGGCCCTGTTCAGCGAGCA

GAATCAGAGCCGGGTGTATAAGCTGTGCGGAGGAGGAGAGCTGTTTTATAGAAAGGCCAGC

CTGCACATGCAGGACACCACAGTGCACCCCAAGGGCATCTCTATCCACAAGAAGAACCTGA

ATAAGAAGGGCGAGACAAGCCTGTTCAACIACGACC rGGTGAAGGATAAGAGGT TTACCGA

TGAATCAGATGGTGCGCGATTATATCGCCCAGAACGACGATCTGCAGATCATCGGCATCGAC

CGCGGCGAGCGGAATCTGCTGTATATCAGCCGGATCGATACAAGGGGCAACCTGCTGGAGC

AGTTCAGCCTGAATGTGATCGAGTCCGACAAGGGCGATCTGAGAACCGACTATCAGAAGAT

CCTGGGCGATCGCGAGCAGGAGCGGCTGAGGCGCCGGCAGGAGTGGAAGTCTATCGAGAGC

ATCAAGGACCTGAAGGATGGCTACATGAGCCAGGTGGTGCACAAGATCTGTAACATGGTGG

TGGAGCACAAGGCCATCGTGGTGCTGGAGAACCTGAATCTGAGCTTCATGAAGGGCAGGAA

638

WO 2016/205711

PCT/US2016/038181

GAAGGTGGAGAAGTCCGTGTACGAGAAGTTTGAGCGCATGCTGGTGGACAAGCTGAACTAT

CTGGTGGTGGATAAGAAGAACCTGTCCAATGAGCCAGGAGGCCTGTATGCAGCATACCAGC

TGACCAATCCACTGTTCTCTTTTGAGGAGCTGCACAGATACCCCCAGAGCGGCATCCTGTTTT

TCGTGGACCCATGGAACACCTCTCTGACAGATCCCAGCACAGGCTTCGTGAATCTGCTGGGC

AGAATCAACTACACCAATGTGGGCGACGCCCGCAAGTTTTTCGATCGGTTTAACGCCATCAG

ATATGACGGCAAGGGCAATATCCTGTTCGACCTGGATCTGTCCAGATTTGATGTGAGGGTGG

AGACACAGAGGAAGCTGTGGACACTGACCACATTCGGCTCTCGCATCGCCAAATCCAAGAA

GTCTGGCAAGTGGATGGTGGAGCGGATCGAGAACCTGAGCCTGTGCTTTCTGGAGCTGTTCG

AGCAGTTTAATATCGGCTACAGAGTGGAGAAGGACCTGAAGAAGGCCATCCTGAGCCAGGA

TAGGAAGGAGTTCTATGTGCGCCTGATCTACCTGTTTAACCTGATGATGCAGATCCGGAACA

GCGACGGCGAGGAGGATTATATCCTGTCTCCCGCCCTGAACGAGAAGAATCTGCAGTrCGAC

AGCAGGCTGATCGAGGCCAAGGATCTGCCTGTGGACGCAGATGCAAACGGAGCATACAATG

TGGCCCGCAAGGGCCTGATGGTGGTGCAGAGAATCAAGAGGGGCGACCACGAGTCCATCCA

CAGGATCGGAAGGGCACAGTGGCTGAGATATGTGCAGGAGGGCATCGTGGAGriAlAGGCCG

GCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCCJACCCNTACGNTGTTCC

AGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACT

ATGCCTAAGAATTC (SEQ ID NO: 229) [001702] Amino acid sequence of human codon optimized Cpfl orthologs [001703] Nuclear localization signal (NLS) [001704] Glycine-Serine linker [001705] 3xHAtag [001706] 1- Franscisella tularensis subsp. novicida U112 (FnCpfl) [001707] MSIYQEFVNKYSLSKTLRFEL1PQGKTLENIKARGLILDDEKRAKDYKKAKQI1DKYH

QFFIEEILSSVCISEDLLQNYSDWFKLKKSDDDNLQKDFKSAKDTIKKQISEYIKDSEKFKNLFNQ

NLIDAKKGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGWITYFKGFHENRKNVYS

SNDIPTSIIYRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKDLAEELTFD1DYKTSEVNQRVF

SLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRKGINEYINLYSQQINDKTLKKYKMSVL

FKQJLSDTESKSFVIDKLEDDSDWTTMQSFYEQIAAFKTVEEKSIKETLSLLFDDLKAQKLDLSKI

YFKNDKSLTDLSQQVFDDYSVIGTAVLEYITQQIAPKNLDNPSKKEQELIAKKTEKAKYLSLETIK

LALEEFNKHRDIDKQCRFEEILANFAAIPMIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEDDV

KAIKDLLDQTNNLLHKLKIFHISQSEDKANILDKDEHFYLVFEECYFELANIVPLYNKIRNYITQKP

YSDEKFKLNFENSTLANGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENKGEG

YKKIVYKLLPGANKMLPKVFFSAKSIKFYNPSEDILRIRNHSTHTKNGSPQKGYEKFEFNIEDCRK

639

WO 2016/205711

PCT/US2016/038181

FIDFYKQSISKHPEWKDFGFRFSDTQRYNSIDEFYREVENQGYKLTFENISESYIDSVVNQGKLYL

FQIYNKDFSAYSKGRPNLHTLYWKALFDERNLQDVVYKLNGEAELFYRKQSIPKKITHPAKEAIA

NKNKDNPKKESVFEYDLIKDKRFTEDKFFFHCPITINFKSSGANKFNDEINLLLKEKANDVHILSID

RGERHLAYYTLVDGKGNIIKQDTFN1IGNDRMKTNYHDKLAAIEKDRDSARKDWKK1NNIKEMK

EGYLSQVVHEIAKLVIEYNAIVVFEDLNFGFKRGRFKVEKQVYQKLEKMLIEKLNYLVFKDNEF

DKTGGVLRAYQLTAPFETFKKMGKQTGIIYYVPAGFTSKICPVTGFVNQLYPKYESVSKSQEFFS

KFDKICYNLDKGYFEFSFDYKNFGDKAAKGKWHASFGSRLINFRNSDKNHNWDTREVYPTKEL

EKLLKDYSIEYGHGECIKAAICGESDKKFFAKLTSVLNHLQMRNSKTGTELDYLISPVADVNGNF

FDSRQAPKNMPQDADANGAYH1GLKGLMLLGR1KNNQEGKKLNLV1KNEEYFEFVQNRNNXRP

A47K&4GgrtXKAXGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 230) [001708] 3~ Lachnospiraceae bacterium MC2017 (LbSCpfl) [001709] MDYGNGQFERRAPLTKTITLRLKPIGETRETIREQKLLEQDAAlRKEMY\'TPS VDDCIRKIADNALCHFGTEYDFSCLGNAISKNDSKAIKKETEKVEKLLAKVLTENLPDGL

RKVNDINSAAFIQDTLTSFVQDDADKRVLIQELKGKTVLMQRFLTTRITALTVWLPDRV

FENFNlFIENAEKMRILLDSPLNEKIMKFDPDAEQYASLEFYGQCLSQKDIDSYNLnSGIY

ADDEVKNPGINEIVKEYNQQIRGDKDESPLPKLKKLHKQILMPVEKAFFVRVLSNDSDA

RSILEKILKDTEMLPSKHEAMKEADAGDIAVYGSRLHELSHVIYGDHGKLSQIIYDKESK

RISELMETLSPKERKESKKRLEGLEEHIRKSTYTFDELNRYAEKNVMAAYIAAVEESCAE

IMRKEKDLRTLLSKEDVKIRGNRHNTLiVKNYFNAWTVFRNLIRiLRRKSEAEIDSDFYD

VLDDSVEVLSLTYKGENLCRSYITKKIGSDLKPEIATYGSALRPNSRWWSPGEKFNVKFH

TIVRRDGRLYYFILPKGAKPVELEDMDGDIECLQMRKIPNPTIFLPKLWKDPEAFFRDNP

EADEFVFLSGMKAPVTrTRETYEAYRYKLYTVGKLRDGEVSEEEYKRALLQVLTAYKEF

LENRMIYADLNFGFKDLEEYKDSSEFIKQVETHNTFMCWAKVSSSQLDDLVKSGNGLLF

EIWSERLESYYKYGNEKVLRGYEGVLLSILKDENLVSMRTLLNSRPMLVYRPKESSKPM

WHRDGSRWDRFDKDGKYIPPEVHDELYRFFNNLLIKEKLGEKARKILDNKKVKVKV

LESERVKWSKFYDEQFAVTFSVKKNADCLDTTKDLNAEVMEQYSESNRLILIRNTTDIL

YYLVLDKNGKVLKQRSLNUNDGARDVDWKERFRQVTKDRNEGYNEWDYSRTSNDLK

EVYLNYALKEIAEAVIEYNAILIIEKMSNAFKDKYSFLDDVTFKGFETKLLAKLSDLHFR

GIKDGEPCSFTNPLQLCQNDSNKILQDGVIFMVPNSMI'RSLDPDTGFIFAINDHNIRTKKA

KLNFLSKFDQLKVSSEGCLIMKYSGDSLPTHNTDNRVWNCCCNHPITNYDRETKKVEFI

EEPVEELSRVLEENGIETDTELNKLNERENVPGKVVDAIYSLVLNYLRGTVSGVAGQRA

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VYYSPVTGKKYDISFIQAMNLNRKCDYYRIGSKERGEWTDFVAQLINOJMrt/XOGOJ

AXXXGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 231) [001710] 4-Butyrivibrio proteoclasticus (BpCpfl) [001711 ] MLLYENYTKRNQITKSLRLELRPQGKTLRNIKELNLLEQDKAIYALLERLKPVIDEGI

KD1ARDTLKNCELSFEKLYEHFLSGDKKAYAI<ESERLKKEIVKTLIKNLPEGIGI<ISEINSAI<YLN

GVLYDF1DKTHKDSEEKQNILSDILETKGYLALFSKFLTSR1TTLEQSMPKRVIENFEIYAAN1PKM

QDALERGAVSFAIEYESICSVDYYNQILSQEDIDSYNRLISGIMDEDGAKEKGINQTISEKNIKIKSE

HLEEKPFRILKQLHKQILEEREKAFTIDHIDSDEEVVQVTKEAFEQTKEQWENIKKTNGFYAKDPG

DITLFIVVGPNQIHVLSQLIYGEHDRIRLLLEEYEKNTLEVLPRRIKSEKARYDKFVNAVPKKVA

KESHTFDGLQKMTGDDRLFILYRDELARNYMR1KEAYGTFERD1LKSRRGIKGNRDVQESLVSFY

DELTKFRSALRHNSGNDEKADPIFYNTFDGiFEKANRTYKAENLCRNYVTKSPADDARIMASCLG

TPARLRTHWWNGEENFAINDVAMIRRGDEYYYFVLTPDVKPVDLKTKDETDAQIFVQRKGAKS

FLGLPKALFKCILEPYFESPEHKNDKNCVIEEYVSKPLTIDRRAYDIFKNGTFKKTNIGIDGLTEEK

FKDDCRYLIDVYKEFIAVYTRYSCFNMSGLKRADEYNDIGEFFSDVDTRLCTMEWIPVSFERIND

MVDKKEGLLFLVRSMFLYNRPRKPYERTFIQLFSDSNMEHTSMLLNSRAMIQYRAASLPRRVTH

KKGSILVALRDSNGEHIPMHIREAIYKMKNNFDISSEDFIMAKAYLAEHDVAIKKANEDIIRNRRY

TEDKFFLSLSYTKNADISARTLDYINDKVEEDTQDSRMAVIVTRNLKDLTYVAWDEKNNVLEE

KSLNEIDGVNYRELLKERTKIKYTIDKTRLWQY'DVSSKGLKEAYVELAVTQISKLATKYNAVVV

VESMSSTFKDKFSFLDEQIFKAFEARLCARMSDLSFNTIKEGEAGSISNPIQVSNNNGNSYQDGVI

YFLNNAYTRTLCPDTGFVDVFDKTRLITMQSKRQFFAKMKDIRIDDGEMLFTFNLEEYPTKRLLD

RKEWTVKIAGDGSYFDKDKGEYVYVNDIVREQIIPALLEDKAVFDGNMAEKFLDKTATSGKSVE

LIYKWFANALYGIITKKDGEKIYRSPITGTEIDVSKNTTYNFGKKFMFKQEYRGDGDFLDAFLNY

MQAQDIAVX7?PT47XX>iGgriXKAXGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID

NO: 232) [001712] 5- Peregrinibacteria bacterium GW2011GWA3310 (PeCpfl) [001713] MSNFFKNFTNLYELSKTLRFELKPVGDTLTNMKDHLEYDEKLQTFLKDQNIDDAYQ

ALKPQFDE1HEEFITDSLESKKAKEIDFSEYLDLFQEKKELNDSEKKLRNKIGETFNKAGEKWKKE

KYPQYEWKKGSKIANGADILSCQDMLQFIKY'KNPEDEKIKNYIDDTLKGFFTYFGGFNQNRANY

YETKKEASTAVATRIVHENLPKFCDNVIQFKH1IKRKKDGTVEKTERKTEYLNAYQYLKNNNK1T

QIKD AETEKMIESTPIAEKIFD VYYFSSCLSQKQIEEYNRIIGHYNLLINLYNQAKRSEGKHLSANE

KKYKDLPKFKTLYKQIGCGKKKDLFYTTKCDTEEEANKSRNEGKESHSVEEITNKAQEAINKYFK

SNNDCENINTVPDFINYILTKENYEGVYWSKAAMNTISDKYFANYHDLQDRLKEAKVFQKADK

KSEDDIK1PEAIELSGLFGVLDSLADWQTTLFKSS1LSNEDKLK11TDSQTPSEALLKMIFNDIEKNM

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ESFLKETNDIITLKKYKGNKEGTEKIKQWTDYTLAINRMLKYFLVKENKIKGNSLDTNISEALKTL lYSDDAEWFKWWDALRNYLTQKPQDEAKENKLKLNFDNPSLAGGWDVNKECSNFCVILKDKN

EKKYLAIMKKGENTLFQKEWTEGRGKNLHCKSNPLFEINNCEILSKMEYDFWADVSKMIPKCST

QLKAVVNHFKQSDNEFIFP1GYKVTSGEKFREECKISKQDFELNNKVFNKNELSVTAMRYDLSST

QEKQYIKAFQKEYWELLFKQEKRDTKLTNNEIFNEWINFCNKKYSELLSWERKYKDALTNWINF

CKYFLSKYPKTTLFNYSFKESENYNSLDEFYRDVDICSYKLNINTT1NKSILDRLVEEGKLYLFEIK

NQDSNDGKSIGHKNNLHTIYWNAIFENFDNRPKLNGEAEIFYRKAISKDKLGIVKGKKTKNGTEII

KOTRFSKEKFILHVPITLNFCSNNEYXNDIVNTKFYNFSNLHFLGIDRGEKHLAYYSLVNKNGEIV

DQGTLNLPFTDKDGNQRS1KKEKYFYNKQEDKWEAKEVDCWNYNDLLDAMASNRDMARKNW

QRIGTIKEAKNGYVSLVIRKIADLAVNNERPAFIVLEDLNTGFKRSRQKIDKSVYQKFELALAKKL

NFLVDKNAKRDEIGSPTKALQLTPPVNNYGDIENKKQAGTMLYTRANYTSQTDPATGWRKTTYL

KAGPEETTYXKDGKIKNKSVKDQIiETFTDIGFDGKDYYFEYDKGEFVDEKTGEIKPKKWRLYSG

ENGKSLDRFRGEREKDKYEWKIDK1D1VKILDDLFVNFDKNISLLKQLKEGVELTRNNEHGTGES

LRFAINLIQQIRNTGNNERDNDFILSPVRDENGKHFDSREYWDKETKGEKISMPSSGDANGAFNIA

RKGIIMNAHILANSDSKDLSLFVSDEEWDLHLNNKTEWKKQLNIFSSRKAMAOAXOPrtflrKO

G2/4KKAXGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 233) [001714] 6- Parcubacteria bacterium GWC2011_GWC2_44...17 (PbCpfl) [001715] MENIFDQFIGKYSLSKTLRFELKPVGKTEDFLKINKVFEKDQTIDDSYNQAKFYFDSL

HQKFIDAALASDKTSELSFQNFADVLEKQNKIILDKKREMGALRKRDKNAVGIDRLQKEINDAE

DIIQKEKEKIYKDVRTLFDNEAESWKIYYQEREVDGKKITFSKADLKQKGADFLTAAGILKVLK

YEFPEEKEKEFQAKNQPSLFVEEKENPGQKRYIFDSFDKFAGYLTKFQQTKKNLYAADGTSTAV

ATRTADNFIIFHQNTKVFRDKYKNNHTDLGFDEENIFEIERYKNCLLQRETEHIKNENSYNKIIGRIN

KKIKEYRDQKAKDTKLTKSDFPFFKNLDKQILGEVEKEKQLIEKTREKTEEDVLIERFKEFIENNE

ERFTAAKKLMNAFCNGEFESEYEGIYLKNKAINTISRRWFVSDRDFELKLPQQKSKNKSEKNEPK

VKKFISIAEIKNAVEELDGDIFKAVFYDKKIIAQGGSKLEQFLVIWKYEFEYLFRDIERENGEKLLG

YDSCLKIAKQLGIFPQEKEAREKATAV1KNYADAGLGIFQMMKYFSLDDKDRKNTPGQLSTNFY

AEYDGYYKDFEFIKYYNEFRNFITKKPFDEDKIKLNFENGALLKGWDENKEYDFMGVILKKEGR

LYLGIMHKNHRKLFQSMGNAKGDNANRYQKMIYKQ1ADASKDVPRLLLTSKKAMEKFKPSQEI

LRIKKEKTFKRESKNFSLRDLHALIEYYRNCIPQYSNWSFYDFQFQDTGKYQNIKEFTDDVQKYG

YKTSFRDIDDEYINQALNEGKMYLFEWNKDIYNTKNGSKNLHTLYFEH1LSAENLNDPVFKLSG

MAEIFQRQPSVNEREKITTQKNQCILDKGDRAYKYRRYTEKKIMFHMSLVLNTGKGEIKQVQFN

K11NQR1SSSDNEMRVNVIGIDRGEKNLLYYSVVKQNGEIIEQASLNEINGVNYRDKL1EREKERLK

NRQSWKPVVKIKDLKKGYISHVMKICQLIEKYSArWLEDLNMRFKQIRGGIERSVYQQFEKALI

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DKLGYLVFKDNRDLRAPGGVLNGYQLSAPFVSFEKMRKQTGILFYTQAEYTSKTDPITGFRKNV

YISNSASLDKIKEAVKKFDAIGWDGKEQSYFFKYNPYNLADEKYKNSTVSKEWAIFASAPRIRRQ

KGEDGYWKYDRVKVNEEFEKLLKVWNFVNPKATDIKQEIIKKEKAGDLQGEKELDGRLKNFW

HSF1YLFNLVLELRNSFSLQIKIKAGEVIAVDEGVDF1ASPVKPFFTTPNPYIPSNLCWLAVENADA

NGAYNIARKGVMILKKIREHAKKDPEFKKLPNLFISNAEWDEAARDWGKYAGTTALNLDHOP

AArAAXG^AAAXXGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 234) [001716] 7- Smithella sp. SCK08D17 (SsCpfl) [001717] MQTLFENFINQYPVSKTLRFELTPQGKTKDFIEQKGLLKKDEDRAEKYKKVKNIIDEY

HKDFIEKSLNGLKLDGLEKYKTLYLKQEKDDKDKKAFDKEKENLRKQIANAFRNNEKFKTLFA

KELIKNDLMSFACEEDKKNVKEFEAFTIYFTGFHQNRANMYVADEKRTAIASRLIHENLPKFIDN

IKIFEKMKKEAPELLSPFNQTLKDMKDVIKGTTLEE1FSLDYFNKTLTQSGIDIYNSV1GGRTPEEG

KTKIKGLNEYINTDFNQKQTDKKKRQPKFKQLYKQILSDRQSLSFIAEAFKNDTEILEAIEKFYVN

ELLHFSNEGKSTNVLDAIKNAVSNLESFNLTKMYFRSGASLTDVSRKVFGEWSIINRALDNYYAT

TYPIKPREKSEKYEERKEKWLKQDFNVSLIQTAIDEYDNETVKGKNSGKVIADYFAKFCDDKET

DLIQKVNEGYIAVKDLLNTPCPENEKLGSNKDQVKQ1KAFMDSIMDIMHFVRPLSLKDTDKEKD

ETFYSLFTPLYDHLTQDALYNKVRNYLTQKPYSTEKIKLNFENSTLLGGWDLNKETONTAIILRK

DNLYYLGIMDKRHNRIFRNVPKADKKDFCYEKMVYKLLPGANKMLPKVFFSQSRTQEFTPSAKL

LENYANEUHKKGDNFNLNHCHKLIDFFKDSINKHEDWKNFDFRFSATSIYADLSGFYHEVEHQG

YKISFQSVADSFIDDLVNEGKLYLFQIYNKDFSPFSKGKPNLHTLYWKMLFDENNLKDWYKLN

GEAEVFYRKKSIAEKNTTIHKANESI1NKNPDNPKATSTFNYD1VKDKRYT1DKFQFHIPITMNFKA

EGIFNMNQRVNQFLKANPDIN11GIDRGERJHLLYYALINQKGK1LKQDTLNVIANEKQKVDYHNL

LDKKEGDRATARQEWGVIETIKELKEGYLSQVIHKLTDLMIENNAHVMEDLNFGFKRGRQKVE

KQVYQKFEKML1DKLNYLVDKNKKANELGGLLNAFQLANKFESFQKMGKQNGFIFYVPAWTMT

SKTDPATGFIDFLKPRYENLNQAKDFFEKFDS1RLNSKADYFEFAFDFKNFTEKADGGRTKWTVC

TTNEDRYAWNRALNNNRGSQEKYDITAELKSLFDGKVDYKSGKDLKQQIASQESADFFKALMK

NLSITLSLRHNNGEKGDNEQDYTLSPVADSKGRFFDSRKADDDMPKNADANGAYHIALKGLWT

LEQISKTDDLKKVKLAISNKEWLEFVQTLKGKR/’ATTXXXGg^XXKAGSYPYDVPDYAYPYDVP

DYAYPYDVPDYA (SEQ ID NO: 235) [001718] 8- Acidaminococcus sp. BV3L6 (AsCpfl) [001719] MTQFEGFTNLYQVSKTLRFEL1PQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYK lYADQCLQLVQLDWENLSAAIDSYRKEKTEEIRNALIEEQAIYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTIYFSGFYENRKNVFSAEDTSTAIP HRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSTEEVFSFPFYNQLLTQTQIDLY

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NQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFKSDE

EVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETTSSALCDHWDTLRNALYERRI

SELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQ

EEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNYATKKPY

SVEKFKLNFQMPTLASGWTDVNKEKNNGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGF

DKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPiLLSNNFIEPLEITKEIYDLNNPEKEPKKFQ

TAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYYAELNPLLYHI

SFQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKLNGQAE

LFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNEiRLSHDLSDEARALLPNV

ITKEVSHEHKDRRFTSDKFFFH\⁷PITLNYQAANSPSKFNQRVNAYLKEHPETP1IGIDRGERNLIYIT

VroSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQGYLSQVIEfEIVDLM

IHYQAVVVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVGGVLNPYQLT

DQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEGFDFLHYDVKTG

DFILHEKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDL

YPANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQMRNSNAATGEDYINSPVR

DLNGVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQEL

RN7i^U7K&4G(MAXXXGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 236) [001720] 9- Lachnospiraceae bacterium MA2020 (Lb2Cpfl) [001721] MYYESLTKQYPVSKTIRNELIPIGKTLDNIRQNNILESDVKRKQNYEHVKG1LDEYHK

DLLEKLPSISEDDYNALESFRNFYIYFTSYNKVRENLYSDKEKSSTVAYRLINENFPKFLDNVKSY

RFVKTAGILADGLGEEEQDSLFIVETFNKTLTQDGIDTYNSQVGKINSSINLYNQKNQKANGFRKI

PKMKMLYKQILSDREESFIDEFQSDEVLIDNVESYGSVLIESLKSSKVSAFFDALRESKGKNVYVK

NDLAKTAMSN1VFENWRTFDDLLNQEYDLANENKKKDDKYFEKRQKELKKNKSYSLEHLCNLS

EDSCNLrENYIHQISDDIENIIINNETFLRIVrNEHDRSRKLAKNRKAVKAIKDFLDSIKVLERELKLI

NSSGQELEKDLIVYSAHEELLVELKQVDSLYNMTRNYLTKKPFSTEKVKLNFNRSTLLNGWDRN

KETDNLGVLLLKDGKYYLGIMNTSANKAFVNPPVAKTEKVFKKVDYKLLPVPNQMLPKVFFAK

SNIDFYNPSSE1YSNYKKGTHKKGNMFSLEDCHNLIDFFKESISKELEDWSKFGFKFSDTASYNDIS

EFYREVEKQGYKLTYTDIDETYINDLiERNELYLFQIYNKDFSMYSKGKLNLHTLYFMMLFDQR

NIDDWYKLNGEAEVFYRPASISEDELIIHKAGEEIKNKNPNRARTKETSIFSYDIVKDKRYSKDK

FTLHIPITMNFGVDEVKRFNDAVNSAIRIDENVNVIGIDRGERNLLYWV1DSKGNILEQISLNSIIN

KEYDIETDYHALLDEREGGRDKARKDWNTVENIRDLKAGYLSQVVNVVAKLVLKYNAIICLED

LNFGFKRGRQKVEKQVYQKFEKML1DKLNYLVIDKSREQTSPKELGGALNALQLTSKFKSFKEL

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GKQSGVIYYVPAYLTSKIDPTTGFANLFYMKCENVEKSKRFFDGFDFIRFNALENVFEFGFDYRSF

TQRACGINSKW'TVCTNGERIIKYRNPDKNNMFDEKWWTDEMKNLFEQYKIPYEDGRNVKDM

IISNEEAEFYRRLYRLLQQTLQMRNSTSDGTRDYIISPVKNKREAYFNSELSDGSVPKDADANGA

YNL4RKGLWVLEQIRQKSFGEKlNLAMTNAEWLEYAQTHLLA7frM/i7AK4GCMAKXKGSYPYDV [001722] 10~ Candidates Methanoplasma termitum (CMtCpfl) [001723] MNNYDEFTKLYPIQKTIRFELKPQGRTMEHLETFNFFEEDRDRAEKYK1LKEAIDEYH

KKFIDEHLTNMSLDWNSLKQISEKYYKSREEKDKKVFLSEQKRMRQEIVSEFKKDDRFKDLFSK

KLFSELLKEEIYKKGNHQEIDALKSFDKFSGYFIGLHENRKNMYSDGDEITAISNRIVNENFPKFL

DNLQKYQEARKKYPEWIIKAESALVAHNIKMDEVFSLEYFNKVLNQEGIQRYNLALGGYVTKSG

EKMMGLNDALNLAHQSEKSSKGR1HMTPLFKQILSEKESFSY1PDVFTEDSQLLPSIGGFFAQ1EN

DKDGNIFDRALELISSYAEYDTERIYIRQADINRVSNVIFGEWGTLGGLMREYKADSINDiNLERT

CKKVDKWLDSKEFALSDVLEAIKRTGNNDAFNEYISKMRTAREKIDAARKEMKFTSEKISGDEES

IHIIKTLLDSVQQFLHFFNLFKARQDIPLDGAFYAEFDEVHSKLFAIVPLYNKVRNYLTKNNLNTK

KIKLNFKNPTLANGW'DQNKVYDYASLIFLRDGNYYLGIINPKRKKNIKFEQGSGNGPFYRKMVY

KQIPGPNKNLPRVFLTSTKGKKEYKPSKEIIEGYEADKHIRGDKFDLDFCHKLIDFFKESIEKHKD

WSKFNFYFSPTESYGDISEFYLDVEKQGYRMHFENISAETIDEYVEKGDLFLFQIYNKDFVKAAT

GKKDMHTIYWNAAFSPENLQDVVVKLNGEAELFYRDKSDIKEIVHREGEILVNRTYNGRTPVPD

I<IHKKLTDYHNGRTKDLGEAI<EYLDKVRYFKAHYDITKDRRYLNDK1YFHVPLTLNFKANGKI<

NLNKMVIEKFLSDEKAH1IGIDRGERNLLYYSIIDRSGK1IDQQSLNV1DGFDYREKLNQRE1EMKD

ARQSWNAIGKIKDLKEGYLSKAVHEITKMAIQYNAIWMEELNYGFKRGRFKVEKQIYQKFENM

LIDKMNYLVFKDAPDESPGGVLNAYQLTNPLESFAKLGKQTG1LFYVPAAYTSKIDPTTGFVNLF

NTSSKTNAQERKEFLQKFESISYSAKDGGIFAFAFDYRKFGTSKTDHKNVWTAYTNGERMRYIK

EKKRNELFDPSKE1KEALTSSG1KYDGGQNILPDILRSNNNGLIYTMYSSF1AAIQMRVYDGKEDYI

ISPIKNSKGEFFRTDPKRRELPIDADANGAYNIALRGELTMRAIAEKFDPDSEKMAKLELKHKDW

FEFMQTRGDOPA47KOGgAAXKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID [001724] 11~ Eubacterium eligens (EeCpfl) [001725] MNGNRSIVYREFVGV1PVAKTLRNELRPVGHTQEH11QNGLIQEDELRQEKSTELKN1 MDDYYREYID1<SLSGVTDLDFTLLFELMNLVQSSPSKDNKKALE1<EQS1<MREQ1CTHLQSDSNY

KNIFNAKLLKEILPDFIKNYNQYDVKDKAGKLETLALFNGFSTYFTDFFEKRKNVFTKEAVSTSIA

YRIVHENSLIFLANMTSYKKISEKALDEIEVIEKNNQDKMGDWELNQTFNPDFYNMVLIQSGTDFY

NEICGVVNAHMNLYCQQTKNNYNLFKMRKLHKQILAYTSTSFEVPKMFEDDMSVYNAVNAFID

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ETEKGNIIGKLKDIVNKYDELDEKRIYISKDFYETLSCFMSGNWNLITGCVENFYDENIHAKGKSK

EEKVKKAVKEDKYKSINDVNDLVEKYIDEKERNEFKNSNAKQYIREISNIITDTETAHLEYDDHIS

LffiSEEKADEMKKRLDMYMNMYHWAKAFIVDEVLDRDEMFYSDIDDIYNiLENIVPLYNRVRN

YVTQKPYNSKKIKLNFQSPTLANGWSQSKEFDNNAIILIRDNKYYLAIFNAKNKPDKKIIQGNSDK

KNDNDYKKMVYNLLPGANKMLPKVFLSKKGIETFKPSDYIISGYNAHKHIKTSENFDISFCRDLI

DYFKNSIEKHAEWRKYEFKFSATDSYSD1SEFYREVEMQGYRIDWIYISEADINKLDEEGKIYLFQ

IYNKDFAENSTGKENLHTMYFKNIFSEENLKDIIIKLNGQAELFYRRASVKNPVKHKKDSVLVNK lYKNQLDNGDVVRIPIPDDIYNEIYKMYNGYIKESDLSEAAKEYLDKVEVRTAQKDIVKDYRYT

VDKYF1HTPIT1NYKVTARNNVNDMVVKY1AQNDD1HV1GIDRGERNL1YISV1DSHGNIVKQKSY

NILNNYDYKKKLVEKEKTREYARKNWKSIGNIKELKEGYiSGVVHELAMLIVEYNAIiAMEDLNY

GFKRGRFKVERQVYQKFESMLINKLNYFASKEKSVDEPGGLLKGYQLTYVPDNIKNLGKQCGVI

FYVPAAFTSKIDPSTGFISAFNFKSISTNASRKGFFMQFDEIRYCAEKDMFSFGFDYNNFDIYNITM

GKTQWTVYTNGERLQSEFNNARRTGKTKSINLTET1KLLLEDNEINYADGHDIRIDMEKMDEDK

KSEFFAQLLSLYKLTVQMRNSYTEAEEQENGISYDKIISPVINDEGEFFDSDNYKESDDKECKMPK

DADANGAYCTALKGLYEVLKIKSEWIEDGFDRNCLKLPHAEWLDFIQNKRYEA7?R/MFAX4G04

AAWAGfiYPYDVPDYAYPYDVPDYAYPYDVTDYA (SEQ ID NO: 239) [001726] 12- Moraxella bovocuii 237 (MbCpfl) [001727] MLFQDFIHLYPLSKTVRFELKPIDRTLEHIHAKNFLSQDETMADMHQKVKVILDDYH

RDFIADMMGEVKLTKLAEFYDVYLKFRKNPKDDELQKQLKDLQAVLRKEIVKPIGNGGKYKAG

YDRLFGAKLFKDGKELGDLAKFVIAQEGESSPKLAHLAHFEKFSIYFTGFHDNRKNMYSDEDKH

TAIAYRLIHENLPRFIDNLQILTHKQKHSALYDQIINELTASGLDVSLASHLDGYHKLLTQEGITA

YNTLLGGISGEAGSPKIQGINELINSHHNQHCHKSERIAKLRPLHKQILSDGMSVSFLPSKFADDSE

MCQAVNEFYRHYADVFAKVQSLFDGFDDHQKDGIYVEHKNLNELSKQAFGDFALLGRVLDGY

YVDVVNPEFNERFAKAKTDNAKAKLIKEKDKFIKGVHSLASLEQAIEHYTARHDDESVQAGKL

GQYFKHGLAGVDNPIQKIHNNHSTIKGFLERERPAGERALPKIKSGKNPEMTQLRQLKELLDNAL

NVAHFAKLLTTKTTLDNQDGNFYGEFGVLYDELAKIPIUYNKVRDYLSQKPFSTEKYKLNFGNP

TLLNGWDLNKEKDNFGVILQKDGCYYLALLDKAHKKVFDNAPNTGKSIYQKMIYKYLEVRKQF

PKVFFSKEAIAINYHPSKELVEIKDKGRQRSDDERLKLYRF1LECLKIHPKYDKKFEGA1GD1QLFK

KDKKGREVPISEKDLFDKINGIFSSKPKLEMEDFFIGEFKRYNPSQDLVDQYNIYKKIDSNDNRKK

ENFYNNHPKFKKDLVRYYYESMCKHEEWEESFEFSKKLQDIGCYVDVNELFTEIETRRLNYKISF

CNINADYIDELVEQGQLYLFQIYNKDFSPKAHGKPNLHTLYFKALFSEDNLADPIYKLNGEAQIF

YRKASLDMNETTIHRAGEVLENKNPDNPKKRQFVYD1IKDKRYTQDKFMLHVPITMNFGVQGM

TIKEFNKKVNQSIQQYDEVNVIGIDRGERHLLYLTVINSKGEILEQCSLNDITTASANGTQMTTPY

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HKILDKREIERLNARVGWGEIETIKELKSGYLSHWHQISQLMLKYNAIVVLEDLNFGFKRGRFK

VEKQIYQNFENALIKKLNHLVLKDKADDEIGSYKNALQLTNNFTDLKSIGKQTGFLFYVPAWNT

SKIDPETGFVDLLKPRYENIAQSQAFFGKFDKICYNADKDYFEFFnDYAKFTDKAKNSRQIWTICS

LLKTLLALRYSNASSDEDFILSPVANDEGVFFNSALADDTQPQNADANGAYHIALKGLWLLNEL KNSDDLNKVKLAIDNQTV'LNFAQNRKRPA47XAS4G(?rtAKKKGSYPYDVPDYAYPYDVPDYAY PYDVPDYA (SEQ ID NO: 240) [001728] 13- Leptospira inadai (LiCpfl) [001729] MEDYSGFVNIYSTQKTLRFELKPVGKTLEHIEKKGFLKKDKIRAEDYKAVKKTIDKYH RAYIEEVFDSVLHQKKKKDKIRFSTQFIKEIKEFSELYYKTEKNIPDKERLEALSEKLRKMLVGAF

KGEFSEEVAEKYKNLFSKELIRNEIEKFCETDEERKQVSNFKSFTTYFTGFHSNRQNIYSDEKKST

AIGYRIIHQNLPKFLDNLKIIESIQRRFKDFPWSDLKKNLKKIDKNIKLTEYFSIDGFVNVLNQKGID

AYNTILGGKSEESGEKIQGLNEYINLYRQKNNTDRKNLPNVKILFKQ1LGDRETKSFTPEAFPDDQS

VLNSITEFAKYLKLDKKKKSIIAELKKFLSSFNRYELDGIYLANDNSLASISTFLFDDWSFIKKSVS

FKYDESVGDPKKKIKSPLKYEKEKEKWLKQKYYTISFLNDAIESYSKSQDEKRVKIRLEAYFAEF

KSKDDAKKQFDLLERIEEAYAIVEPLLGAEYPRDRNLKADKKEVGKIKDFLDSIKSLQFFLKPLLS

AEIFDEKDLGFYNQLEGYYEEIDSIGHLYNKVRNYLTGKIYSKEKFKLNFENSTLLKGWDENREV

ANLCVIFREDQKYYLGVMDKENNHLSDIPKVKPNELFYEKMVYKLIPTPHMQLPRIIFSSDNLSI

YNPSKSILKIREAKSFKEGKNFKLKDCHKFIDFYKES IS KNEDWSRFDFKFSKTS SYENISEFYREV

ERQGYNLDFKKVSKFYIDSLVEDGKLYLFQ1YNKDFSIFSKGKPNLHT1YFRSLFSKENLKDVCLK

LNGEAEMFFRKKSINYDEKKKREGHHPELFEKLKYPILKDKRYSEDKFQFHLPISLNFKSKERLNF

NLKVNEFLKRNKDINIIGIDRGERNLLYLVMINQKGEILKQTLLDSMQSGKGRPEINYKEKLQEKE

IERDKARKSWGTVENIKELKEGYLSIVIHQISKLMVENNAIWLEDLNIGFKRGRQKVERQVYQK

FEKMLIDKLNFLVFKENKPTEPGGVLKAYQLTDEFQSFEKLSKQTGFLFYVPSWNTSKIDPRTGFI

DFLHPAYENIEKAKQWrNKFDSIRFNSKMDWFEFTADTRKFSENLMLGKNRVWVICTTNVERYF

TSKTANSSIQYNSIQITEKLKELFVDIPFSNGQDLKPEILRKNDAVFFKSLLFYTKTTLSLRQNNGK

KGEEEKDFILSPVVDSKGRFFNSLEASDDEPKDADANGAYHIALKGLMNLLVLNETKEENLSRPK

WKIKNKDWLEFVWERNRKRPffi47KAL4G0AAXKKGSYPYDVPDY [001730] 14- Lachnospiraeeae bacterium ND2006 (LbCpfl) [001731 ] MSKLEKFTNCYSLSKTLRFKAIPVGKTQENIDNKRLLVEDEKRAEDYKG VKKLLDRY YLSFINDVLHSIKLKNLNNYISLFRKKTRTEKENKELENLEINLRKETAKAFKGNEGYKSLFKKDIT

ETILPEFLDDKDEIALVNSFNGFTTAFTGFFDNRENMFSEEAKSTSIAFRCINENLTRYISNMDIFEK

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VDAIFDKHEVQEIKEKILNSDYDVEDFFEGEFFNFVLTQEGIDVYNAIIGGFVTESGEKIKGLNEYI

NLYNQKTKQKLPKFKPLYKQVLSDRESLSFYGEGYTSDEEVLEVFRNTLNKNSEIFSSIKKLEKLF

KNFDEYSSAGIFVKNGPAISTISKDIFGEWNVIRDKWNAEYDDIHLKKKAWTEKYEDDRRKSFK

KIGSFSLEQLQEYADADLSVVEKLKEHIQKVDEIYKVYGSSEKLFDADFVLEKSLKKNDAVVAIM

KDLLDSVKSFENYIKAFFGEGKETNRDESFYGDFVLAYDILLKVDHIYDAIRNYVTQKPYSKDKF

KLYFQNPQFMGGWDKDKETDYRATILRYGSKYYLAIMDKKYAKCLQKIDKDDVNGNYEKINY

KLLPGPNKMLPKVFFSKKWMAYYNPSEDTQKIYKNGIEKKGDMFNLNDCHKLIDFFKDSISRYP

KWSNAYDFNFSETEKYKDLAGFYREVEEQGYKVSFESASKKEVDKLVEEGKLYMFQIYNKDFSD

KSHGTPNLHTMYFKLLFDENNHGQIRLSGGAELFMRRASLKKEELVVHPANSPIANKNPDNPKK

TTTLSYDVYKDKRFSEDQYELHIPiAiNKCPKNIFKINTEVR.VLLKHDDNPYViGIDRGERNLLYIV

WDGKGNIVEQYSLNEIINNFNGIRIKTDYHSLLDKKEKERFEARQNWTSIENTKELKAGYISQW

HKICELVEKYDAVIALEDLNSGFKNSRVKVEKQWQKFEKMLIDKLNYMVDKKSNPCATGGAL

KGYQITNKFESFKSMSTQNGFIFY1PAWLTSK1DPSTGFVNLLKTKYTS1ADSKKFISSFDRIMYVPE

EDLFEFALDYKNFSRTDADYIKKWKLYSYGNRrRiFRNPKKNNVFDWEEVCLTSAYKELFNKYG

INYQQGDIRALLCEQSDKAFYSSFMALMSLMLQMRNSITGRTDVDFLISPVKNSDGIFYDSRNYE

AQENAILPKNADANGAYNIARKVLWAIGQFKKAEDEKLDKVKIAISNKEWLEYAQTSVKHKRR4

JFXJO-lGtyXJQvXAGSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 242) [001732] 15~ Porphyromonas crevioricanis (PcCpfl) [001733] MDSLKDFTNLYPVSKTLRFELKPVGKTLENIEKAGILKEDEHRAESYRRVKKIIDTYH

KVFIDSSLENMAKMGIENE1KAMLQSFCELYKKDHRIEGEDKALDKIRAVLRGL1VGAFTGVCG

RRENTVQNEKYESFFKEKLIKEiLPDFVLSTEAESLPFSVEEATRSFKEFDSFTSYFAGFYENRKNI

YSTKPQSTAIAYRLIHENLPKFIDNILVFQKIKEPIAKELEHIRADFSAGGYIKKDERLEDIFSLNYYI

HVLSQAGIEKYNALIGKIVTEGDGEMKGLNEHINLYNQQRGREDRLPLFRPLYKQILSDREQLSY

LPESFEKDEELLRALKEFYDHIAEDILGRTQQLMTSISEYDLSR1YVRNDSQLTDISKKMLGDWNA lYMARERAYDHEQAPKRITAKYERDRJKALKGEESISLANLNSCIAFLDNVRDCRVDIYLSTLGQ

KEGPHGLSNLVENVFASYHEAEQLLSFPYPEENNLIQDKDNWLIKNLLDNISDLQRFLKPLWGM

GDEPDKDERFYGEYNYIRGALDQVIPLYNKVRNYLTRKPYSTRKVKLNFGNSQLLSGWORNKE

KDNSCVILRKGQNFYLAIMNNRHKRSFENKMLPEYKEGEPYFEKMDYKFLPDPNKMLPKVFLSK

KGIEIYKPSPKLLEQYGHGTHKKGDTFSMDDLHELIDFFKHSIEAHEDWKQFGFKFSDTAIYENV

SSFYREVEDQGYKLSFRKVSESYWSLIDQGKLYLFQIYNKDFSPCSKGITNLHTLYWRMLFDER

NLADVIYKLDGKAEIFFREKSLKNDHPTHPAGKPIKKKSRQKKGEESLFEYDLVKDRRYTMDKF

QFHVPITMNFKCSAGSKVNDMVNAH1REAKDMHV1G1DRGERNLLYICVIDSRGTILDQ1SLNT1N

DIDYHDLLESRDKDRQQEHRNWQTIEGIKELKQGYLSQAVHRIAELMVAYKAWALEDLNMGF

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KRGRQKVESSVYQQFEKQLIDKLNYLVDKKKRPEDIGGLLRAYQFTAPFKSFKEMGKQNGFLFY

IPAWNTSNIDPTTGFVNLFHVQYENVDKAKSFFQKFDSTSYNPKKDWFEFAFDYKNFTKKAEGSR

SMWILCIHGSRIKNFRNSQKNGQWDSEEFALIEAFKSLFVRYEIDYTADLKTAlVDEKQKDFFVD

LLKLFKLTVQMRNSWKEKDLDYLISPVAGADGRFFDTREGNKSLPKDADANGAYNIALKGLWA

LRQIRQTSEGGKLKLAISNKEWLQFVQERSYEKD.OPAdZXKAGgdA'A'A'AGSYPYDVPDYAYPY DVPDYAYPYDVPDYA (SEQ ID NO: 243) [001734] 16- Prevotella disiens (PdCpfl) [00173 5] MENYQEFTNLFQLNKTLRFELKPIGKTCELLEEGKIFASGSFLEKDKVRADNV

SYVKKEEDKKHKIFIEETLSSFSISNDLLKQYFDCYNELKAFKKDCKSDEEEVKKTALRN

KCTSIQRAMREAISQAFLKSPQKKLLAIKNLIENVFKADENVQHFSEFTSYFSGFETNREN

FYSDEEKSTSIAYRLVHDNLPIFIKNIYIFEKEKEQFDAKTLSEIFENYKLYVAGSSLDEVF sleyfnntltqkgidnynavigkivkedkqeiqglnehinlynqkhkdrrlpffislkkqi lsdrealswlpdm:fkndsevikalkgfyiedgf:ennvltplatllssl:dkynlngifirn nealsslsqnvyrnfsideaidanaelqtfnnyelianalrakikketkqgrksfekyee yidkkvkaidslsiqeinelytnyvsefnsnsgnmprkvedyfslmrkgdfgsndlieni k tklsaaekllgtkyqetakdifkkdensklikelldatkqfqhfikpllgtgeeadrdl vfygdflplyekfeeltllynkvrnrltqkpyskdkirlcfnkpklmtgwvdskteksd ngtqyggylfrkkneigeydyflgisskaqlfrkneavigdyerldyyqpkantiygsa yegensykedkkrlnkvhayieqikqtnikksiiesiskypnisdddkvtpssllekikkvsi dsyngilsfksfqsvnkevidnllktisplknkaefldlinkdyqiftevqavideickqkt fiyfpisnvelekemgdkdkplclfqisnkdlsfaktfsanlrkkrgaenlhtmlfkalm egnqdnldlgsgaifyraksldgnkpthpaneaikcrnvankdkvslftydiyknrry

MENKFLFHLMVQNYKAANDSAQLNSSATEYiRKADDLHIiGIDRGERNLLYYSVIDMKG

NIVEQDSLNIIRNNDLEIDYHDLLDKREKERKANRQNWEAVEGIKDLKKGYLSQAVHQI

AQLMLKYNAIIALEDLGQMFVTRGQKIEKAVYQQFEKSLTDKl.SYi A'DKKRPYXELGGi

LKAYQLASSITKNNSDKQNGFLFYVPAWNTSKIDPVTGFTDLLRPKAMTIKEAQDFFGA

FDNISYNDKGYFEFETNYDKFKIRMKSAQTRWTICTFGNRIKRKKDKNYWNYEEVELTE

EFKKLFKDSNIDYENCNLKEEIQNKDNRKFFDDLIKLLQLTLQMRNSDDKGNDYIISPVA

NAEGQFFDSRNGDKKLPLDADANGAYNIARKGLWNIRQIKQTKNDKKLNLSISSTEWL

DFVREKPVLKAZi/Mzi/XAZE/aiAXYYOSYPYDVPDYAYPYDVPDYAYPYDVPDYA (SEQ ID NO: 244)

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PCT/US2016/038181 [001736] 17- Porphyromonas macacae (PmCpfl) [001737] MKTQHFFEDFTSLYSLSKTIRFELKPIGKTLENIKKNGLIRRDEQRLDDYEKLKKVIDE

YHEDFIANILSSFSFSEEILQSYIQNLSESEARAKIEKTMRDTLAKAFSEDERYKSIFKKELVKKDIP

VWCPAYKSLCKKFDNFTTSLVPFHENRKNLYTSNEITASIPYRIVHVNLPKFIQNIEALCELQKKM

GADLYLEMMENLRNVWPSFVKTPDDLCNLKTYNHLMVQSSISEYNRFVGGYSTEDGTKHQGIN

EWIN1YRQRNKEMRLPGLVFLHKQILAKVDSSSFISDTLENDDQVFCVLRQFRKLFWNTVSSKED

DAASLKDLFCGLSGYDPEAIYVSDAHLAIISKNIFDRWNYISDAIRRKTEVLMPRKKESVERYAE

KISKQIKKRQSYSLAELDDLLAHYSEESLPAGFSLLSYFTSLGGQKYLVSDGEVILYEEGSNIWDE

VLIAFRDLQVILDKDFTEKKLGKDEEAVSVIKKALDSALRLRKFFDLLSGTGAEIRRDSSFYALYT

DRMDKLKGLLKMYDKVRNYLTKKPYSIEKFKLHFDNPSLLSGWDKNKELNNLSVIFRQNGYYY

LGIMTPKGKNLFKTLPKLGAEEMFYEKMEYKQIAEPMLMLPKVFFPKKIKPAFAPDQSWDIYN

KKTFKTGQKGFNKKDLYRL1DFYKEALTVHEWKLFNFSFSPTEQYRNIGEFFDEVREQAYKVSM

VNVPASYIDEAVENGKLYLFQIYNKDFSPYSKGIPNLHTLYWKALFSEQNQSRVYKLCGGGELF

YRKASLHMQDTTVHPKGISIHKKNLNKKGETSLFNYDLVKDKRFTEDKFFFHVPIS1NYKNKKIT

NVNQMVRDYIAQNDDLQIIGIDRGERNLLYISRIDTRGNLLEQFSLNVIESDKGDLRTDYQKILGD

REQERLRRRQEWKSIESIKDLKDGYMSQVVHKICNMVVEHKAIVVLENLNLSFMKGRKKVEKS

VYEKFERMLVDKLNYLVVDKKNLSNEPGGLYAAYQLTNPLFSFEELHRYPQSGILFFVDPWNTS

LTDPSTGFVNLLGRINYTNVGDARKFFDRFNAIRYDGKGNILFDLDLSRFDVRVETQRKLWTLTT

FGSRIAKSKKSGKWMVERIENLSLCFLELFEQFNIGYRVEKDLKKAILSQDRKEFYVRLIYLFNLM

MQIRNSDGEEDY1LSPALNEKNLQFDSRL1EAKDLPVDADANGAYNVARKGLMVVQRIKRGDHE

SIHRIGRAQWLRYVQEGrVEOPAd7XAriG0dkXXX.GSYPYDV.PDYAY.PYDVPDYAY.PYDVPD

YA (SEQ ID NO: 245)

Example 15: Computational analysis of the Cpfl structure [001738] Computational analysis of the primary structure of Cpfl nucleases reveals three distinct regions (Figure 109). First a C-terminal RuvC like domain, which is the only functional characterized domain. Second a N-terminal alpha-helical region and thirst a mixed alpha and beta region, located between the RuvC like domain and the alpha-helical region.

[001739] Several small stretches of unstructured regions are predicted within the Cpfl primary structure. Unstructured regions, which are exposed to the solvent and not conserved within different Cpfl orthologs, are preferred sides for splits and insertions of small protein sequences. In addition, these sides can be used to generate chimeric proteins between Cpfl orthologs. Example 16: Generation of Cpfl mutants with enhanced specificity

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[001741] Primary residues for mutagenesis are all positive charges residues within the RuvC domain, since this is the only known structure in the absence of a crystal and we know that specificity mutants in RuvC worked in Cas9 (see Table below: Conserved Lysine and Arginine residues within RuvC).

[001742] Without wishing to be bound by theory, positively charged residues of this region of Cpfl may act to stabilize the interaction between enzyme and DNA by interacting with the negatively-charged phosphodiester backbone of the non-target strand of DNA. By substitution of positively charged residues of Cpfl, interactions with the non-target strand may be disrupted. Sufficient disruption of this interaction can maintain appropriate activity towards target sites but reduce the activity of the enzyme towards non-target sites (which will ordinarily be expected to have weaker interactions with the guide sequence on account of one or more mismatches compared the target sequence).

[001743] Other domains display similar features. A region of interest is the RECI domain, including but not limited to mutation of one or more amino acid residues analogous to N497, R661, Q695, and Q926, of SpCas9, and including but not limited to muatations to alanine at those positions. Mutations at such residues also disrupt enzyme-DNA phosphate backbone interactions. Furthermore, combinations of mutations located in the same or different domains can be employed .

Table: Conserved Lysine and Arginine residues within RuvC.

As Cpfl	LbCpfl
R912	R833
T923	R836
R947	K847
K949	K879
R951	K881
R955	R883
K965	R887

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K968	K897
ΚΙ000	K900
R1003	K932
KI009	R935
K1017	K940
K1022	K948
K1029	K953
K1072	K960
K1086	K984
FI 103	K1003
R1226	K1017
R1252	R1033
	R1138
	R1165

Additional candidates are positive charged residues that are conserved between different orthologs are provided in the Table below.

Table: Conserved Lysine and Arginine residues

Residue	AsCpfl	FnCpfi	LbCpfl	MbCpfl
Lys	K15	K15	K15	K14
Arg	R18	R18	R18	R17
Lys/'Arg	K26	K26	K26	R25
Lys/'Arg	Q34	R34	K34	K33
Arg	R43	R43	R43	M42
Lys	K48	K48	K48	Q47
Lys	~K5l	~K5l	~K51	K50
Lys/Arg	R56	K56	R56	D55
Lys/Arg	R84	K87	K83	K85
Lys/Arg	K85	K88	K84	N8€>
Lys/Arg	K87	D90	R86	K88

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Arg	N93 K96	K92	K94
Lys/'Arg	R103	K106	R102	RI04
Lys	N104	K107	K103	K105
Lys	lllllll!	1! Κ12θ	K116	K118
Lys/Arg	KI23	QI25	K121	K123
Lys	K134	K143	-	K131
Arg	R176	R186	R158	R174
Lys	K177	K187	El 59	KI75
Ara	R192	R202	R174	R190
Lys/Arg	K200	K210	R182	R198
Lvs J	K226	K235	K206
Lvs J	K.273		K251	K267
Lvs J	K.275		K253	Q269
Lys	lllllll!	1! K314	K269	K285
Lys/Arg	R301	K320	K271	K291
Lys	K307	K326	K278	K297
Lys	K369	K397	P.342	K357
Lys	lllllll!	I! K444	K380	K403
Lys/Arg	V409	K449	R385	K409
Lys	K4I4	E454	K390	K414
Lys	K436	I A483	K415	K448
Lys	K438	I Ε49Ϊ	K421	K460
Lys	K468	K527	K457	K501
Lys	D482	K541	K471	K515
Lys	K516	1 K581	llllllllll	K55O
Arg	R518	R583	R508	R552
Lys	K524	K589	K514	K558
Lys	K530	K595	K520	K564
Lys	K532	K597	K522	K566
Lys	K548	K613	K538	K582

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Lys	K559	K624		K593
Lys	K570	K635	K560	K604
Lys/'Arg	R574	K639	K564	K608
Lys	K592	K656	K580	K623
Lys		K660	K584	K627
Lys	K603	K667	K591	K633
Lys	K607	K671	K595	K637
Lys	K613	K677	K601
Lys	C647	K719	K634	K780
Lys/Arg	R681	K725	K640	llllllllllllll
Lys/Arg	K686	K730	R645	K792
Lvs J		K763	K679	K830
Lvs J	K739	K782	K689	Q846
Lys	K748	K791	K707	K858
Lys/Arg	K757	R800		K867
Lys/Arg	T766	K809	K725	K876
Lys/Arg	K780	K823	R737	K890
Arg	R790	R833	R747	R900
Lys/Arg	p?o =	K834	R748	K901
Lys	K796	K839	K753	M906
Lys	K809	K852	K768	K921
Lys	K815	K858	K774	K927
Lys	T816	K859	K775	K928
Lys	K860	K869	K785	K937
Lys/Arg	R862	K871	K787	K939
Arg	R863	R872	R788	R940
Lys	K868	K877	Q793	K945
Lys	K897	K905	K821	Q975
Arg	R909	R918	R833	R987
Arg	R912	R921	R836	R990

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Lys	T923	K932	K847	K1001
Lys/'Arg	R947	I960	K879	R1034
Lys	K949	K962	K881	11036
Arg	R951	R964	R883	R1038
Arg	R955	R968	R887	R1042
Lys	K965	K978	K897	KJ 052
Lys	K968	K981	K900	K1055
Lys	K1000	K1013	K932	KI087
Aro-	R1003	RIO 16	R935	R1090
Lys	K1009	K1021	K940	KI095
Lvs a	K1017	K1029	K948	N1 103
Lvs a	K.1022	K1034	K953	K1108
Lvs a	K1029	K1041	K960	Kll 15
Lys		K1065	K984	KI139
Lys	K1072	K1084	K1003	KI158
Lys/Arg	K1086	K1098	K1017	R1172
Lys/Arg	FI 103	K1114	R1033	K1188
Lys	ιιβιιιιι	K1201	K1121	K1276
Arg	R1226	R1218	R1138	R1293
Arg	R1252	R1244	R1165	A 1319
Lys	K1273	K1265	K1190	K1340
Lys	K1282	K1274	K1199	K1349
Lys	K1288	K1281	K1208	K1356

[001744] The Table above provides the positions of conserved Lysine and Arginine residues in an alignment of Cpfl nuclease from Francisella novicida U112 (FnCpfl), Acidaminococcus sp. BV3L6 (AsCpfl), Lachnospiraceae bacterium ND2Q06 (LbCpfl) and Moraxella. bovoculi 237 (MbCpfl). These can be used to generate Cpfl mutants with enhanced specificity.

Example 1.7: Improving specificity of Cpfl binding [001745] With a similar strategy used to improve Cas9 specificity, specificity of Cpfl can be improved by mutating residues that stabilize the non-targeted DNA strand. This may be

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PCT/US2016/038181 accomplished without a crystal structure by using linear structure alignments to predict 1) which domain of Cpfl binds to which strand of DNA and 2) which residues within these domains contact DNA.

[001746] However, this approach may be limited due to poor conservation of Cpfl with known proteins. Thus it may be desirable to probe the function of all likely DNA interacting amino acids (lysine, histidine and arginine), [001747] Positively charged residues in the RuvC domain are more conserved throughout Cpfls than those in the Rad50 domain indicating that RuvC residues are less evolutionarily flexible. This suggests that rigid control of nucleic acid binding is needed in this domain (relative to the Rad50 domain). Therefore, it is possible this domain cuts the targeted DNA strand because of the requirement for RNA:DNA duplex stabilization (precedent in Cas9). Furthermore, more arginines are present in the RuvC domain (5% of RuvC residues 904 to 1307 vs 3.8% in the proposed Rad50 domains ) suggesting again that RuvC targets one of the DNA strands. Arginines are more involved in binding nucleic acid major and minor grooves (Rohs Nature 2009: http://rohslab.cmb.usc.edu/Papers/Rohs_etal_Nature.pdf). Maj or/minor grooves would only be present in a duplex (such as DNA:RNA targeting duplex), further suggesting that RuvC may be involved in cutting.

[001748] Figure 110, 111 and 112 and provide crystal structures of two similar domains as those found in Cpfl (RuvC holiday junction resolvase and Rad50 DNA repair protein). Based on these structures, it can be deduced what the relevant domains look like in Cpfl, and infer which regions and residues may contact DNA. In each structure residues are highlighted that contact DNA. In the alignments in Figure 113 the regions of AsCpfl that correspond to these DNA binding regions are annotated. The list of residues in Table below⁷ are those found in the two binding domains.

Table - list of probable DNA interacting residues

RuvC	domain	Rad50	domain
probable	DNA	probable	DNA
interacting residues:	interacting residues:
AsCpfl	AsCpfl

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R909	Κ324
R912	Κ335
R930	Κ337
R947	R331
K949	Κ369
R951	Κ370
R955	R386
K965	R392
K968	R393
ΚΙ 000	Κ400
ΚΙ 002	Κ404
R1003	Κ406
ΚΙ 009	Κ408
Κ1017	Κ414
ΚΙ 022	Κ429
ΚΙ 029	Κ436
ΚΙ 03 5	Κ438
ΚΙ 054	Κ459
ΚΙ 072	Κ460
ΚΙ 086	Κ464
R1094	R670
ΚΙ095	Κ675
ΚΙ 109	R681
ΚΙ 118	Κ686
ΚΙ 142	Κ689
ΚΙ 150	R699
ΚΙ 158	Κ705
ΚΙ 159	R725
R1220	Κ729
R1226	Κ739

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R1242	K748
R1252	K752
	R670

[001749] From these specific observations about AsCpfl we can identify similar residues in Cpfl from other species by sequence alignments. Example given in Figure 114 of AsCpfl and FnCpfi aligned, identifying Rad50 binding domains and the Arginines and Lysines within. Example 18: Multiplexing with Cpfl using Tandem guides [001750] It was considered whether multiplexing is possible with the Cpfl enzyme. For this purpose, guide RNAs were developed whereby different guide sequences were positioned in tandem under the same promoter, and the ability of these guides to direct genome editing to their respective targets was determined.

[001751] 150,000 HEK293T cells were plated per 24-well 24h before transfection. Cells were transfected with 400ng huAsCpfl plasmid and lOOng of tandem guide plasmid comprising one guide sequence directed to GRIN28 and one directed to EMX1 placed in tandem behind the U6 promoter (Figure 115A), using Lipofectamin2000. Cells were harvested 72h after transfection and AsCpfl activity mediated by tandem guides was assayed using the SURVEYOR nuclease assay.

[001752] The results are demonstrated in Figure 115B, which demonstrates INDEL formation in both the GRIN28 and the EMX1 gene.

[001753] It was thus determined that AsCpfl and by analogy LbCpfl can employ two guides expressed from the same U6 promoter without loss in activity. The position within the tandem has no influence on the indel formation. This demonstrated that Cpfl can be used for multiplexing using two or more guides.

[001754] The invention is further described by the following numbered paragraphs:

1. An engineered, non-naturally occurring Clustered Regularly Interspersed Short

Palindromic Repeat (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system compri sing

a) one or more Type V CRISPR-Cas polynucleotide sequences comprising a guide RNA which comprises a guide sequence linked to a direct repeat sequence, wherein the guide sequence is capable of hybridizing with a target sequence, or one or more

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PCT/US2016/038181 nucleotide sequences encoding the one or more Type V CRISPR-Cas polynucleotide sequences, and

b) a Cpfl effector protein, or one or more nucleotide sequences encoding the Cpfl effector protein;

wherein the one or more guide sequences hybridize to said target sequence, said target sequence is 3’ of a Protospacer Adjacent Motif (PAM), and said guide RNA forms a complex wdth the Cpfl effector protein.

2. An engineered, non-naturally occurring Clustered Regularly Interspersed Short Palindromic Repeat (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) vector system comprising one or more vectors comprising

c) a first regulatory element operably linked to one or more nucleotide sequences encoding one or more Type V CRISPR-Cas polynucleotide sequences comprising a guide RNA which comprises a guide sequence linked to a direct repeat sequence, wherein the guide sequence is capable of hybridizing wdth a target sequence,

d) a second regulatory' element operably linked to a nucleotide sequence encoding a Cpfl effector protein;

wherein components (a) and (b) are located on the same or different vectors of the system, wherein when transcribed, the one or more guide sequences hybridize to said target sequence, said target sequence is 3’ of a Protospacer Adjacent Motif (PAM), and said guide RNA forms a complex with the Cpfl effector protein.

3. The system of paragraph 1 or 2 wherein the target sequences is within a cell.

4. The system of paragraph 3 wherein the cell comprises a eukaryotic cell.

5. The system according to any one of paragraphs 1-4, wherein when transcribed the one or more guide sequences hybridize to the target sequence and the guide RNA forms a complex with the Cpfl effector protein which causes cleavage distally of the target sequence.

6. The system according to paragraph 5, wherein said cleavage generates a staggered double stranded break with a 4 or 5-nt 5’ overhang,

7. The system according to any one of paragraphs 1-6, wherein the PAY! comprises a 5’ Trich motif.

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8. The system according to any one of paragraphs 1-7, wherein the effector protein is a Cpfl effector protein derived from a bacterial species listed in Figure 64.

9. The system according to paragraph 8, wherein the Cpfl effector protein is derived from a bacterial species selected from the group consisting of Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 I, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011_GWA2_33_10, Parcubacteria bacterium GW2011_GWC2_44_17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens and Porphyromonas macacae,

10. The system according to paragraph 9, wherein the PAM sequence is TTN, where N is A/C/G or T and the effector protein is FnCpfl or wherein the PAM sequence is TTTV, where V is A/C or G and the effector protein is PaCpflp, LbCpfl or AsCpfl.

11. The system of any one of paragraphs 1-10, wherein the Cpfl effector protein comprises one or more nuclear localization signals.

12. The system of any one of paragraphs 1-11, wherein the nucleic acid sequences encoding the Cpfl effector protein is codon optimized for expression in a eukaryotic cell.

13. The system of any one of paragraphs 1-12 wherein components (a) and (b) or the nucleotide sequences are on one vector.

14. A method of modifying a target locus of interest comprising delivering a system of any one of paragraphs 1-13, to said locus or a cell containing the locus.

15. A method of modifying a target locus of interest, the method comprising delivering to said locus a non-naturally occurring or engineered composition comprising a Cpfl effector protein and one or more nucleic acid components, wherein the Cpfl effector protein forms a complex with the one or more nucleic acid components and upon binding of the said complex to a target locus of interest that is 3’ of a Protospacer Adjacent Motif (PAM), the effector protein induces a modification of the target locus of interest, wherein the complex comprises Mg^2r.

16. The method of paragraph 14 or 15, wherein the target locus of interest is within a cell.

17. The method of paragraph 16, wherein the cell is a eukaryotic cell.

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18. The method of paragraph 16, wherein the cell is an animal or human cell.

19. The method of paragraph 16, wherein the cell is a plant cell.

20. The method of paragraph 14 or 15, wherein the target locus of interest is comprised in a DNA molecule in vitro.

21. The method of any one of paragraphs 15-20, wherein said non-naturally occurring or engineered composition comprising a Cpfl effector protein and one or more nucleic acid components is delivered to the cell as one or more polynucleotide molecules.

22. The method of any one of paragraphs 14-21, wherein the target locus of interest comprises DNA.

23. The method of paragraph 22, wherein the DNA is relaxed or supercoiled.

24. The method of any one of paragraphs 14-23, wherein the composition comprises a single nucleic acid component.

25. The method of paragraph 24, wherein the single nucleic acid component comprises a guide sequence linked to a direct repeat sequence.

26. The method of any one of paragraphs 14-25 wherein the modification of the target locus of interest is a strand break.

27. The method of paragraph 26, wherein the strand break comprises a staggered DNA double stranded break with a 4 or 5-nt 5’ overhang.

28. The method of paragraph 26 or 27, wherein the target locus of interest is modified by the integration of a DNA insert into the staggered DNA double stranded break.

29. The method of any one of paragraphs 14-28, wherein the Cpfl effector protein comprises one or more nuclear localization signal(s) (NLS(s)).

30. The method of any one of paragraphs 21-29, wherein the one or more polynucleotide molecules are comprised within one or more vectors.

31. The method of any one of paragraphs 21-30, wherein the one or more polynucleotide molecules comprise one or more regulatory elements operably configured to express the Cpfl effector protein and/or the nucleic acid component(s), optionally wherein the one or more regulatory elements comprise inducible promoters.

32. The method of any one of paragraphs 21 to 31 wherein the one or more polynucleotide molecules or the one or more vectors are comprised in a delivery' system.

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33. The method of any one of paragraphs 14-30, wherein system or the one or more polynucleotide molecules are delivered via particles, vesicles, or one or more viral vectors.

34. The method of paragraph 33 wherein the particles comprise a lipid, a sugar, a metal or a protein.

35. The method of paragraph 33 wherein the vesicles comprise exosomes or liposomes.

36. The method of paragraph 33 wherein the one or more viral vectors comprise one or more of adenovirus, one or more lentivirus or one or more adeno-associated viius.

37. The method of any one of paragraphs 14-36, which is a method of modifying a cell, a cell line or an organism by manipulation of one or more target sequences at genomic loci of interest.

38. A cell from the method of paragraph 37, or progeny thereof, wherein the cell comprises a modification not present in a cell not subjected to the method.

39. The cell of paragraph 38, of progeny thereof, wherein the cell not subjected to the method comprises an abnormality and the cell from the method has the abnormality addressed or corrected.

40. A cell product from the cell or progeny thereof of paragraph 38, wherein the product is modified in nature or quantity with respect to a cell product from a cell not subjected to the method .

41. The cell product of paragraph 40, wherein the cell not subjected to the method comprises an abnormality and the cell product reflects the abnormality having been addressed or corrected by the method,

42. An in vitro, ex vivo or in vivo host cell or cell line or progeny thereof comprising a system of any one of paragraphs 1-13.

43. The host cell or cell line or progeny thereof according to paragraph 42, wherein the cell is a eukaryotic cell.

44. The host cell or cell line or progeny thereof according to paragraph 43, wherein the cell is an animal cell.

45. The host cell or cell line or progeny thereof of paragraph 33, wherein the cell is a human cell.

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46. The host cell, cell line or progeny thereof according to paragraph 31 comprising a stem cell or stem cell line.

47. The host cell or cell line or progeny thereof according to paragraph 30, wherein the cell is a plant cell,

48. A method of producing a plant, having a modified trait of interest encoded by a gene of interest, said method comprising contacting a plant cell with a system according to any one of paragraphs 1-13 or subjecting the plant cell to a method according to paragraph 14-17 or 19 to 37, thereby either modifying or introducing said gene of interest, and regenerating a plant from said plant cell.

49. A method of identifying a trait of interest in a plant, said trait of interest encoded by a gene of interest, said method comprising contacting a plant cell with a system according to any one of paragraphs 1-13 or subjecting the plant cell to a method according to paragraph 14-17 or 19 to 37, thereby identifying said gene of interest.

50. The method of paragraphs 49, further comprising introducing the identified gene of interest into a plant cell or plant cell line or plant germplasm and generating a plant therefrom, whereby the plant contains the gene of interest.

51. The method of paragraph 50 wherein the plant exhibits the trait of interest.

52. A particle comprising a system according to any one of paragraphs 1-13.

53. The particle of paragraph 52, wherein the particle contains the Cpfl effector protein complexed with the guide RNA.

54. The system or method of any preceding paragraph, wherein the complex, guide RNA or protein is conjugated to at least one sugar moiety, optionally N-acetyl galactosamine (GalNAc), in particular triantennary GalNAc.

55. The system or method of any preceding paragraph, wherein the concentration of Mg²⁺ is about ImM to about 15 mM.

56. An isolated protein having at least 60% sequence identity with AsCpfl or LbCpfl, and capable of binding a target DNA through a complex with a guide RNA comprising a direct repeat sequence and a guide sequence, without requiring the presence of a tracrRNA.

57. An isolated nucleic acid encoding a protein according to paragraph 56.

58. The method of paragraph 17, which is a method of treatment of a disease caused by a genetic defect in said cell.

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59. The method of paragraph 58, wherein said method is earned out on a cell in vivo or ex vivo.

60. A non-naturally occurring or engineered composition comprising a Cpfl effector protein and one or more guide RNA comprising a direct repeat sequence and a guide sequence capable of hybridizing to a target DNA at a locus of interest, wherein the Cpfl effector protein forms a complex with the one or more guide RNAs and upon binding of the said complex to a target locus of interest that is 3’ of a Protospacer Adjacent Motif (PAM), the effector protein induces a modification of the target locus of interest.

61. A non-naturally occurring or engineered composition comprising a polynucleotide sequence encoding a Cpfl effector protein and one or more guide RNA comprising a direct repeat sequence and a guide sequence capable of hybridizing to a target DNA at a locus of interest, wherein the Cpfl effector protein, when expressed, forms a complex with the one or more guide RNAs and upon binding of the said complex to a target locus of interest that is 3’ of a Protospacer Adjacent Motif (PAM), the effector protein induces a modification of the target locus of interest.

62. The composition according to paragraph 60 or 61 which is a pharmaceutical composition.

63. The composition according to paragraph 60 or 61, for use as a medicament.

64. The composition according to paragraph 60 or 61 for use in the treatment of a disease or disorder caused by a genetic defect at the target locus of interest.

65. The method according to paragraph 58, or the composition for use according to statement 64, wherein the cell is a HSC cell.

66. The method according to paragraph 58, or the composition for use according to statement 64, wherein the disease or disorder is a blood cell disorder.

Ϊ5< -F # [001755] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skil led in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

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Claims (56)

1. WHAT IS CLAIMED:

   1. An engineered, non-naturally occurring Clustered Regularly Interspersed Short

   Palindromic Repeat (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising

   a) one or more Type V CRISPR-Cas polynucleotide sequences comprising a guide RNA which comprises a guide sequence linked to a direct repeat sequence, wherein the guide sequence is capable of hybridizing with a target sequence, or one or more nucleotide sequences encoding the one or more Type V CRISPR-Cas polynucleotide sequences, and

   b) a Cpfl effector protein, or one or more nucleotide sequences encoding the Cpfl effector protein;

   wherein the one or more guide sequences hybridize to said target sequence, said target sequence is 3’ of a Protospacer Adjacent Motif (PAM), and said guide RNA forms a complex with the Cpfl effector protein,
2. 2. An engineered, non-naturally occurring Clustered Regularly Interspersed Short Palindromic Repeat (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) vector system comprising one or more vectors comprising

   a) a first regulatory element operably linked to one or more nucleotide sequences encoding one or more Type V CRISPR-Cas polynucleotide sequences comprising a guide RNA. which comprises a guide sequence linked to a direct repeat sequence, wherein the guide sequence is capable of hybridizing with a target sequence,

   b) a second regulatory element operably linked to a nucleotide sequence encoding a Cpfl effector protein;

   wherein components (a) and (b) are located on the same or different vectors of the system, wherein when transcribed, the one or more guide sequences hybridize to said target sequence, said target sequence is 3’ of a Protospacer Adjacent Motif (PAM), and said guide RNA forms a complex with the Cpfl effector protein.
3. 3. The system of claim 1 or 2 wherein the target sequences is within a cell.

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4. 4. The system of claim 3 wherein the ceil comprises a eukaryotic cell.
5. 5. The system according to claim 1 or 2, wherein when transcribed the one or more guide sequences hybridize to the target sequence and the guide RNA forms a complex with the Cpf l effector protein which causes cl eavage distally of the target sequence.
6. 6. The system according to claim 5, wherein said cleavage generates a staggered double stranded break with a 4 or 5-nt 5’ overhang.
7. 7. The system according to claim I or 2, wherein the PAM comprises a 5’ T-rich motif,
8. 8. The system according to claim 1 or 2, wherein the effector protein is a Cpfl effector protein derived from a bacterial species listed in Figure 64.
9. 9. The system according to claim 8, wherein the Cpfl effector protein is derived from a bacterial species selected from the group consisting of Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW201 l_GWA2_33_10, Parcubacteria bacterium GW201 β GWC2 44 17, Smithella sp. SCADC, Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium MA2020, Candidatus Methanoplasma termitum, Eubacterium eligens, Moraxella bovoculi 237, Leptospira inadai, Lachnospiraceae bacterium ND2006, Porphyromonas crevioricanis 3, Prevotella disiens and Porphyromonas macacae.
10. 10. The system according to claim 9, wherein the PAM sequence is TTN, where N is A/C/G or T and the effector protein is FnCpfl or wherein the PAM sequence is TTTV, where V is A/C or G and the effector protein is PaCpflp, LbCpfl or AsCpfl.
11. 11. The system according to claim 1 or 2, wherein the Cpfl effector protein comprises one or more nuclear localization signals.
12. 12. The system according to claim 1 or 2, wherein the nucleic acid sequences encoding the Cpfl effector protein is codon optimized for expression in a eukaryotic cell.
13. 13. The system according to claim 1 or 2 wherein components (a) and (b) or the nucleotide sequences are on one vector.

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14. 14. A method of modifying a target locus of interest comprising delivering a system according to claim 1 or 2, to said locus or a cell containing the locus.
15. 15. A method of modifying a target locus of interest, the method comprising delivering to said locus a non-naturally occurring or engineered composition comprising a Cpfl effector protein and one or more nucleic acid components, wherein the Cpfl effector protein forms a complex with the one or more nucleic acid components and upon binding of the said complex to a target locus of interest that is 3’ of a Protospacer Adjacent Motif (PAM), the effector protein induces a modification of the target locus of interest.
16. 16. The method of claim 15, wherein the target locus of interest is within a cell.
17. 17. The method of claim 16, wherein the cell is a eukaryotic cell,
18. 18. The method of claim 16, wherein the cell is an animal or human cell.
19. 19. The method of claim 16, wherein the cell is a plant cell.
20. 20. The method of claim 15, wherein the target locus of interest is comprised in a DNA molecule in vitro.
21. 21. The method of claim 15, wherein said non-naturally occurring or engineered composition comprising a Cpfl effector protein and one or more nucleic acid components is delivered to the cell as one or more polynucleotide molecules.
22. 22. The method of claim 15, wherein the target locus of interest comprises DNA.
23. 23. The method of claim 22, wherein the DNA is relaxed or supercoiled.
24. 24. The method of claim 15, wherein the composition comprises a single nucleic acid component.
25. 25. The method of claim 24, wherein the single nucleic acid component comprises a guide sequence linked to a direct repeat sequence.
26. 26. The method of claim 15 wherein the modification of the target locus of interest is a strand break.
27. 27. The method of claim 26, wherein the strand break comprises a staggered DNA double stranded break with a 4 or 5-nt 5’ overhang.

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28. 28. The method of claim 26, wherein the target locus of interest is modified by the integration of a DNA insert into the staggered DNA double stranded break.
29. 29. The method of claim 15, wherein the Cpfl effector protein comprises one or more nuclear localization signal(s) (NLS(s)),
30. 30. The method of claim 21, wherein the one or more polynucleotide molecules are comprised within one or more vectors.
31. 31. The method of claim 21, wherein the one or more polynucleotide molecules comprise one or more regulatory elements operably configured to express the Cpfl effector protein and/or the nucleic acid component(s), optionally wherein the one or more regulatory elements comprise inducible promoters.
32. 32. The method of claim 21 wherein the one or more polynucleotide molecules or the one or more vectors are comprised in a delivery system.
33. 33. The method of claim 21, wherein system or the one or more polynucleotide molecules are delivered via particles, vesicles, or one or more viral vectors.
34. 34. The method of claim 33 wherein the particles comprise a lipid, a sugar, a metal or a protein.
35. 35. The method of claim 33 wherein the vesicles comprise exosomes or liposomes,
36. 36. The method of claim 33 wherein the one or more viral vectors comprise one or more of adenovirus, one or more lentivirus or one or more adeno-associated virus.
37. 37. The method of claim 15, which is a method of modifying a cell, a cell line or an organism by manipulation of one or more target sequences at genomic loci of interest.
38. 38. A cell from the method of claim 37, or progeny thereof, wherein the cell comprises a modification not present in a cell not subjected to the method.
39. 39. The cell of claim 38, of progeny thereof, wherein the cell not subjected to the method comprises an abnormality and the cell from the method has the abnormality addressed or corrected.

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40. 40. A cell product from the cell or progeny thereof of claim 38, wherein the product is modified in nature or quantity with respect to a cell product from a cell not subjected to the method.
41. 41. The cell product of claim 40, wherein the cell not subjected to the method comprises an abnormality and the cell product reflects the abnormality having been addressed or corrected by the method.
42. 42. An in vitro, ex vivo or in vivo host cell or cell line or progeny thereof comprising a system of claim 1 or 2.
43. 43. The host cell or cell line or progeny thereof according to claim 42, wherein the cell is a eukaryotic cell.
44. 44. The host cell or cell line or progeny thereof according to claim 43, wherein the cell is an animal cell.
45. 45. The host cell or cell line or progeny thereof of claim 33, wherein the cell is a human cell.
46. 46. The host cell, cell line or progeny thereof according to claim 31 comprising a stem cell or stem cell line.
47. 47. The host cell or cell line or progeny thereof according to claim 30, wherein the cell is a plant cell.
48. 48. A method of producing a plant, having a modified trait of interest encoded by a gene of interest, said method comprising contacting a plant cell with a system according to claim I or 2 or subjecting the plant cell to a method according to claim 15, thereby either modifying or introducing said gene of interest, and regenerating a plant from said plant ceil.
49. 49. A method of Identifying a trait of interest in a plant, said trait of interest encoded by a gene of interest, said method comprising contacting a plant cell with a system according to claim I or 2 or subjecting the plant cell to a method according to claim 15, thereby identifying said gene of interest.

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50. 50. The method of claim 49, further comprising introducing the identified gene of interest into a plant cell or plant cell line or plant germplasm and generating a plant therefrom, whereby the plant contains the gene of interest.
51. 51. The method of claim 50 wherein the plant exhibits the trait of interest.
52. 52. A particle comprising a system according to claim 1 or 2.
53. 53. The particle of claim 52, wherein the particle contains the Cpfl effector protein complexed with the guide RNA.
54. 54. The system or method of claim 1, 2 or 15, wherein the complex, guide RNA or protein is conjugated to at least one sugar moiety, optionally N-acetyl galactosamine (GalNAc), in particular triantennary GalN Ac.
55. 55. The system or method of claim 1, 2 or 15, wherein the concentration of Mg²’ is about ImM to about 15 mM.

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    FnCpH + -:- + -:κιχ· x|-:· >'

    6 7 8 9 10 11 12 T3 none

    9'.'.. S X U· S US s 'sfo'ss-Us ill .-1.::: .- :.8-: i . ii .:,1 .’ '5:8 :,8 . ii ii -.> .8 7 ..iii 99:;-8i:^:i5?55 ^;:5 , :1 8 1--:-8 , -„,8 - ... . ..................., . .......A........................V............... ..................................... '7w'·>A·$-2*4·' w'-^:-y>2^:·. 4 .·. -.-. .'.I-.i -,:.1. .-.:59,11 . . . ... . . .. . . ... .. . ---....................... . ... ...................................................j,. . ......... . . . . ............. . . . .................. X V - X XV $<- i>- iSS/SS+BiWiiWiiliXiilZ:®.®®:®,,,,,,,. . ' ---.,. _______________________________ SSSiSS-SdsilVViiMVSiiiSS: iSS+s5-i5ii:55i:i.^:i-i5,, 418:58545:277135:14:15 4 ...SSs^SSiifrtrtVisiisiai. ^<SS4^S4iSK4Sag«_ 4. ________ . ........ ..+5S58 4555+:99:+...................................................... ·$ 'YV ·. ' ' x- Υ'χΥ v . xY \ YN $< ,®.:®'.illllX5.1::18199:8:: 8;;:59:.1:1.:5::........ ..............................i.li.iililliil.ii.;:4.5llll.li3il.i,,. ..1......il.5...i..:..l...i.:.5..... ::5 3955818898151:388888451431455 518588831844885884518818 5ΪΥ;·>?ν:Λ·Α<<·;ΐΛ:.χ7Υΐ:χ·;·:·Λ:·Α:ϊ:χ% ii ...iVViidflsiiiVitiXVViiViiVVVVi....... ........................................ --58..3--= 4. . -.·,. - 1 -X :i:J I..:..:.-.:;:.::..-:.,:- Ill ...,: : 8:: -- :*11 --:, 8-85::585-1 XsYYYNi YSYYiY-YxA'iYsYxiYYxYxYi-xt. i® χ-ΥΥΥΥιΥχΑ.ΥΥχΥχχΥχιΥιχ.Υ-'χΥΥ'ιΥΥΥΥ-Υχ YYYi ............................................................. ΥνΥ<:Υ\Υ?:.?>.χΥΥ':Υχί:χΥ^:.χ5ί<.Υ;Υ<

    FIG. 59

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    Fulllocus

    A Cas ore re ..re re χ χΐ ίχθ

    - Apis tressOA

    OR tisreres

    OresreOOi'iKSi

    A Cas A tracer

    FIG, 60

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    CyJA. Ufa %&&&

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    CM to a

    as ss sss

    SM

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    Fi.Vij CjiU

    3 SiViirtii 0j5U d

    u.

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    &

    »»

    9s 4 9 9 rt, : ^!

    1 ' s WW * W® ' 5 tort, 7 to 7W ++ to s Wto ,i

    Λ<· -xx w·w xx· 0^ «$? wSSx· >xx xx· w «& :^{w Nxi xx· $χ· ·χχ :Nx· xx&xxx«sv oN x$- '•x· ·χχ· xxSSsx x? 'W'vN xx- §N+ -:N§S\x 5+ ·χχ xx· w $Xx ϊ ··· :&5: ' > ^s$$ ' &' W> ··$&. \* Μ Ni ij: φ >· -5 N ·%: >

    3V '>7 •itvN· .·$· \<x aW

    Χ'ΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧΧ to sssXssswXswwwwsssXssXsXwwwwwwssXssXssX'.....

    XS45

    Bto1to91ve Fotoi titon toto-to sskW+sX+N

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    153/338 estrlction Enzymes ' ' , ^x χ

    TxO, I Έ

    -' Al atgcr gg'VL·' \ v 1 € o t'VJ τa V _s v A χ?. ' x?x Y Ίΰ'Ζ Λχ.,, χ,S ⁷ TfogARTTAfo \€? 'Jx\7x''2'

    X ,,! 'X ' 'X ' ,χ 'X '

    X , X 'x 'xt'F TO χχ / χ' ϊ Af χΐ g <^;, , χ €v,',0^:' . ⁵ -xx,' y cas, 10 ' T’?

    \ , ',4 ,? S TC

    ARE

    CIS-Acting Elements Sr re ,0 ^x ' Splee(GG'TGAT)

    Poi yAs AATAAAI PoiyAiATTAAAl OestaP Rzmqs AJTT Al PoiyTtTTrrrrj PoiyAcAAAAAAA;

    Antiviral Motifs tt ^! s S':''': '

    6jt| w

    After Optimization

    Max Direct Repeat: SizertS Dfetaeca :.2686 Frequency:^

    Max Inverted Repeat Nona

    Max Dyad Repeat: Sac 13 Trn: 46,8 Start Poattbnc 066₁1908

    FIG. 65E

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    V, ,,,,,, ,, ,, ,

    A AAA A

    A ->A

    77 +,' 'y'7++,7St 77'7'-A''-.7 77',-777-++ '-7-+67-'7A77'-',''- '-7' \\ \ A A'- ''α'''α'α'Γ aa'a'-a^'A^-' ' \ A \\ A \'a , \' '' A ' A \ \ \ ' ' 'Cx'T'T'α^χΤΤΤΛΑ , 'χ··''· Γ'a' Txx'bT aWAa'a'A 7'\'' \a'a'C,'x' j''t+AaB?·'·-'Va'2\'ax'xΑ'ίχ,χ'Α'ΐΆίχ'·,' ^X Afc\ A X ' ' ' A Xi' i A A ' A ' A · ' \ „A A A ' x

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    As , , A\ A AAA.A , 7 S' A ' A , A ' '7 Are . , · A ' A A ΆΆ ' A ' - Ά 7 ,A\As'A,AA ,, .. ,ΑΑ' , As' AA--,= ---. 7=,, A, ,,'7 - A =,. ,-.- , α,'Μ ' -,,,'-',=,, <A.7AAAA'A37s'AAeAAxsAs-xre-77AxAxA.Asx.A77AAAAA7777'==-xA‘x7AA-s:xA7Ai7AAA7.AAA=^:JAsArexA77AA77/7sA,.sAs=7Jx.A — A - ' - A - -χ A? ‘ ' 'V ' - χχ . ί',,,.Α. ..Αχ.' ,ΑΑ . χ χ'.7'. >. =,Α .,', '.χ 7 j-Χ. Ά. ,χ-χΑ ,-..re ,'re... A'.,. A.'. . ..χ' AAAsA ΑΑ . \ Α ,: = .' ', ' ' a ; 7=- = -r - ' 77 : : ,Α r A', ,=.= a'7==A-;.a= ' a-;-,: a ' = == = a. 7' A Ά\ x χ xx χ χ χ -xx χ χ, χ χχ χΧ'ΧΧ,ΧΧΧ'χΧ xxxx χ X. X XX x \ X xx . ' X X \ X- \ ' X X XX x xx X X xxx χ XX X _s XX V X X xx χ X, X XX XX χ XXX X \x X, X X xA \ AXxA X'i\ x x= 'x X ' ' XX X X · X XX X V\ x' X X χΧχΆΧ x ' χ χ χ x x‘t x Xxx '•x'x'xxxxxxi X '

    A ,AA\ A' A' 'A' , AA, AA A AA',' AAA x A A -., A,',- A= ' ,= AA' A A' χ^Χ χ X 'x ' ?k\ X W x ' 'xx T<\ χ’ χ' \Λ χ χ^Χ ' χ \\ ΊΆ χ χ Λ \\* Χχ\ χ χ A ' ? ' V\ χ X χΆχ'-'·'· > < χ'\\ \ ΑΑ A i Χχ \\

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    EXMXALCPFPTFYDPFCLSNAXSPPDSKMXFKPTFFYP.FPLA.EYLTFPLPDQLPFYPDX ΕΑΑΑΡΙΟΟΧΑΧΑΡΥαΟΟΑΡΕΕΥΡΥΟΡΑΕΥΕΧΥΧίΕΥΕΡΑΧΧΕΧΧΑΡΤΥΡΑΡΡΕΥΡΡΕΡΝΧΡ IPNASJAT X LLPS PLFFFXEFFLXXfoFYYAXfoEFY AL-FLYYKPIiX XELII 2YLYAPLFY E?XPXlF 12 ΧΥΚΥΥΥΕνΎΡΡΥXFL s'FLF.^EFQXLEFL RFAFf YFY..AEX?XX*AFL XLL* XLFFTSELSFF; lg^HFAF'AsFPTA'ⁱYX?F^KE«'?H'T ARFFAELXpI T FFFRXFS : FFL MFTLP FFSR FRREFPLR YLRRE XR K Y TYTSDRLFR YR SEFYFAAY I YAYSSF 2 Y·S1 MR ES

    KPLR7LLY Y.RPYFJ P LPTRHP'TLX YFLXYFFRPTYSEFLXR XLRR EFSXSXPRPFYFYLRDF v;\ ' ?fyf'f ;; ay rr;fy; ' x ^v; vmy *v ?' mffffp’' ^sR'f;yf'ry ' yr'

    D XF.LY YF ILF FYAFPVFLELEEYDL XFLvMEKI FEET I FLPELVFKLPFARFFX EPPAER 77L σ X xEFY XFEX ϊ EP, F , 2,L, XR *_’Z LY X LE'A SEE , LY PLL_V YFT ~ , EE-LEASE X YAP L.NFLFFLLPPYXLPS SET X EFVLTHKTFECFLFYFF S FLEDLYES LP YLLFEXPLEE LXYYXYYPYGPXXI'LYLpsLYPYXVIAYXXXX/DXXXYLYYSEPIXXLPSPFELV'YPPKYXSXiEFEYYPXXXFX

    FΥΥΓ'Ρ FFFF FEY T RPPLFPFX .YRFFPLF L T ERF? YXSFFR F T 3.REF FYFYFYI .EP FRYEAR FRY EFLFAYTFP V FFYAEFLLT T FX' LR A Y LMR< Y F BP R FLX L X FF'XX'D X LY Y LY LLRXXRF V LFL R P Χ..Έ1X PFPAFFVEPFR FRFLYTFFRMRAYR FFFY P F'XP MFLY FYY LFY ALPS TAB

    AYLFYEF I LX X FFLFEAFFEFY X FL EEYT?FPPFTFXL,.APLPELSPFLX FELFFFXFXLX⁵ ,QW>\'PF\V ifi? Π χΜ'.^ LPLLR«LEL» 22 .iPERKFtL ΕΡΕ<1 V

    YSSSOYLXREXSaDSLPTEOPEPWECCCEHFIXWPPFXEEXmRXBBFYFlLEPYLPl

    NSXETPTELXXFLNEPEXXYEYFLL'FA X YPLYLNYLR LTYPLYXRGFPAVYYF EYE YEEYL1 A

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    WHI xx S

    NxxxxxxxxxxxxxxxxxxxNxxxxxxxxxxxxxxxxxxxxXxx· -%>

    .w'Xwxx'Xx'Xxxxxxx'Xxw'XXxxxXxxXwxxxXxww'X

    IX Art

    ΟχΟ

    SM tad, I uo FfNtioa «I cutf&Ri χχχΧχχχχχΧχχχχχχχχχχΧχχχχχχχχχχχχχχχχχχχΧ.'ΧχχχχχχχχχχχχΧχχχχΧχ'ΧχχχχχχχχΧχχχχχχχχΧ.χΧΧ’ a pa ·χ·όρ a to paw

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    Restriction Enzymes Optimized BarnHAGGATGC} A0TT8] :E co S b G A. AT T C). A :1Gb G 1A o a 1111 a AG01 t $ S SereBlAGGTCTCi a AeaeGG t G : G) G RtoTGAAGAC- A Ape: (ACC GOT) 0 XhobCTCGAGi G Gd e 1( CAT ATG) a; 1GAT HadtGCGGGCGC 1 0 KpedGGTACC) AA1A SS χ X G SpexACTAGT) G XAG (TTT AG A) 0 GheAGCTAGCA G ARE 0 CIS-Actmg Elements Optimised S pi! ce; G GI eA.G) 0 SphcepGGTGAT i 0 FoiyA(AATAA,Ai 0 F’olyAc ATT AAA ? 0; DeetaPAGngi AlTTA s a GG> Is Η Π Π * 0 RGyAi AAAAAAA; 0

    Antiviral Motifs Optimized o

    After O ptlm ization

    Max Direct Repeat Size: 12 Distw®e:3285 frequency:2

    Max Inverted Repeat Size: 12 Tm: 43.5 Start Poeihne: 1631,1547

    Max Dyad Repeat: Hone

    FIG. 66E

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    Α Λ Xxyk.Yx x©'v .'^^Γ<χ-ίχίχ<Χ<χ<·^:

    XX X \\ χ X χχ χχ;χχ·χ·

    XX XX

    Χ^ΧΧ\ Α

    X XXX X

    X Χχ χ

    X χ χ χχΧχχχχ X

    Vx

    XX X

    XX X αΧΧΧΧΧΧ χ χ

    XXX

    XXX xxXSx.’.χK..x.'XX$x^::.x>x'Xxxx>?^:b>;bx.^:?^;iK.xxN.xxX v.xWSb-i?v>x.· :-.:·;·:χ. ΧνΧχχχχχ^ϊχχχ-χΝχ>χΛχ:^;χ.^::ν.χχΧ χχί-χΐ xvx.'Avb χϊχχ.χχ^:.ΧχΧχ>·χ?Χ·ίχχχ.χ. i Χ-.Χ.Χ. X

    X. X>XbiXZy ,'^,XxX ,x '-,S<X<..X.. x..?>X:. bxrx-XX^w<iX> Xs.?X.i:'- .x>XX>X. i*< X· ·χ··χ· ΧχΧχΧ χ ΧΧχΧχ. χ. X. X Χ>ΧΛΧχΧχΧΧΧ χ Χ Χ. Χ. ΛίΧΧ.νχ'νΝ-χΧί'ΧχΧχ.χΧΐ.χ.χ^ Χ· Χ· X- χ-·χ·ΧΧ χ χ?χ.χ>Χχ·

    XX X XXX ΧΧΧΧ X XS X XXX χχχχχχ χΝΧ Χ·χ·Χ·χ:χΧχίΧ\χίχϊΧ' Χ«ΝΧ Χ· X ΧΎχχΧνΧΧχΚΝ. lxi<N<NX?iNi\-x-XXiX:L ά kXXxiiXX.x'XX Χ-ΧΧχίΝ· χ x^kxii'YXi'xiS'xX X Χχ<·ΧΧ λ X^S-X χ. χ?Χ?Χ Χ-.ίΧίΧΐ.ίΛ.ίχΟν.· £ SX ;ά<

    ΚΚΧ ΓΓΛ ,'Λ Κ''Χ.\ ν \ 5' ', · \ 7X? κ; , ΜΛΛΚΧ χΛ Αχ- ' ' χ χΑ s'X - s χ * s' χ 'χ l· xsx'- ' 'χ'’^-’ ίΑΐχ'· .< ,·»<χ· ,. j ϊ ;χ'. W ί WxA. χ.Χ; ;

    ί-Χ,ΐΧ·ΧνχΑ·Χ·Χ·>^Χ·>Α.Αχ·ίΑΑχ'ΑΑ·ΧΧ·!>.’,ΧΧΧ,sX-X^AAtA-xAx->^>AkX>>SS-X^X-.\.s'i.ΆτχΑϊΑ·Χ·ϊ·ΧΧ·>ί» X Xv

    ΛΑχ.χχ^Α'χκ’-Λ ' ΑΑ ΑΆη-Α Υ ΑΑ > ' γ A ' ' V ,Υ^χχ γ\>\ Ύλχχ,> \ A- Α

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    161/338 ' ' ' κκ'κ ' Ϊ + < ' ¥ ¥ ¥G'G/A/GS'XGiAiAirA¥7\X¥'GG:AAGGA/vEAsX'FiAG<AGXGAXrXA«i7'iAK&^ i-v<v:7:7';A7REwX;?C<:GA{7<'?G?C'rTriAAl?+7AA'ri:._;/Ai7;7AG<EfoS7A::;:7<:+XX7-7^:7'¥¥CA7\:T-'77'Art:7-7:;.'<77R'<;cA;/ GWW/GAAXXAATAACGGiXAAin'eTXiATriAiAXAiWNGTGAX’GTAXGXTGGXAXAATAAGGGeAAAfoGGXXAGAGGCW ?GCi7GTGATA'7CGG3GTTTGT^;.7G.ACGT3G7TCG.A?AA¥GAC¥7GGGCT'GATGACAATGCAGTGTAAGArtAGAGTT^!GTn· κ>. , AAgGGAGG/Gv. ΑΪΧΑΑΑΑ 1® 7AG+ AXM J .-XAgAGV' 7?? v A. GXTFAAvxX\>G+vaXAgTAG-X . TAGAAAG AGGCTGXXT i^xRC<rtxⁱ7^AG'k^.RGTG(MACi7GTGAArt4TCG.CC&»^!.7GATSGi?T'^!G^!'..’’r‘ATT^:TC'ixACAAf»C>ATA?iGGS^!GGArt 'r.3XX¥X5X\X?5'X'A?X>'?XA!X5Ai?Gi,A¥XA'X'Xi\XrG;iVAⁱX¥XA,i.i¥XA¥-?fXX'r¥?A'./'.GXiXAGG¥?GXi '.A?'i\«i.)A¥AsAX.'X\A5'.i\A?¥?iX'r\X XX'Xi'AAX^'GXA?

    ΑΧ 'κ κ κ\ 'κκκ ' 'X ' \Λ' / κκ - A W κ\\κ κκΧ ' ' κ X ' ' κ κ X' X

    AAGGGCGX^:?GXAGGi3CATCrATGAGAAAAAAiAXAiGGGGGAGAAGATeXACGXAXAAGGGGATiXACGGGAA.¥GX?XMXGX'G gAGG'I vAGaAAGa+a. AGaaGAX'Aa .AAViAVGGvG.AAvAA-G’/’AA-VVv iT'lAAGCAvGAG’J A X'aGAGGVvACG+A-'GAA ^:r^:TG^:<?GGGA<:¥>GGTT¥?C'¥^:GAAX^:TACA/^:/G?AGGGCGAG¥XGTAGGGC<X:G'G

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    162/338 lAOTLOTCBLSFWMHFBSWKO/MXBSSLKOIWTLX^LPlOXGKlSEXBSA

    KYBFGV BYDBIDBTKB.DS BBBQF X ESDI t BTFBYBAB BFKFBTFRI TTBBBBMPKR7 X BB'

    FBIYABF IPKMRTX B B R GAVS-7a! S YES XT X VD Y'YFQI BFQgBlDF WFLXSGIHDBSGA , Y '^v ' ' ” ' ’ ' ' ' “ t i’ ', ' ' ’'' ’ V Ύ.

    swyTKEgwo kkissfyasdfsp i tlf i wsp^qthvlsqlt ypspdrxslloiye \υ «> m , o '\ '-rt \r,\ih\ mm^XGTF^^XLKBWGimWOX^QBSLWFYDBLTKFRS^BIXmG^DBm^XF YB rPBC IP BRASS ΪΎΒΑΒΒΒΒί S YFTAA ASSAM MAbYBSTBARSR BRASS SBBB'FBIS BRAS?FRBSBYVVFVBfrnvr«ΒΗ RTRBFTSAQ(S'V<BKAAkSFBSi FFBBFFIT 1 FF^V FSSFSSKBBXFCVI SEY VSBFBTXBFBAYDX FFNGTFKXTHXGI SGBTSS BFKDDCBY BX

    EABY AS BI ΑΛΑΤΑΥB ABYSS ABKFATETAB SIFFFBDYTTPJL BYTES 1STB ^EAISIABBSF FEGBB-BBVAS'MFBYBFFE'FFYFFTFXQXiFSDSFFFFTSBBBF'SFAFigYFAASBGAAATS EFASALEABADS >®SX F«X FEAT YBGRNF'BBIBSBBFXGAiiXABAFABiVAXKKAAABI X BSBBYTFSKFFBX BSYTRFASI F5B.RT.BFY J SBB7BBBTQBSBAA.FX VTBSBFSBTTVAV yB7i/RSSAB.BR.RS.R.BBIBG7BYB.FBl.KFB'YKIKYXiSKTR.BRYA'IASSRGB.B.BAYVBLAVTQ ISFMTFYTGWW.BSMSSTFSGO^:SFI>SQIF®E'B&RIAAFFSBSSFSTXK.BG_:BAGSX SFBXQYSSNNGSSYQ.DGYXYBAAAAYTATXAAPSTGFVYVEOKTRIA.TGgSBAQBBA.FMYB TBlBBBSPfoFTWBEBWTOBBDRKBRTTKXASDSSyFDFDBBByWVIIDXWSgilRA. B_;BiBOAFSGBMAERFBSFTA.ISGKSVFB:XYFFFAFAB¥GIITFFDSlFIYFSFITSTFT TABFMTTYSBBRRBAFRBAYRGTAX FBTAPBSYFQATBI AV

    FIG. 66H

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    0 443 133? 105 3313 2653 31 vt 3544 39^ 44»

    Relative Rasa ti cm of eodkms

    CAL 0,96 r-a go

    A

    A

    A

    A gg

    A ά

    A

    A g-irt 11 -> A A M~O M--A VI* A A-A Ζ1*Α 81 *00 §1-100

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    ν>\· %<> .{ ?χ.<

    Λ& 1' ' 1.0 { :Λ·^Λ ,+: '+ ,w.

    .. . ,.,, ,-, ©>· s ,-,,-. ,S. -£, /, y ^,:w v a<?W X.-rt© ©.'S''.· ,/1/¾ ;.:©> S. ΐ'Ά -ίΑ©

    Kfi LGw ©s+h ΐ« ,λΓ <'©wl\5^i?,'

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    Restriction Enzymes

    P 7+ 'Τ'

    CvRU-VJ?

    H :77/ -aPPC'''''' £?’£ CYK';

    7? 7? 'A t s F s-'' f7YAO7,?,g _s AvM ’'XWv' \M GTG? <2

    NMF 3 ?''?'?< C< )

    G ? ; AC' (gg “UN < -v-g xrx A?' iBloOBi· !\0^x!'-_k \'T F'?'?

    CIS-Acting Elements Sohee* GGTAAGl SpHce(GGTGAT) PolyA(AATAAA) PdyA(ATTAAA) DestabGz?nq; ATTTA s ΡοΙχΤίΤΤΤΤΤΤ)

    Pol > Αι ΑΑΛΑΑΑΑ) b + 4G\!

    :> o /' / Ci /': a;:- Ci & Ca ca :i <?“S © © o © o © ©

    Antiviral Motifs

    Optimized

    After Optimization

    Max Direct Repeat Bice: 15 Ofetanee:3543 Frequency/S

    Max Inverted Repeat None Max Dyed Repeat: None

    FIG, 67E

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    ,.. 7. ,../.,4: ,/:: ,7,....4 '/ :„...,.,/,$', 4/,: Λ-κί/λχΑχ- 7 W ΧχΧχχ'7χχ77'«ΑχΑ7’-χχ .7 Τ-χ'Ά/χ-ν7 ,7 74-4:7/4 :/ 7«-7*77v7-7x7>x/· χ- 4' 44445/44445554444444445^ 7'Χ'744:_:7Α:77,7777.74.7 <7 .77,.<A.A77.74x.-Ax?AsVaS/·,/., 7-34(.4'4 /,7' ,7,x;5x77x«4xj7>./ x.x..Ax.:«A<.x7,x5x<,v,x 4 7.A7Α<74<7444 ; .7 7,.7 '„.7 7χχ/5χχ/·

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    XXX XX XXX XXX XX i ,i 7.\·.<:Ανν77ϊχϊΑ77ϊ 74·ϊ7,.χχ.7?7?7?47Νί7· $7 4;A'77''7A'777^777<::‘7<A7ii7?777?'77 ?χ $77·^χΡ77<4 <χ <7 χχ WN AiAAW 7 VW A V$ ;···.,· ., ..,χ ., .,x,^7^7-,7^,^-77,7-.,7^-^-:,77^7^,7:,·,,Χ·χ,'χ.7:77'χ,,7Χ..χ,·χ„''7,χ^,7',?χ,.ί 'χ7,··,7·.,·7<·,7χ.. A χχ ,-77χ·< 7. «χχ χ «««χχχχχχχχχχ χ χ ,.·-$.··>·.>, ,··-:,··;·>,-,· ,-·,· w ·:·:: ,χχ χ: 7 ·χ·,·χ7··χχ,χχχχχχ.··χ/χχ ,χ χχ ,·· \·,χ .·.χ.·χχ.·>.·χ> :·. χ.,:·. ..·: ..; ; „ς ,ς-χ.^χ.·. XXX- X X X X 4-Λ V\.7.7,. χ «.VxTA .7Χ,-ΑΛΤ..7. 7 A 7 χ7 ,7>^s\x^s77 >?::· νχ-χ<.·χ.χ«χχ-χχ.χχ·\ -χ.<»4:··χ-χ;-·>..·χ:.·χ:-,··χ5<;4χ·χχ·\χχ,·>χ >.,-.χ w.fVxS.'W <- ,···ϊ „ i 7, .1 χ ί ·,ί ·,χ«χ«.χ·7\«.χ·77«ν,/,χν ,:,·«-··«·< ϊ i χ χ,-',<„· τ, 7 XyXv.,·, -χ, ,χ XXX -χ χχχ,χχχχ χχ ,,χ;χχ /χ:«χ; V ,χχχχ X ,χχ.,χ.χ -χ ,χνχ, χ, ,χ,χχχ. ,χ ,χχχχ .χχ','Χ·?Χ:,χχ..' χ., 7 χ.χ.χχ,χχ Λ >χ>. Λ χ..,χ7777--:Α\- 7-.Α.7.-- - >: >.·χ'7.·'7χ ·47$7χλ5;»ΧΧ χ,. 47 7 7.-7.- 4Λ. 47 7 ^:7,χ^χα7α^77\77$57>7+777χ7Α:,Α7?7^χ74$·4777 777x:7_v3Sx?-77‘7777?x7?7 ???3R?7A,^xX7C7+Nx'777AA7$79?V^ χχχχ,χ χ χ χχχχχ .,χ>. .χ \.· χ. χ χ.. \·>χ>·7.·:·.χχ:,χ7 Λ Λ .7 χχ«\ν.·.7\7\χ.·.77χ.·>χ.·>χ..-7. >. >χ;·>χ;7:·; ·-.-. ,7 ..χ,χχ,,χχ . χ _? 7 χ χ χχ χ,χ χ

    FIG. 67F

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    ΟΑΟΑΑΟΤΤΥΑΤΟδϊΟΟΑ^ΜίΟΟΟΑΜυΟΑΟΟσΟίΜΑΟΓΟΟ'ΙΜΟ'ΟΟΜΤΑΑΟΟΑΟΟΑΜίΤΟΑΑΤΐχΑείΑΤΟΜΝίΑΑΟ , \ ’- ''.' - ' 'V' _ν' - Λ' ν' - V Ο Ο'\ 0'

    7 ' '-. XX ' V V \ ' χ χ χ χ\ χχ\χ,χ5' χ X - '- 7 5

    5?550Α05.5ΑΤ<5ΑΑ0χΑΑ5Αί0>.ΜχΑ0ΤΑ€Ί5Γ·'ΓΓΑΊΑΑ<?ΆΡ<Κ.500005Ο0055.5ΑΑ05Γ04005<0:5;?0'ΑΑ0^Α5Α00'Χ50'ΓΤ<50Τ0'5 AATGAOAOO'AOOOOGOTOOAOOOGAtOGGGA'GTAAGGGGriAOfO'GGOOAGAAA^GAMG'GGOAGAG-'GATOOGGAOO ATCAA«5AC<g0RAaW5TKA7TAaTT7AGCCTGGT<-ATOACXWACWT7OCa5ATCTt3<7C'0r3TOAATAACgAA3OOC 0'05>000'η?0Α5Α?0·Τ0Α''Τ0050Ο0Α<·ΟΤ0·Α?;ΓΑ0?ΑΑ_:Κ?'ΓηΑ\Α55??00Τί'0,Α<0?χ0Ο5Α.Α0·ΑΤ0'Μ5ΤΑΑ0·Α0·0?ΑΧΑ5Α0 55Α<5ΑΑ^Τ'ΓΟΟΑ007^:Πχ700<:ΤΟΟΟΟΑΑΟΑΑΟ^ΓΟΑΑχ5ΤΤΓ<.'Μχ70^^:Οχ7ΑΟ.ΑΑ<5ΑΑΤΟΟΟΑΑ.ΰΟΟ_!ΟΰΑ^<1^!ΟΑ4Α^ίί\.'00<: '00'5A:07A5:AAAG<05O<.'TGO'MA5'l050OC0'5A:O0'ⁱrO'iOAAT/aO<5TA0'5AA?OA5.5AX''r55AiiAACAA5kSAGO'AgOO’.'.'OgO ATCA05.5O0O550rorAOCO0'O''5:COA.STTATSC?5'TOTOAx5AC.5AO.yyOOAOO0.ACAQOOTiMA0<AA.t;.55.5O'.5A'0OTATOTO AA.>\5:.:^;.:^:*.>\>*G^;.:^:.. GxsA: sa-AGAr: AAG Α: χ.5χ05χΑχ5Α5χχ?χ-Ακ:χ3,ϊΟ.ΑΑρ/5 5'x: Α/5.<5,ρΑχ..ΑρΟ?ΑϊχΑ50 i-x-AAGaAG:.: Axarl x.AGG «χΑΟ<ΟΟΑΤ·Γ(.5ΑΟΓ55Α.ΤΑ'ΓΟ'ΟΟΑ?'ΓΓ·ΤΟΑΟΟΑΚ.50.ΑΟο:θ050ΓΑ(.ΟΑ··ΟΤΤ€''·Μ.ΟΤΑ<·55ΑΟΑΑ«Οϋί·<5ΑΟ^'Γη?0·'Γ<Α5ΑΤΟΑΟ AAAACOxgCGAGATGAAGOGxMAOAAGTGGGGGCTG'YAGToGGGGAtAGAATGGx AAG'Ox CCti'GGA GAGOTTCCGC ΑΟχΡΑΑ005<Α1ΑΑ<5ΑΑΟρ?;ί5?ΑΑΑ'?5.ΡΤ<5ΑΟΤ^ί:Α/ΑΑ5.Μ·ΓΟΟχ:χΟΑλΟΑΤΟίΑΡ'ΓΑ'ΓΟ'σ?Α'Α',Αζ5ΑΤχΟΊ·ΟΟ.ίΑ'ΟΑΑ·ΓΟΤΟ··ΓΤΟ GTOAAT5^:0''A5AGGAOAAGAa'CGGO'<'TGOOGAAOGAG--5Y<OxG5GAOOOGGYGGAO<'O/A-5G<X50AG55AGGAOOG5' , ,' , -, O’', , G , O W ' , x x ' ' x \

    AA„- ΑΟΆΜΑΟ A : -.. 5 Ox05 Ax.-^χ ΜΟχΑΐ GGx AGO 0ΆΑ.. 0„AC0.. 5',.X'\'.x>'\G AGax<AAGAAGGA5 aO.AAAGG005X5AG4ACOOTC.AGC®TGOCxtA-G<.5G'OOGx5CGA5'GOOaAⁱA'MCGOO?'r;?O.A»C,PT<.':''.500i.5Ar5AA':'.5GGOA.TO ATGATC^CSCCCACATCCiggeCAATAACSACTCCMgGATCTgTCCCrSTrCGTgTGTSAeGAi^AbTGGSAT tx' ' '' 05 \ , \\x ' x5 ' '^x ' ' s' - 5 'x \ \ O' ,\ \χχ x \ ' χ , xx

    AAGAAG riG»67G

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    RSHFP^FTALYFXA KT LR FFXA FYXXXXTL YRFKXAX SAT DR RX,pTFXA.DQXX IDD A YQA R RP

    QFDglHSSFIT&SLSSKKAKSIDFSEYLDLFQSKKSLRDSSKKLP.KKlGSTeNFAGEK^K

    EERY PQYEDEEGSKX AXXGAI; I LS CQDHLQE XFYEF FEDEYX PAYIDDTERAR ETYPESEE

    ΑΆΕ A ' ;w v\< y A . A '' A? , , O' \< A ΑΆΑ AY

    YQYLRRDEKXTQIFDASTEKMXESTPXAFYXFEYYYFSFCRSQRQIFRYXXE1 XDEYEEEI ELYEQAOSEPAXYLPPAEERY'FSLPEXAXlAY’ECAFADFEAXAEY'IFFCDTEEF.AX'-rESREE XR FSK X FRF X i R ΚΑζ S A X R R Y R RFMD DE RE X ΑΧ V FDRXEY X LTR RE YCAV YES EAAERTX FDR Y RAEYPXDRgXA REFARY ER KAFR RF RPP X R X FRA X R RFFXASY R/RFXRAX XX g RTF FR F S X X.ARFDKR R X X TDSQTPSEAEIAEX RXXDX FREE REFER ETEXX X X TLREYFDRR.EST R R X RA A? YTIA X /ALLEY P RAEEEE X ER R FIF Γ/X X F EXT F TR X Y © X Y ΑΕΆ PA Y? ALE/XY RF gpXFQDEAXAXxD'/LYYaEFSPPFSLSADPYDYAKECPXDFRYILYXEEXPEKEYLAXPPRRAEETEFC.T·/ EETEDR SSELTP/KSXAL FSXDEREILYEEEYLFEAI' VSR.F/1 FLYSTgLKAYYAPPFXASEF PXEXFFX'XYRYXA XXXPASEEC'R/XFPXCCAALDDRYPEFAFLSYX'AEPY'DLSS'XAFXXpYREAP' ζ AEYFSLLFRQEFFFTELTEBF1FSEE1 FF ARREY XELLSFEPKYRAALTEE X DECRY EX, SF Y P KTTXAE Y SRREFERYES REEFY RD'YE X CAY RRE XETCX XX RS X REELYR RSEXALFR A\\ x Aw * ΑΆ X'/ \ > A w \ F -x , ' ' ©a xA' ' AA

    ΙΈΚΑ'Ρ ΐ ; REYFFFP/ERRIIAYXA TREAXFDERYY/AXYRTLRYECFREER® X TDRSR AS Ι,ΑΥΎ S LYPXPRRRX R X VDCCTEYDAFTEEXAEQP S X EEFEYFYEE gFLKEEAKEYYCEEYE Db EDAEASEFEEARAXEQFItXT X EEAEXAXYVS LV X FRY ADIAYYXEEPFAPX YbFDLETAFER FPQF X DESVYCEF EIALAEXXK F LAPISIAERDE IF FFTRAL. YL'X'E F'ATHYFF X EERECAS XX'7LYTRFFXYrSQTDX'AXAXAXRCX'XYLXLRFX>FXXTTYXRFASXXXRXXEF'XFX)OX'XETFTDX'SFDF KD Y YFSYIY/GEXXFETSEYEPEOFXLYF OEDAESLDP FPSESEKDLYESRlDEIDIYKX I ΆΕΑ ' / RF Wx IX'R\ X ,\A\AA A FA'

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    FIG. 67H

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    Αχ w 5

    -S I.. St.

    66 h ft sfcx'Vi wV

    ReIat iw Fee it ien ma :«·?

    x

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    Restriction Enxynies

    Optimized

    At ft

    A

    8:

    ft

    1111:1/1¾

    111181¾ _{: ::} 8f_::::: apfffit 8/ a..

    ^: i^r 8/

    1;

    if

    CiS-Actmg Elements Optimized

    8pfee(GGTAAGl 8

    Sehee<G&TG^T s 8

    FMyAtAAIAAA) 8

    Po;yA(ATTAAAi Cl

    C e *' t:; s ©g / < ATT ~ A' 0

    PoiyTfrTTTTT 8

    PoNA; AAAAAAA) 8

    Antivirei Motifs Optimized o

    After OptMzAtiOR

    Max Dtect Repeat; Size; 14 Dbteeee;200t Frequency/2 Max Inverted Repeat; Nene Max Dyad Repeat; Nene

    FIG. 68E

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    A A'A ' ' A ,, Λ , Y 'OX ' , a , AX, , 8 R,'' * ' A ^x

    RYailBAlAYRORYRSRQRRRYRRRYFMKXXXARlYWYRRRRRRRRRYYIDRlAYYXBY or ; '\a?\vtBR'hC'ocag;von :r axn χχχ yaaayxx i I A - a As- RRyRs,FR',,+R\\R i \ a a ⁴ aA? R b ' b , Μ Ό a, 8R, as 'L a\ yx ,,By y a —.; τ 7'A, a;'$ : a.yy p a ; eg y s - xy pa +p v t y ya ; aa p p y; a- + ? ++ ++ yaya R r όχόχαυαίχ x rr ; r?vnxiTTbayrf ;ύ r ??rx no; 11 y ayfar x; y:

    nnno ronn: o no?; yrreoa non ;χυ;χυυ:ά??υυ?υ rr ι υχμχυχχυα; RXi X'RRR, AAR ΚΟΆ'.Α' 'RFRRaY ARAR A '.Ab . Y X Ά.Χ X 1RKA, . Y+RR'. y ;- AM gy + \ - -,++ +y - rrr; ; pp ργ Ά+' .a A' ya y ;. - y RRy FRAME MAY AA' IXI: YPR, A A Ab 1F YOF AY /1t A RF .a X? YbAbybA AXFR A + O X V a RY ? ? ? X RY Y R RF A A Μ'ΆΆ ?Y A AR-AAA ⁴ ΥΎΥΑΧ b + RFRA'A kPRRRA'R XAXXW RA+ AAAA MMAAMA'AYAYi'; AYARYAAAYAT A yP.HRYYRA\ Y X '. ΑΊΑ · 'YR' ⁴‘ A' FARRLYRXaARlRaYRRRY RyYRRXSRRRRRRyFYYRYyR ΠίΧΥΤΥΓΧΥΥΚΥΥγΥΑΥΧΥεΥ ; ; RYAbRAR RF ΊΑΑΊ?8'-^ΧΊ-.'7 MRbRR RRMAMX. , YbA+AARARRRRA RAYA ROM , , O' b ' ' ? Ά , A , ' ' Ά ' A . '?,'?,

    AMMO'. ; -, RARbAXR X A R A X ,y b a-A AMR AM ARyM: FA X A AX M\,y , ”AR' .'^-. ⁴ K-MR .X A AM AM RriOylA:

    F b i- a' LA.' y -8... RR ,- r s Ri

    1 -MAX yYAARA X! A'A-bORAA ARIA- -VRR-':'AY gy+yyg + + ;-y+;yg bXRYYRAYY-Yl YR ?? RX ,'Y ΐ YRRYMXb'R'. F YAAR YYAbARFARRb YYYFYAR YbRRXRF A Rb RRM Yb'A AMA YAAR' ? FY RRRR A Ab XRb'F EbR YXYR YRRbRRAYRF YRRbAl FA'1R b ; Ay: E R Ό X R\ e .XX ' - R .. R F A A F , ArA R , , - FA a', .. \ MX a. -. ^; F. b i Y-b X -b F FARM YRYaRYAARRY I RAbb YAMXFRXXbR YbYE '. ERR A AT RRRXF'ntRKRROFK

    A ΑΊ YA'RbbARYRbRyYR Y YRbYARXRl R

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    FssoiAlun of

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    177/338 iclion tnzymcs ggyggy ⁷ ii⁷ ' /g_:

    ΧχΧ ii /1' gggmg xfc ' ? x , xs \ i ? h fc ?X fc Y\^X ' fc \\Yfc γγγ

    NT :

    ill g

    CIS ^Acting Elements 3 phwgG GTAAG > SpOce(GGT@AT) RoiyAs AA? AAA 1 FalyAi ΑΪΤΑΑΑ)

    C'a Mat shis r<a ATTTA'

    FAyT(TTTTTT)

    RAyA(AAAAAAAj w vital motifs o

    A fcw.x

    Optimize o

    After Optim mm aa

    Max Direct Repeat BAaAS Qbtence:93 FrequeecyA

    Max Averted Repeat SAe; 12 Tm: 36 A Slat Ayfcfcm: 842, 2867

    Max Dyed Repeat: Nene

    FIG. 60E

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    A37AAAAA/A A-A/Aa aAA?aa /AAA?jAAA/A^AAAAaAATAAAi/i/GCAAGT/AAT??A?AAAA?A AAAAA Aλ^:ί;<'<;ί\ι<ΛΊ a i'A·:3G/.ΐ.?Ay'1 SYnOsGxAAgOLA'7ΑΑ^:λΑΑΟΟ·αΑΑ\ΑαχαΑΑ^Ν74ΑΑ??Α\72Αχ?·κ?^:υΑΑ?:Α<Α$Α;><χΑΟΑ

    Γ><' - ^?αΤ\7 - vrc >?\\ ?a\ rrr' ?ΰ'χ;??χΛί.Α\.\?Λ ΰ· i^: Υ^νΥΥχ/Α'Υα.Υϊ.χ AY? \. ?''ΑΑνΛΑΑΑχ.ΛΑΑ^νΛ?Α.ΑκΛ7χΑ\ΑΑ??ΑΑ.\Α'ΑΑ<Α.ΑΑ.ΑΑΑΑϋ^^^^

    Ο??ΑΑΟΑΑΤΠ??ΓΓΓγΟ?ΑΑΑη?·ΓΤΑΑ<?Τ·:?'ϊ·ΑΤ?Α'ΟΟ?'ΓΑΑΑ?ΑΟ?ΑΑΑΟ?<^:ΟΑΤ1'ΑΟΤ?·ΓΟΑΟ'·ΑΓί:?Ο?Α?ΤΤ·ΓΑΑΟ

    XXX^V\''\ XX XX X XX X X X' \ XX 's A x x' ^vx' X X x'x X \ Ά X ' \ x\x ' x’· XX ' ' ^;'.>x?0.< \y.>AA‘i A\s)'.{CC^;. ΆΛΛΑ θ·:ϊ{<ί^ΑΛΆί>,ΑΑ?χ ΑΑΟΟ'χ?Λ·ΟΟΛ*?«αΑΟ').'ACG.O,Α ΑΟΛλ ΑΟΑ^?. ΟΛΟ?' ΡΟΛΑ·',? Γ0^;?? ·Χ>

    ί 7\'*.Ο?ί \>·0·ΑλΑ\Λ7 ΐ Α ,χΥ-Οχο 1'\.'ί χ'χϊΑ.'Οϊκ/χ'χΑύ j \χ Α ΑαΑαα ΑαΛχΑ'χΑ* x^; g\:\.< aA<a.a00aa .< \ k.Α\ Ά>Α' jW \ :*ΑΟΛ^ΑΑΑ7^ΑΟ?ΑΑΟ$<?ΑΑΑ;ΑΑΑ0ΑΑ^ΑΑΑΑ:-ΑΫ?ΑΑ0ίΑ0ΑΑ^:ΑΑΑν0 Α?ί.Αΐ.ΑΑΑθΑ\ΥΑΟγγ:Α<?)ΑίΑγ·\<Α^:2Α77ΑίΒγχ<ΑΑΑΑ'AAAyAAAA .AGAA^A'WACfo'TOAAA;

    χ-ΝχΆ.Τ-Αί <. χ :G χ \<7<7\ν\χ..7χ 7 \χ χ< <χ· ΑχχΑ7Χχ·.χ^:>χχ···7\χ'\χ'4^:χΑχ· Α\χ''χΑ··χχ S \x'\rti?X-'.<7xV Λ A-AxYXx'AxxAAxAA-.xYxV GxAxx-SAxO·?.

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    ^X* \ V AX \ -X s s Ύ s' ' ' sss V ss Vs Υ V ss sis sss \K-X As is 'Ύ s Ass s' s x s s' S s ss s ss ss ss Xs X i'-iV* s s' ss fss s s ss sss'^s' s'· is s'\s\ s'. N ' Sss s' U A S s s sss X Ns's S\_s'sss Γχ xs'N's ss s^ 1* sx'\V sx Y s'\'\Ysi\ xsxxx\s s$ Nssi'\s $x xX λ s'x's's V s' s' sis V S^ S^S S ' S Χ\ΧΧ·χΧ·χΧΧ^Χ·χ<. S, χ ,Χ ς. Χχ Χχ χ XX ' ' Ϊ si ' s' Ϊ ss'Xs^x' S' X s' i x 'XX _s \ < 'X s' x'X ' χ ' ' Ϊ ' ' S'N '' i X ' s' ' 's\s s' .·&< siN-Y .sX ·χ<·χί\ s', χ χ-«· A' :<<«s \s\ ^,«<-^,<s5'ssi<s'.iN..s^:< ·ί?χ':<χχ·.·Χχ· <?<· i'Xx' ' ' xX i ' X x xX ' X' s' s ' X 'X X ' ' X s s s s ,χ^χ s χχχ s_x ,s, x, xs sss, χχ ix· x' .Y\x>· isX -.XsssiNsXs-x ' s .s XsXs·· X* sv. v'vY .N .V. .sXs' Vx' sXs· .Xs s ssX sXssss·' sX Ύ <s ·>: .XX si Xss< Xs \.v Y '.xi «·. .«· sss >< .i. Ns' Xs· x\ χχ ;ss ;<« .kN'.N .<··<., .N .<YsN xY-isV.^ssXs ·' X * ' N'^x ' ' X ' X X \ Y ' s'» X χ _χ'^?ΝχΧ^Λ'' Xs ss s ' Xs sss X -X' \s ss\s SS s sXsXsss ^ssX SS S S S Xs Xs xNNs .X Xsss Xs X s ,s s'ss Xs' s xss Y N 5 Ύ ^x Y <s s ' ss X sx SX χχ ^χχχχχ.χχχχχχ ·ζχχ X· 'XX-'XXXX' s ' X» >X ' ' -f '''X''','X\X **' ' X· XX 'XT X >' s' ' ' ' ' ' * ' > ' 1*$ Ύ ' X V's' ··> >Χ \'Χ· X X XS ·.,.· v < ;. ·.·,s-\ i riv s·.^ ssx ·ς? Tx: s·^ χ ν' v φ Χ χ χ s'N s'ss .·. ss· Xxx ,· sxx^.vx.s^.; ssh < s s s s s' 's' ' x\x' ss sX s ' s s s X < · ' x ssx ss,s s, ,x XX _s XX ,XX x x s X X X s X s χ χ χ, χχχ, χ χ χ χχχ χ χ χ χχχ χ χ χχ xs X \ss _ss , s xs s sss xs ss ς.χ s s ' k s * s s S' ' V Vs^ ’ sV'K is V 5\ \s*s \i' \s s $ Υ' λ ^S s ' s' _x\ i s <x, 'V ' ' ' ' γ X',' N'x A 'Ys' ' ' i χ ' \ V's \ 'sx' ' X s\ ' \ \\ ' . ' \ \ \ S \ \ ' x xsiis _K'xlx'' ' ' ' x s ^X X s s r 'ix\ s' ' X ' s' ' s' ' γ γ, χ ' Y - ' Y'' x' '' Vs Y ' \ *s ' s\ XX ss' s s's x 's' si ' s Υ X Y \ V X X ΐ γ Ν' \ γ γ γ ' ' γ γ \ ' γγ Ύ ' Ν' γν· ' ' ΐ·Ύ ' Υ ΥΥ V ί?\χ'ί'<yY >'TSVs l·' VLii? Γ χ'Τλ^χΤ1χx s xli ΥνΥ-γ' '^χ-' Υ γ· γΝΎ '-''' γγ>' --- γ-ΝΥ χ·---'·-·ζ· γ.·>Ν'^λ Υ^: ΥΝ *γ· Υ

    'θ'' ο-Υ Τ”Κ ^; ΥΎΎΥΥ· Ν'' ''.Υ . '-' ι '' s ' s ϊΑ , 'ΐ . Ν' ΐ' ΐ ' '' \ Υ ;·$' w , ' Vs?Vs;v's s ssss_x ss\s s X ^Χ ' ' Υ ' ·' -\\ ' X ' S S χ ' is-\ \ i Υχ'> ?\\υ ' V χχχχχχχχ χ χχχχχχΝχχ'χ ' -i <· ' S X χ\ X XX ΑΥΥ ΙΑ ?ΝΥ' ι' Υ \ΚΥ? < ΓΥ\ΑΗ INI 1ΎΙ' ΙΥ - C1 ΧΧΧΧχΧχΧ X \Χ\\ xxS χχχχ < S \ X s χ XX i λ!\ <\ ί\ . 1' ι { Ο Ν ' 5 ' ' s V' ΐ ,ΥΥ Α ΥΑ.ί'ίΥ ν .Υ,: γγο-ΑΥ. L YVT ΙΑ V .1 .ΥΥΧ Qr Υ.Υ Η ϊ ' i χϊ' χ - Ύ \ X γ s xsx S^s χχ S X SSS s^s ' ί Α',ϊ Αχ ΥΑΎ'χΥΎ Ή^!' Ν' ίΎΥ' ΐ ΊΝΎΝΥ ΥΑΆ - . χ ^ΧΥ. _χ V κ Υ Υ' )Ν- s^χ s X s' sX sx ' χΧχχΧ'χχ , χΥ χχ χΧ '

    S S_s \ χ X \ S X S \'-γΝ' \ Ύ'ΝΥ ' XG \s'\C^A N ' \ \ γ ; γ ' YN' '\ V γ s \ ' N \ '· Υ ν'

    Ns s ss' s sx' ss' ss s' s s' Ά s'. ' Nx xi xi ss' Xxsxix Vs sS s' x V' χ·ί s\s' X xss'x x X i x<: s' ss ss \' ss's s' ss x'xs si si s s ss χχχ XX Y xxx s' Sx SS X \ ss ' x s ss' xs'Y x'xs isss' s'

    \χ' χ - i G _Λ χϊ'\ 's Ni 'χ' ''' i s'' χ X S S X X i S Υ ΥχΛΝ'Ν χχ ix' 'χ Υχχ X χ i χ. Υ Λ.Χ S > λ; ' Ν 'V ix χ\ χ' κ\ Ύ χ'χ' six Χ'Χ' S χ'χ Υχ χ, ' V. ' χχ'χ - χΥχ Υ Υ X X i X X X X' X X ί »'Χ*·\Χ·\Χ'\Χ\' x>.X·' 'S ' sss, χ <. X, χχ, XX χχχ. χ χ- s -γ-γ χ—χ ·ί - x ' Ύ ' V* s'- - χ xi' X X X χ Ν •X' s'X .Χ·Λ'.»Χ·?».\·Χ».\ X·. s'.s' s'.x'X' ·?·>.χ' ·Χ' -X·. .·>? •Χ'ΧχΧχΧ-Χ'Χ’ί,Χ·» ΧΧΧ Χ»Χ·Χ Χ·.χ·Χ .»Χ'?Χ· ν.Χ'.χ'Χ' . ΐ s '1 ? 1 c sS 1' ' ϊχΐχ \ χ' ϊ ί '5 '

    FIG. 69Η

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    1 . S x^: x \ χχχχχ $ 4 $:.

    \ 5χ »'Λ'·'' cs ^{w x}' n ^v' ^Λ' Ν' ^v\ *·' 5 K $· v ^s A' ^v> \^Ή^Λ $· hMc tv i ?Χλ*'*^τ * * u, v

    I «, , ·« ,77, ' '9m V W -7>' A -_v r*......

    > >>.· '. χ ·:· >: < < + ^:>S « X x·: χ

    4-+ 4s> (XW ·· i to 7, 1 7 i

    ItoX to ivto Fotoi :toto tof totodtotob

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    CIS-Acting Elements Optimized

    Sps i € & _λ 3 D T A A 3;

    Sphce:GA I A At j PdyA/AATAAA:

    PoivAiATTAAA}

    Destab A z Agi attta }

    PetyA( AAA AAAA)

    Antiviral Motifs Optimized

    Alter Opt muz a Aon

    Max Direct Repeat: Max invested Repeat: Max Dyed Repeat::

    SiaePS OstanceOS Frequency :.2

    Rene

    Rene

    FIG. 70E

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    X X

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    186/338 , _ i _x ·. cf.i .-4-/ '...,1 :' A'FFA’RLFFAYAEYAFF' yafya yh aa afyyfyaf yahf Y'f-arhhhfhf arrayffya αυυααα.ϊηαα y t ah::hi r.\ fh+fyfafayra wahHxYXFfryaf\aaa fyayf-wu .yyiaaayy ' a yaffrwyy AARF : s Y \F R HRF WAA' ~ A AH FFFF.Y R. FF F R'Y'< tF Y A Y'R Y Π Γ AF: RAF FA' HHA F YFR F .AY A Y ;Y ;F' FAAAA+'AA HHYA FA : FA, FA ,Α,Η Y. F ® AAAAYREF A FHKHFH YAAA FF 'RAF HTAYF F YAH', HR A A + F.F-” F F FA'AAHIA.HHFF RF n-.-rr.’;; FA'HA'x FA F AFFRRYAF FA AFAF-'KFHA A AYR AAF' 'FFRRF F'F ': WA-ARRA F : HA.+ AAF Y F' YAH F RHAAYRtA ΑΉΑΆΑΑ ΑΠ x R F : +A A A' ' ΑΛ - WF AY - R F F . AA H+ F FAR'' A' · A A\ -'ARA F: HH A -FA F A Art F F HHAYFAHFFHYF' FA FFAAAAAAHF EYRRRF.A AARAAAAj ARRAY AAAFHHHF HR FAY Al AAA .A A HR HR YR A : F.'AY AAA RY F AFAAF K. AAA A A ' RY RrtHTRR ARY'rtAYYRY YR'F .ΑΑΎΐ,Υ ' ΑΑ?χ YrtAYAA.HRFAA.A A„A,,AFH ...FRF.Y1 AA: F FA AAAAL. AFA F _x FFAA.A ΑΑΆΆ,ΑΡ·' Y'A: ,+-'”A' ; ? <4 FAA\Y'' ⁵ 's WWRRF F-YFF

    FERRY FARKFAAYRYRY AA Yi R?' Y Ar'ARArtYF FRYFEYrtF HAFA'ATFHR. A'RAF. AFY.A R F.FF.A'AHYYYY+F ,i WARFFArtA: ARF.AAAF FA RF J'F - As A A \ _x AHYF A YFFFFrt' RFA ASF W' A F FAFAAFF'V AFAF AA F ' rtYR'ARYF FAV'A.' W'RAAF' Y ' RFAA'FAAFFAF'F P” FA RAY : A-A H-AAAF F A F ΓΥ 'FA- FA ARY A A WFWWYW'A F RY'Rrt As AA-A- _x F WY

    YAirtF ΗΗχAYF.E Y YF YFY F\:A.YAYAxW YRFAFERY AWRY . F WRrAWAW R-EWF F ΆΑ YF AY A' A Y ' W FF. ^x A ( R Y YA\ WF _s HAY' ' ' F Ai ' W F F F'F YARY . , Y .HA F F FA ..A. 3 F,:F: F.xF.A' - F' F.4FY - 'A: F' R s- , FF '..ArtA. R: A\A A-F' FRA '.'xA. .. \ F F Fs AF' F', F A - F A .A'^; .4 A . Y F; AF' F' A F A s ' - Art > . . AF,F FFF' F A \ A' F RrtWRRYYHRYxiRYYYYW WRYE YYRFFHFxYWAAA Y.R A'YFA HR YY YYARErt YHF RAW -YxxA.F .-'.Αχ AA'U F AHR.A AFAH-F AFAF.ΙΑΑΥΥΗΑΑΑχ H.Y F ARARAHAY F ;£H.W

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    Χ«Ν· a

    I a-© 1 //

    5^f>

    4/ | gag ξ

    88 f rt ij XX X

    5V /8 8«· \sssssssssssssssss+s/ssssssssssssss«ss+sX++++s+ssssssssss+sssXs+sss+++sssssssss'.++/ssss+s+ssssssss+ss+/s+sssss+sssssss+sss+Xsss\+s+ssssssss+ssssXss++sssssssssssss++s<S++ss++sssssssss+s+s/++s<ssssssssss+s+s+sX :

    rt' , ϊ'» , \' rt ' η

    Relative Feci tiers of eodene ·:/:·<<····. ·:··-.·::·;· z-x ····; .<'->.<·<· ,,_λ <. ,-..,.,,. ..., <:... g :5:/+. ’’ x χ»χ·. ’ /s' + '''s'' χχ+5: \+<- \+<.«rt

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    Optimized

    Cl5-Acting Elements SMAe>GGTAAG;

    St \toiGGTG~G'

    2 A

    PolvA; ATTAAA j Ge $. m a Acs a 2's τ jg'A > PAyTuTTTTTi PoyAiAAAAAAA}

    Antiviral Motifs optimized o

    o

    AhW Optimization

    Max Direct Repeat; Sice: 17 DfetanoeASSO FreqneneyG

    Max Inverted Repeat: Nene Max Dyad Repeat: None

    FIG, 71E

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    191/338 λ\·\<'·7\= .C.V^:dAc^<xk/:'kc\:-\.. /Ad DC \GV\A\>Ax7;fC:^:.\A Α.Ο.-ΑΑΑΝΑχ.,βΑ/’ΐΝ^Αχ vxO;Ax\;n\\,\a\xx^\;;\\a\\x\;\ <λ ccocc ^\\'χ'Γ;\<\?Αχ\αα c\w_soccvc; ;

    A ?Ά.<<:\?Αθ?'.ΆΛ·.cAC·3AGCc CCA..G f ACa ACC·OreAC'CCAC'-: C. AA'ACC a A.? ACC ACCAJ' AA-C·. CAA. AGA'; GAGC'.A.A-C ιΑχΝΑλΑη/Ν/ζ'ΑΐΝ^χΐ'Α.ΝίΝΝςχχΑΟχ/ΑΑχΑχΑ^ΑΑ’ίΐ'ΑΝΑη.ΑΝ,.Αϊ.ΑΝίΑ A'C/tJD.AC’iiNAdsCCkfj A AkAGAAAGcOPdCCAcpC AOcAAniAGCddanO : . k \ΐ ί \'^: .ΌΑ-Cv .kC A Ν' j· <> A^s* A., λ.·ΖΧ?ΝΝ\ΝχΑΝ< Ci.'N'Nk A A Ox CfN-iNx χ>Ά’-..N?GC k A'x.A'GO: ?> A N-N'C’. A χϊ-ΑΑ-ίΝ θ\ϊί.)\ \ C-Ai ΟχΑΛ 0 xk C’ A kA^:.>?AC’\DO<A>G:'x.A\\A;:k\. AvAAAGONaGAA^nGGxϊΟΟ^νΝ^νΑνΟα λΌ A-.AC O' i;GC’.O. A A A GnAa .On .A-/COkAd x.x:<GDi’AONA,dA<?fAk.CG· AAC i \k <<·Ν· ·χ·.<Ν χϊΝΝΝ. Axxk'Ax.·:\·< λ:<k?Ν·: Ν\¥.

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    MY ¥ £ S L T FQ Y F V S NT I NN SN I PIG Κ T LDF1P QNN1 L Y S TV FFFQF A SNA K GAL DS YHNQF. :::; FAGP F X T G ? GG FI AAA1A A', G1 OSYA P GPFNFY- +GG1 ? AAV'A AN AAAI FAN FTF T GKP AAN:AANSNFTT:GGNNNYNaIGGSFNNNTFA:ATGTNaYNXNF:YG©NNNNGTYMYNaTNWFN NFNAGPPGAPFTFTA γ tAADGGNESSgF GNFF VpTFNFTLA GPGGPTYYG GYGNINGGAG G/YNQFNgNANGPFNIPPNAnAFFQGFGDPANGFIGNPASNPYNGNNYFGYGGYGGFGNKG G F TAN FFAAtP FG GA ΑΝ V Υ V GG GFAGT GF GN GA FFNNP T FAFF GN QG A ANNA A GGGG AAG:. AGGGGPGGAFGGGGAGFAAI+GALA'NNSNGAaAAANYGNAGSAAAGNAAANNATFGAiAGAA'SA DNSNNNANNBOYOGNNEi+DAGNYANNNNNAINNSGgpGiNNNGAYYWNGTYNAVSANiGY' DGT.AYMTN'G YNTKKPPGTFFYKFN'ANPGTNNNANGNNNNTSNIMVFFFENGFYYFAGMNT GNNFAFYiTFFYNFTFFTEFFTDYKLYYTYNgMYFFY'FFNFGFITWYNFGGFiYGNYYFGT AAGGFNGAAA:AAANGGAAAAAAAAGGAGGGGAAGAAAGGGGAA:GAAAAAAAAAAAGGGGGAGAG

    ATPi FATA1 F'Gl GPNGGAGG'AA ANFNA -FYGF'FFFNGFY GG FNNGGYY GN .AAAA'APNF κ Ά' Υ κ A A ' <'< \κ<Μ _k ' ' '' F< ’ ' ' A 7 κ κΑ

    GFFMAAGAWYNAFNGAYNGAGFGGFAYXN/lArGFGAGlAAAVYYlNYFGNAGFQXAAN G AAGGAAGG RTNYNANGGPPAGAPPPG/AFANNYVFNIPGAFACAFPiGVVNYTAFNAFGYN .ATIGAFNlGYFGFFFGFSNYNIKgYYgFFNFNATAFANTNYlGNGNFgYSF'FFASaAGAAtiQ NTNNSNNPNS;NGNQAgYIYYYNAYNTSNTN.PTTGSANNFYNKgPNYYNA:NNNFANAANAN FNANAFG ( APGFP ₅; FG FppA+ OF O AaAYGOA A APNFGA GANG GGGAAAATGA' i G AGFA AA F ANAANNFAN ΓI GNFA\FF ATP G X Y G GG A AG <NNN Y TGG ATFGA IY G FAY FTP FA YF'NG PNGG A FT F FNNGTGi GNAGANPF YGNAGA'G G G ? < KG EG FAIN NNNTNNPNFPA AAAGA'

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    6 371 742 1113 1Μ· Χ637 ΜΑ MB? MB

    Re+Utiw iWltimx cf eixlcm

    BO :/: 1:1-44 21-74 :21--44 41-74 41-44 21-44 41-44 21-44 41-144

    FIG. 72B

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    FW F9 | 99 I

    WyC·'· <**> <+$$ t

    9 4:: to .9/ * + A A 7 7 9Α7 iU Wy A 77 iWW+F+y y , ,7, wW 7 9F7 ' ' >9> ,?9 :N W; < >.· : > '·. λ : : ' ,:-: λ + N $5+ :. $ ^:'· :+: $<' ' --:-·§ ~ S' : 'Xssssssssssssssx.ssy>sssssssssssssss^>sss<sy>sssssssssssssssx>>ssssssssssssssssssss«x.ssssssssssssy>sss«y>s\ssssssssssssAsssss^>sssy>ssssssssssss<sss(ASS^>sssssssssss<sx,SA'*^s»^s'*'*'*'*'*y»X’''S> ssssssssssssss»\sv

    ...........797...........1179......UF.......1799.....::97.....9997......9979......7799.......97 elatiw ftmUw nF »dws :+^- 7>\ «'•X•'•'•x· £>^ rt,+·: $·>$. / .+5/'

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    Restriction Etw

    X H, ,> ,

    X ^κ ' s s

    -,,, ,: V BePOrtGGAGlw^::

    ss ss \s Xs'

    X S SSS S_? X

    A ϋ

    χ·.····:-/χ<· :¾

    Ss'ss* Hsss's γα;

    ΐίΟ

    X ss χ '-'V

    Vs x s s S

    Ss Ss'' ss

    CiS’Actmg Elements

    Spteet G GTAAG} SphoGGGTGA') PetyAtAATAAAf PolyA (AT T A A A;

    Α~ϊϊ A: PMyT (TTTTTT)

    P d v A i AAAAAAA}

    Antiviral Motifs

    G e

    o

    Optimized

    After Optimization

    Max Direct Repeat SIzeNS DGMneeGSOS FtepyeneyO Max hwehed Repeat: None Max Dyad Repeat Nene

    8”ϊΖ*^ ’’ΨΛ»”

    Mis, /2L

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    197/338 /ΑΑΑΑΑΑ:Α7?ΑΑΑΊΑ ΑΛΑΑΑ<7ΑΑΑΑ:Α'ΑΑΑΑ A?/A^:AA7AAA7'A?<7A/AA7AAA7TAAAAA7;'AA7aAA,:aaa??A< AAAi.7A7AA'.S^:AAS7SaAxAAssAAf7A<sA'7SsA?7AiA7\'S/ASi5SsASAa7ixSA'xA77SJAA'7xA/'SAjAA77A\AAS?s7Ai./AAAi/i7sGAAi7’<Sg3 ΆΑΤΤί- As AA,·-AAA As,χΑχ Α.7Α.Α\.α ΑΑ\· ΑΑΑαα.sS's/:-,-'.S\x A’.S'S's'AsAxS's/Asjs,. ΑΑΑααΑΑ'/: As Aa AsX7s7Aa7AAx/saAaaAA Ax'S/ ΑΑΑΑΑΑ: s'SssSSs'.sAAA'iAA'S:7:S' s’ AAA ASssSA'AAA Si' A S. sgASASAXAAAsAS xA'iAAsgaSSSAsAASAaAssS S' AAsS'Aa'AAsASs ’ΑΑΑδΑΒ8ΑΑΑ7'ΑΑΑΑΑΑδΑΑδΑΑΑΑΑΑΑΑ7^:ΑΑ7Αί·7Μ7ΑΑΑ7ΑΑΑΤΑ3ΑΑΑ77δδΑίίδδ7Α7ΑΑΑΜ^ΑΑίΑΑΑΑ7ΑΑ ,,,''' ' 7Ά ' ' AA \ , ,7 , ' s ' s ' \ , A , , ,

    ΑΑΑΑΑ7'ΑΑΑεΑΑ·ΒΑ5ΑϊΑΑΑ’ΑΑΑΑΑΑΑΑΑΑΑΑΑΑίΤ7^Τ6ΑΑΑ»ΑΑΑΑΑΑ7ΑΑΑΑΑΑΧΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑί7 A:AgmAAAAsASAXX/Ai<iAA,A:sXXA:A!AiXsASAAsA\ASA.AAAASXAXA:A;AA':Ai Α/ΑΑ;ΑΑ’ΑΑίΑ7ΑΑΑΑ«ϊΑΑ'ΑΑΧΑΑ/ΧΑ:’ χ, , A , a χ A ·. ' '', e 7 ', ' Ά\ χ χ Wa /7,, S' , ·. χΑ, A,, s<, A A Ά, 7A, \ A χ W ,,,, ' A, ,7 ,,

    Α®ΑδΑ7ΑΑΑ:>ΑΑΑ7ΤΑΑΑΑί^ΑΑ6ΑΑΑ7ΑΑΑΑΑΑΑίΑΑΑΑθΑΑ67Α7ΑΑΑ7Α;77ΐΑ7ΤΑΑ»ε'ΑΑΑΑ7/ΑΑΑ6ΑΑδ θΑΑΑθΑΑΑΑΑΑ^δΑΑίδΑΑ/7Αΐ7|ί7ίΡΒί<ΑΑΑΑΑΤξθΑΑΑΑ7ΑΑη7ΑΑΑΑ;|ΑΑΑΑΑδΑδΡΑθΟΤθΑΑΑΑΑ7 SAA/A_:AAa7'';A7AA7a7/7;;7aT7aSxAA<sA7AAS:sa7<A;aaA

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    FIAPHFTiRA FFWFFAFQIF gX YXXXPAPFXAXVPFFFFFFMFQF1VXFPKXDAF.PXDFP /Ffa p, ϊ/? μ*ρ;\ακαίικ;απαχΧ' fffp,a yyp jrt't+xhmwFi» aa γ.υαάυ ;v BFFFFFFAFFAFKY8PA«FKYFFFX:X:FX.FFAAYAFFX:AFAFY'PAA:FYFFFYAFOFGXQFY FFALYGYYTYXXXiYMAXFAALFFAMOPEFFYPGFFFHYFLFXXrFFFFFPFPYlPAYPT FAFF F—-..Fs' FAPFF.Y,' ,,FY'FA,+Art / FF s-YAPA TAAYFP FT FFF ..:. +.©.<?.L AA\ ΑΆ a ΐ / SP FArtXAAPHPFYPAASXFAXMAAXCAAYAABPDAiFFFAFSDYABAXKBTGWBAXAFYIA ΧΚΧΧΑΑΧ.ΚΧΧΑΑΧ/ΚΑίΧΧΑΧΑΡΧΧΑΑΧΧΧΧΑΧΙΧΥΤΧΑΑΑΥΧΑΡΡΑΧΒΒΡΑΧΑΡΧΧΪΡΙΧΑ £~gVF'\g'7H 5R\,.\'\p v> . AAA, A FAFF VFR I YUAAA *A$\\Rtrt\' art;· y© 4

    XI FI X FABy y PA ; : γ yy y y rg T FFFX FA. ag y y y Y AFi< Y Y Fy F PA p YPAFFFYFF Y FTRPR :ΑΐΥΒΡΒΒΒΧΥ/8ΒΐΒ:ΑΧ/ΒΒΧΒΑΑΒΒΒΡ1ΒΒ»βχΧ»ΒΒΚΐ8Χ:8Β1«ΒβΒΒΐΡΥΡΒΒΥΐΒΥΑ| BXBBFYPDYBXXgBYFXPitBB^BYBABTXDFYYBBBPP'FPFAXYBKXAYXXAATBRRBBRTXYB RAAX'P FXBFpAYYYRPFA BABPFYRXAAD I KFX YF.P.FAX Ϊ F YRPX YRARTF V PPYX H XEP lXAiOA8XOA8SiSAAFWAXFFAAX»X.iF0FA:XA80XiXAWffFAXiFFFAFAAOlA^ FAYS PPPi APPFPA X ' ^x TAP PPBYP \ PR /1PPP A I I F 'ΆΤ AY p'rt y ga y PFF8FTF I FFFFrtA QFFF A i A a a y y FK FA X FP P.A YF X XT PAA1 γ Y A A X Y YAPP FR YA FFP A P. FAY X X.p -I YAFFFFAI: XFFFF'YXAYADAYDAY ΥΑΥΥΑΡΑΥΥγΑΡΑ PAPS FAKFARATAF FFYsAAAYT :ΑΑΥΥΥΤΥΧΥΑΧΡΥΧΑΑΑΥΧΑχΤΧΑΧ7ΧΑΥΑΑΥΪΥΥΥΑ«ΑΑΑΤΡΑ.ΧΑΥΧ:ΥΧΥΥΑΧΥΥΥΥΥ SPPYBYAYYBQFPABYIBBBBBBBAPBBSBBBKPAI+YSSSXBXFQOyBIB.PBXBBBBBBPiP X'YXAYSFFXABXQBBVYDBBBBBXI SPXBRSRSAFFBXDFABBBAPXBAAAF0AY8XAXA AFF , FI \ , Fa X HAy f <>A F AX R©\FF a PFS + A R\ A

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    200/338 κ,»γ gg i

    ί.ΡΆ

    X5 :·: x-.'b.v S

    O

    PT

    P£, w

    3V ,,< A MM Μ Apgqg, M; ~ V |> W g m 6/ 'M M ' M 1 T * 1 'W y jgg ggg

    Relotigo of andoos

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    201/338

    Optimised

    OIS-Aeting Elements

    SplWGGTAAG)

    Spdeet G GTGAT |

    RGyA(AATAAAj

    Por/AvGtTTAAA;

    OestabGGngtATTTA)

    RetyTtTTTTTT)

    PGyA;, AAA AAAA,/

    Optimized e

    0:

    ivira sS

    Optimized

    After Optimization fefex Dfeet Repeat; Slze:14 Dbtenee:S94 RreqwneyG Mex Inverted Repeat; Nene

    Max Dyad Repeat; SGe; 13 Tm; 49.1 Start PesGena; 2322,3031

    FIG. T3E

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    202/338 χ\ χ\

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    '' αο

    203/338 ’ A ϊ:· · '? 7 .·

    FIG. T3G

    WO 2016/205711

    PCT/US2016/038181 ^04/338 gg irf ατααρραα fgi ;g igtafgrkaag arfi fri iggfpx isritfpfr ira

    PYRRR X X ARA PAGVTPPPRTPARRAMPIGGAA PARARKPAPPPFPARRRRGIGTRLGSGA PFKXGRFG^:GAARRIPPDFIKIFG<GPFFIGGGRAATAAARRGFAIX/TTIRTAXGGXIGRGR ''ΆΙΑ'Ά :k! '' FGGBI iri 7Γ2,'Ο’! / L_f AF - F GIG F P'GRP 8 F ''AG'

    FGPWAXQAGXARxRRRGGGPPARPPPYAQQTGGSGAXyPRRRRARRQXAAYTATSR'RGRR

    RFAIG RAVFAAVRAF I1 FYKRGGI IAFAsPTVRRGPIIPFKR1 I 1. MI AFAFPA IF MIFF'

    FRF, GGG'FFM; MG AAGG M8FGFF AF FRF VFFG RG'GU ,A’F\> G'MGFFMFF I'NARR X ί R F i M 1 I 'IGF ATM,' 8' M IΠI, I, 1 FA FPPATFR p A F i IG FRAG G M\RA? I' - F RTARRAFMFyAPIPPlTPIARRIVRAypRFRRyTFQRRTAMGXRRRFpSRTAARGAAQA RR FRRXAII AI RITGTYAA IREARRRFR KF IIR GR A? ERRATPYRRAY GA LI Γ GAR BRAF RT2AARRGXSTRRRRPYR.I8GYRARMlXWGRARPISRGRAPIATPMBXlFlAyRRGRYA FR2AATPAYAPX8RRTRRGRRQGYR.XSWTYXSAAAIARPPRRGRITAFAXYPRPRARAST G?iFIA8ITPYRI8GRGRPPl_;RPIIXFX+A8GMARYGAA8TRRFTRllFRX:GFIaTAIG'YKRTI: ARA A'G IP X AFP I GG1TRAYAG XI REA PIG FA A RA '1AARYAYG YAQRPI GAG AM a v ;> - -xx ' g _v\\ F ' ' GM GM A χ

    A< MIITAX ARM FARM M MAX GRAAFF ΐ M IAEA' FAX T c GGGRF I MGG FAX FI, MRGFAMX'MM R'RiGFAFG'lYyF M TAG RFARX A G'FMFYPRF - A MM'MT' GF IGIRG GAR' IΜIII 'Y AAR ΓIR1II I ΤΙ ?X 'GYYR F '1 F1 AYR AA F R'< F FA ?F1'F 1RX RAF F IGF A AGRI G\F' FIT GF I TAG ΚΙ I RIGA 'G' FRF IR I R FGRRKRRG FI FA 1G LTRTI1 RAI AMA I GT RPGKPI RI MRRRPFDRF AEF^: R ApGAR AYRARYGRRA A X'TFRPEQEGGX I RPR , , A ν'A A’ *' ' G ' ’ I I, G G \ ' ' ' I M

    18 RGL FA PF18XG APRXQGRYYS

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    205/338

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    206/338 rt**

    Rt

    Vwrt

    7's>

    rtrt·*··'’ >4«'; BY ,4,,

    21122 m sO'lWfWlM Wffl

    -4-¼ « ' -o--0/-- -·- --- ->« - -«O- γ-y ^:4-.-o-' · - i 4 - l.r- ; - -- X jg_ - -.. -.............. .. 11.. 2 ..ll/.. 2., - -II J 2 - ..2.. - 2.......

    it x /YSGXR itt

    417.0

    Fotltiot of codons

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    207/338 esthction Enzymes

    Optimized ·: ? x .·:· 'N^: . X ·.

    χ·Χ _ XXX

    X L o

    X·' :A

    A

    X·’ xxi^<X V

    X Xx χ x ' /I· ’ ' ιΐτΐ

    Mr a

    XX· <·:- <

    XX x<

    A

    CIS»Acting Elements Optimized

    SphcxgGGTAAG * 0

    Sphce(GGTGA7j 0

    Paly A( AA I AAA) δ

    PMyA( ATT AAA) 0

    DeetefcdlaingC A TTTA} 0

    PelyTfTTTTTT) 0

    PelyArAAAAAAAf δ

    Antiviral Motifs Optimized o

    After GpfMzatimi

    Max Direct Repeat: Stee:14 DAtenca:S2S FreqyencyG Max inverted Repeat: Hone Max Dyad Repeat Mena

    FIG. 74E

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    209/338

    X X

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    210/338

    XLF RL ATHAYPLPFYVRFELRX'Xr R7FFYXHAKF TLRΑΥΧΥΧΥΧΥΓΜΧΧΑΑΥΚΥ^ 1 .XXL YXRAX.'F IAFFSYGFYKLTFLAEFYDVYLFFPYXYFFDGFAGFGAKGLQAYLAFE1YKF1ANGGKYHAY ΥΥΑΧΧΫΥΧΧΧΥ2.. YYXXYXYXFLGFYAX/FYYALEXXTYYXAFXL/YXFARFFX/FFTYFYYXFXFFY/FXYFFXYSD FEKXn^:AX.AYEEYEAHEFAEX^:EXFECXX.EXAXYEQEAEAEYEQYYF'FETAEGEEFFAAE.F:EEGY HFEEY RFXYTYXR 'XXX. L-'fo X YXEA-YXYXXX 'FINER.XΝ.'.ΥΠΠFRRFF EF FAFYE ΡΕΒΕ RFT. g rex' ;rfr yrffylyf''x *. >,y.ya?. everyyfyfrfyrry ~ύ we yr-r< <s lyrrfrfe : EES XXGARGGFAXYYYR'X EDGY YVYAAXF SSEHE EEAEAETGX3A.KMEEEEEGEFY Wffi LA FLSQA1FKYTAEF'^XR''\\ RGKEGEYprEGX.G.GV&FPTLBXnXYBE~ EXXfo'R F^:; EPFAGF YXYX. LA X FXGFXX PE Ύ x X . _x EREFREEAXR A'AFEAFLLTY FYY RL YRE FX.FYGS L X' XLYGXX X.iAEIFTGYF<ESEEESEiEEEETEFYFXG3FGFATLAFGEDEEAEXXX ΧΒ.ΈΥ ΥΧΥ: .X FGYYLA ΕΑΕΥΧΑΧΧΥΥΧΥΥΥΥΥΑΡΒΥΥΥΧ: IY QEMXYYLXEEYXXELFFYVEFY EGA! AI EYFPRFERYEXFL 'AF.GF YR RPX-FXG'EFY LRL'-^V.IH UFA L'Y.HP'YI AA' J F.'YTFF ,4'G?F RXRRR XR X'sXRXFR-XF.FYXLFFFFFF3 XF'' XEY.FF'ΆEEVArAXXXYYFXFAFPFAFFE⁵:RYFXXAFX.XRXF F2.YAYYYERY.XFEEEYEERFEYYFEERF XGR YYXYGEX-EYE FEE iXEXRXYF XFF'FXFLAXY X X FX.YF XYGXY AER X YU EXT FY FFYG-FXYYF F2YXXX. Y EXXAEFBELURAX’P XYXYRYXFX.X XFYF FAYXEAGXETTIXXYXYYXEYLEX/EEYEEYFKX/QFVYGX. YEGXXRYYGXBXEEXBsYYYEXGYFGYLYX ELY FEES XXXXXΥΧΧ^: A IRGXEGEWF XEX EEGEE.BX/L Y LYYXXXRKGF Y ΕΕςΑΥΥ Y2XY^: XYYXAS VYiAXY TQPXTT'P Y YXF1LAFFEY EF XXEAELYXFXXF X. YP.X EGA AYR; ΥΙΥΧΒΥΥΕγ X YR YGXF'FXXAI X'YXXF LV<FFAPFELFiFY/YAYGlY^:XGEEFALY2XFLXX/XEVLFX2F.AX2r^:RlG:YYFFFEGLYFFFYL:YLXY XX.R._V. XYXPFBY YFY -<HXL '< X F X R LYEX'LR Y AR A GE X ?\\Υ XP FF .. EX'AFF FAX-FLY FFR ^ΥΧΥΥΥΧΥΧΥΥΥΥΥΥΥΥ2ΥΥ22ΥΥ?'ΧΥΥΧΥΥΕΧΥΥΧ2;ΧΧΥΥΥΧΥΥΧΧΥΧΥΧΧΥΥΧΥΧΧΧ^<ΥΥΥΥΧΧΧΥΥΧΧΧΥ.ΥΥΥΥΥΥ2ΥΧ F.F’X X NX ΆΑ2 X KFX'FEFHI Y?X.AAYY.FXY. L-ALP.YXYXARYLBLP XX. FFYAYGFY 'FFF FAX. ASF' XY X RFAAAXXGL'XXX X ARAR XAXXY. FAX. FF.Y XL. LG FR'E R A X X UR Y AAAYYRAE

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    211/338 ss

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    212/338

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    213/338 estnctlon Enzymes ized

    N < ,S < ,· .''•'K ZN 2⁵ -2 .ZN ;0\ t $ ' ' ( s'

    CIS-Acting Elements Optimized

    Spilee(GGTAAG) 0

    Spltee(GGTGAT) 0

    PdyAiAAIAAAl 0

    PdyA: ATTAAAi 0

    DeetadAAeeiATTlAt 0

    ΡοΑΪΓΪΤΐΤΪΟ ' O

    RelyA(AAAAAAA) Q

    Antiviral Motifs Optimized

    A Per Optmnzauon

    Max Deed Repeat: Size: 14 Distance: 111 Freqeeney:2

    Max Mxerted Repeat: Nene

    Max Dyad Repeat: Size: 13 Tm: 36 A Start Positions; 1027, 221

    FIG, 75E

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    214/338

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    215/338

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    PCT/US2016/038181 ϊ 16/338

    YP YYS XPYY J YS I pF'I YE FEZ FI YE F FP PFX PPPEFIAPT FI FAFF PIAYPFX I PIIYFIA YIEEYFDSYXPXQFFFEAIFTEFSPXFPIFEIFEPEEEXYIOEIOIIYEPEEEEAPEBFIAPMP YEYPYEEPSPYYPYFFFPXASFEYIFPFIEKYEFFYEEFYYYSPFFFFTTYFTEPHFFFQ :AI YYlPPFFiYYYYPIPIFFXYTIFXFFYFYlFP YAYFPpX IFF FIX STASI: AYAFFMYIIMXFT/PIF/ PA'S i FS AAP F\AS I IA YET I' τ Ktvgp vg;A ·' ' _v 7 x/w i g' w gy gy _: gpr\t q_r;.

    X FFX XX YIPXYFX Ft PI ΙΑΥΕΙΎΡ^λ’ΆΎ IEEPYFX FFFFXE 1' SEX vPPFSSPFEX

    A 1' Ά AY AS A, ' AY A F F PAA I A :TS χ MAX 1 FF\ 1 FSi FFYA PFxvAF FAY X TI F FI ΧΓ P T PE Y' FFFPFPE YFIPI AY VPPP PS FIT S FAX ;PPI F FFI X PP FYIs 7 F XX X SPY FF FE FTPS YFPEX AF X FYFFE-1XFIF FFFF FI F F x PP X XFPPF F X F XX 1 IF P I xa

    ΡΕΙΡΡΙΕΕΕΥΥΡΥΕΥΥΕΓΕΡITS BSFPPUIFPFS YXPPY'AYIF Y PFAFF FT X FFFF <F

    YYlAYXsDPPWY.XYFYXPIFYPPBFPPFFYBYFEPXXiTEFBOEEFXXYFFYBEgiYFFEYE iYKYAEBFF:FFFAFBFFFADCFKFIYFYFEETEEAlDEEEYSFFFE.FTEEYEETEEFT.F.E YPPYYFPXAYYYYFKYFXYSFASYYYIAXAYXFIYAFSXFFYYYFYIFIYXFYFYXYFYAY FFFACYKPFYSPPMFPPPKPXBFDPAFKPFBHHAFYFEKIAYPXFFDBFYPFBKEQFAEP XPIAFFEFFRLPFPAKVPRFLFRFXEIF1IEEFAEPRIIIXEL AIIII7AGEXLKQTLLDSH YSYYFFFSXYTFEEAQEFETEEAFEXXFEFEYYFFXKEFFEYYXAIAAYQT.SPLYYPPYPI YYXADXFA F FKFEFFYYEFFYYFFPE A1XA FFXAPXAFFPHKPTE FF:FYLKFYF;PTFE FF 'X X It x 17?XFT FPF FY YF ΑΥΤΙ X .. FsF E EF IFPF;FXF', PP.. ΙΎ FPF F11IP IF E .. S EEIEFPI A- PX TAPE FFX SPP1 AY AFEXAF 1 ' IE PX AA « ?pp I FFAY 1 AY A X 111 SP F- X t XI F IFFSFXPYIFFFPIFIJYIFIIAFPEFPFX'EYIIA'XYYYIIYFIFIXYYAIFXEEYXFFIIYSPYYXYIFFP

    FPPEPPPSPYEPFFPPRPiXPYHIRFAEXAFXPAXAPTREEFXAFXAPRIFPRFWXAFYWE

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    I

    746 44 74 AA 24<>6 4446 4944 4414 464« gfointivo Fes it ion of codam :4 AA

    7. ,x \<7\x7

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    PCT/US2016/038181

    Restriction Enzymes Optimized

    219/338

    CIS-Acting Elements Optimized

    Spiee(GGTAAG} 0 r Gy A: AAI AAA) 0

    PGyA/ATTAAA) 0

    DosGbOMMg(ATTTAt 0

    ΡΑνΤ/ΤΤΤΑΤΤ) 0

    PGyA/AAAAAAA; 0

    Antiviral Motifs Optimized c

    HG. 76D

    After Op 11miz At' on

    Max Direct Repeat Size: 14 DIetanceilSO Frequency^

    Max Inverted Repeat: None Max Dyed Repeat: None

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    220/338

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    221/338

    7Μί11:::'1Α7>'+7=17,':2ΐ7:1:77ΐΤ:ί7·1::::·Α=1&7β'Α^ . ΙΆ.. . ' + i Ί Ά i : 1/7,1' \7. ^s.Ά . .7 \.1'?'5 - 'V,\ x. '. , χ . 1 .'T \ ,'7 χ

    -irt/lorCWAtoATrtGi.TxCATfl'Arttofrtl+TTriirrtGAcrorirtTtoWAS-r/toxivTTA'tlCCrttortAiCGCxtoAFt'rtfiAirtl .119::71Α1'77171+71':::+:+71. :1797.:1 Alxll7:,77llll.:x.y7+7l9i7=:'l=7l 7:ll=il+l97:=:i::97:77:7l9=:9779=i7+ ' ' , ' ' '. χ .', χ ' χ' 1, xxx ' X χ ' ' ' X X χ 9 ' ' ' ' '

    7171++7+:97+1+771+7:90--971+1=7+++:=777:/::++7+7:777-/-11+4 177=91=117 = 7-17=+:97+/7/1.+=-7=:79/7:+++9 + :+= 7+7+7 +7+7 iiii+l- :1::. 7477+77197+++9=:/71:+ :177711:797=:,111:77= +11, ::+19=:,:9:777:771+, ++7:+11,7:99=:,1:1+:7=-./+.: SAsitOiiiiliOAiiiiiA

    IT-1ΐ:;;?-:ο:ΐ;7::ΐχΑ+7\Λ 1:0-:0:1:1-/0.:7:.:75.:: :/::1:11//-7071. :;,ΐ:?1':71:.1;χ7:ο:7χθ-;χχ;ο;;7;::77Χ4Αί''χ.:ΐ7Χ.χ.χ:χ; 9+l+ll+l+l\+9777l97+l:+li:::17=77++77:l:iAl79=977=:.l:9991l97+7=7l::7:illl»+i:.i:illll/:7991:'9xA77al+77: +:+=+:9::+1=::+=91:,.7+1.:+11++:: + :-.++71:::+71-7'::: 7::11-.-/+1+:../.+++, 91::+.:+'ii:.'1+++, +,:.9,1=::+=91:-.-7=:11-1,- += =711:·.+=1χχ’··1-·:+χ.-·=::=:1χ',χ.+7+·9χ,1·9χ.:

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    222/338 ^x V '' 7 4 , v , X 2 , , ' . \ ' ''' ^x '

    0 t /0 4/ 44 1 /- -7/ L't.?,'fPC', ^v - 40/- 4- 44 24,,-74 '440 2-020-240,7 .7'

    14 ; 107//7 400/-,00/2 742-0/4 > , ,, ,484-48:2. 0400402-7, ,4' 2 /47/2 0/1: /,-4 27724/7, -5,202-207-7:2,,77 -44,42 4 4 7 22,' /4 ,: 7 22,

    0: 24T4 22'-'42 /7472 71 7070410^74 44444-44442 ,27 7 724244V 40070/ Γ474 2227 41444442 4244242 4 22424 424 4444'F 1200470 4442444414442242'24441Γ 4/4/7 0 1 4, /24 00,'„ 4 1,12,14-4 2 /.,4444/-,444 T 11-1 01/-.14 242 72- 77' ''424,22' 24044422 4242,, 144 2427 0070-740 ', 2 4,2/22/ 444,2,4 444/-./-24414,414 42444, /./04:4/..2 2,4,40 4,4' < 020/24444/41 1 02,44 X 224 242 44 2244 444,. /../ 41441142 4242 2/4/-4.,,1.1 ,_; / 442442220 ////1-244 00424?2'20 4244412 4444212411 0X227X 22442244 /42-0,, 04 2'4'4 τ 4 :- ./402-414- 4/2 - 14-4442-V'- 44-- 400-2'/-020-0 / 4041 4,742-44 '0: 44 /-, '1/2 2244042424' /7,' 22 1,244/7404'442 04/ 2 1422 4 2244244-4-4-422,/ 4 0' 4 41/1 1/1/ '0 0 04-11'2 /' ,114 '421 2-/ / 04 / 4 40'' 0' '1X :- 414121 0' 2 21 0-1/4 //', 14 174212/022 01-4,-4 02/4114444-442: 022 24242424012244 2072 /00 2/040 0 2.1 7-- - - .,02 '2 X 27' / 1- 0. : 2- 2-7 -- 2 Χλ',2' 1 02-': .. ,:/-44: 4

    2-472-7 --77 7./4 00107 -447 -7 1 : 0 2 72 4''0/02 /:4,, 2744--77 '/I 4 770004/- 2-7,72 '7 7 '0 ' / 0040' 7 4'- 7-7 -' 07/10/, /241, ,-/0/- 14/ / 017 01 ,1-4-01,400 -,, \,4' / 0,44' X -700,-2 .-1.,4/41

    V, ,

    ../.20./,4/..+2040

    40000002012 0X^::02/S2/2 0400000000022/l:221272027 20000X,002407/0 001200000120 X 07240240478 000

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    Ά ΆΆ ,i-s^M ' 4;»> ΗΆ Άχν ΆΆ*

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    On I

    S 6v J,

    5$ f i§7$ 4' $«· ' A ··> $

    5 χ * \ &+S·.

    ' lit t ftWttertA -to is r wt ο tor to fto to totftfc g fA PR r y04... ... v ..;.y 9 vy :.,7/, g,..... ,g'/g .//¾),;., ·$

    4<X-Xx·· ^::x->\-x··

    Xkto?

    totototo

    0 P^siUoR of c«

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    Restriction Enzymes Optimize

    225/338

    CIS-Acting Elements Optimized

    Spfce(GGT.AAG) 0

    SehaetGGI GA t1 0

    PGyA(AATAAA) 0

    PGyA(ATTAAA) 0

    DeataPAenMATTTA: 0 fWTibTTTT) 0

    PelyACAAAAAAA} 0

    Antiviral Motifs Optimized

    After OptMiAoeo

    Max DkeM Repeat: SMeitS Dleieaea:.2O43 FrepuaaeyM.

    Max Inverted Repeat: Size; 13 Tex 41.,3 Start Positions: 14SB, 2633: Max Dyed Repeat:: Rene

    FIG. 77E

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    YPP'.,Υ,Υ FPF.7 F V A' TIP PELF'F YP FPL P': i FPPY <'. FPPFPFCP E A'FF YPPF P F FY HP' FYDSSLFRMFLASIEFtElYAhAySPoPAYKKDHFYFOFLFLXiDYIFAYLFALIYOPPYSY PYpAFAPYPoLKY EP LEPL FL I KE ILPE PYLEYLLSL LAPP PLPLTL P L KEELPEYSPLA ,'V G\'\ og ; o ' K\\ gsa ' ,v,y ' X go; \ ; 03; ; OFF ; ^OF' oo i ;;o APP > '

    PP F. FLAP. PALP PFYAFY.uPF IPFYPPFEFYYP.F: ΥΡΡΡΡΑ'ΡΡΡΡΑ ΡΡΡΑ,ΑΈΡΡΙΡΥοΡ QLFPPE PPFL.PLPFPELF , LL, L FL, ...,< YLPFPPFPt. FYLFHF.LFFs PPF1LLL iLPLTPxLRPPL PFYLjLPFFYVRLEPpLTPPPFPYLPFHYLIYFPFFFP'FPFEyPPKPlYPPPLPPPPFLIH G£PFTPLMFLnSPFLFLDN7F.DPPVLPALATLGLH£PPLALHn:VENYE.PPYHEAE0LLP

    PP _x χ ' , ' ' , Y , ' ' χ - P χ ' -A , > ,, P \ ' ' ' ' P Ax' s,o \ P P'PL'PP FPL F Ft HP P PFY F.FPF IA L 0 PP FPL L PL 5 PHP ML I L < FL ALLY J. F L V F t A ? F LLL pYLYLPP'tY0PAi:5FPP0PPPl,EPPPLPPPKFSF.FPLLL.oPPp?'LP3^:P£PF'oPFPYPLYLLPPPPEYLP L'CYPLPFFPVF FPYV'AP' yPOL ΥΡΡρΥΡΥΡΡΡ,Α 'P''FPPP TLVFFFU FPPLAP 1YFPPP ALL :p / pp _? p; ;,: 'pof pry LPF?i FPPPR; ρρ,.,ργ A F FPF ', YPP F F Y'YVYPF xP, ' 'APPLY-'· \Y 'x _ PNP's ... „ - P \ xx xx χ _χ

    3. , ’ i !! . x USX ., . , -x . <’ ' ' '

    P O ' 00'

    - s O 3' \'O' _A'x^ p';. ; y ρρν 'p\ γ ;ο.γ-',Ο ', γ- : v HP,' '♦ OFF F 0 χ pl a; ; p f η f y : flap ' :h ::: ? f y p f f pp yap pp; p y l pf pp f ' lam o pph l p p p f r f pf PPPAFPYYPPPt'PPL ,'' F PLOP ,'',' LY'F LPFPLPPy H-t - p<\'> PPPPOLoPPPOF-HP F U Y ΓΡΡΙ Γ YLP YO AJ-OPYP 5 ξ i t Ft- P 0L\'-HOPFF - 0'O '. 0 '0 : ΆΠΡΎΥ FF' F . Ox'tx^s 3 : ο t ,,,χχ, ,χΝ *? ! F . λ o ¥, Ό o : ι,χ': - r ,χ,' ? O' : .; .Όχ :P , o i , y., - -u o,.

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    ,<-Ο m

    •*N« Λ\

    2 V o

    AMyg •OX

    IX ;« x< ·$% .«·: x< ·;«: <·.- ;« <« «·.:«%.·χ·. ς «· %·> ·><·^: ·«· ··«< «·- :« ·.·.<: w. .<·.· ·χ%- w <%%<< χ,· TAXX· ·.<·. χ·χ^*χ«.· χ«: χ< ·χ< χ<< ;·χ· ·.·.<

    a + Β, ,Η'\ ;\.ΆΒ 1 } Ο -Ο s- ρΛ , a 3 93 : 19^

    Ο 30 * * ' > ⁴ Μ * I ν^⁸ V ^fW

    UW nS4 DO Ό'Β ReUUve Oaasitiassa of t

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    CIS-Acting Elements

    S ρΐ rcer G G T AA G)

    S puce: G G7 G AT) GGyA(AATAAA) RolyAi A'? 1 AAA) DeMabMzMgt ATTTA / PdyT<TFTTTT|

    PcA AC AAAAA AM)

    Antiviral Motifs

    Optimized o

    o

    Oi

    Optimized

    After Optimization

    Max Direct Repeat: Size: 15 Distance: 1842 Frequency;2

    Max inverted Repeat: Gone Max: Dyad Repeat: Done jr’SZ’* 'ΤΟΕΞ Γ/Q£L

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    X

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    AaAΟάΑΑΟ $ AAb ΑχΑ.χ ΑΟα g lAAA aayA ^ΑΑΑΑχ·χ>ααΑΑχ>χΑΑαΑ>ΑΑα YA.xAAAAa AaOaa Α.Ο.χ^χΑαΟΥ s*AOxA5-xiA<A.\.\51Ά AAAaaAOaaAAOaAAAasAAAAaaOAa ^YxOAAiYbAAAAA^AGsAAAYAsAA’AAAAO'yAxYiAAYxAAAAAAx.AAsGAAAAAAOA: ΛχίΑ· Av ' .·;< ; vAA \.\>%. * 'Ά ΑΑχΆαΑΛ ΓΑ l AaAA AAaGA \> * lA A -^: A:\A\A A-\ ^:Λ>2 ΑαΑΓΑ\ΑΟ, ί V AAvAAvxA-Av. ^: ?· sA A xAaA \ΆχΟ,> A A 1 i v \nOOAAaAaa < ΑΑΑϊ aAAa αΑΌ .- PA X^; AP PAA A ί ^:'ΡΑ λ ^: Α?Α ΑΑΑ ΑΡΑα A. ΑΑ- .-·. ; Α ΛΑ ΑΑ'Γ a-OaA'a * ?ά^:.Ά

    Αν.' . X X AA . χ Λ\λ XXX x A X χχί'\ X Ai'x X X X ΑΆ\ X' X? ? V X¹·; Χχ' χ X Άϊ χ7 XX χ\ X ϊχΑ X i X V-'3 X X \7\ Χχ^ X χ^ A * V X x5 A' X X Χ Xx ' X X x' X X

    AWWPSaBOyaPWB^

    7·εα A? A .aOaAAsayA -GAA Αίγό'ΑΑχ'ΡΡΡ Α\χ A A ΡαααΑαα' υ αΑαυΟα yaaaAXaA/aAXaaOa.AaOAAanaaPAaAaAAaayAAaaa'A.A'xA'A ΑΛΑΑ:ΆΑ:ΥΑ^;χΑΑ^;χΑ'ΡΡΡ7'Α<\^;.Ά’7'·Άι^:Ρ.ΡχΑΡ^:ΡΡΑ^;5ΑΑαΆ?\ΆΟ^;.Α';\'^:?ΟΑΑ;ΆΑΑ\?ΑΟ7 ^:?;Ά'·.-ΑΑΑΆ< < ΑΑΆλΡΡΧ Α· Α Α-ό/ϊ Α PAv^PyAyAAA^aAAfSaA 7 ΑΑΥ.Α AAA Α AA ί AgAA ΑνΑ Α;ΧΑαΑΑΑα.2 AvaA-AaPaAxAAAAAAA/A2 αΑΑΥΑΑαΑ αα* •Α’.ΓλΥίΥΐ. αυυΑϊΑ α.χχΑ αΑχ-αΑα α.··ΑΑ’αΑ.ΑΑ· aaαΑαΑαα 7Χ,Αυ.ίν:άτλ ΑΡαΑΑ Ααα Α7·>αΑα.'ΑΑ·ΑχΑΑ.α ΑααΑ α.αα a αΑ Aa.', a 0ΡΆΤΡΑΑΑΤΡΡΡΑΑΡ\?Ρ7ΑΑΡ:Ρ?7?Α0Ρ*ΡΑ7ΑΡ?λΑ^??Ρ^:Ρυ’ΤΪΑΑ ????'\”Α?^'?χ«.??ΑΑ\?.?·?Α7Τ.ΑΑΑ<Α-Α?Α?7Γ2?^:?;Α.ΑΑΑΑΓΑχΑ'Α'\ A AAA-Α.υαϊΛ'ΑΑ'ΑΛΑϋ 7- - ΑΑαΟ·? Ά <ΑΑΑΑΑΑΑ χΑ.ΑΑΑΑΑΑ ί A?? Αα/ΑΟ-Α ΑΑΑ’Λ.'ΑΑα ί '..ΆίΥ^χίΥ.ίΟΟΛνΛ.χΡΑΥΑΐΑγ^Α’ΌΑν. aaaaaaA aaaaPa .α αα.Α'ααλ. .Γα α αΑΑΑα. ΑΑΟαυάΑΑαλ>Αααα/ΑαΑα ag?AaaAAAaaagyaA.a?a a aaaa

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    234/338 ετμττ^αττττυιχορτυατυυχερτ owrcmaLFFYKTFAFaFTXYAAKTFARTTLTTKAFx: llllfx ey fftlfe γρχεμχυυκουροχΑΖαέαραγκκχυκχ : feftkxy aletoot : ;f alley: ΥΥΕΎυ^; jo;: λ; yet , fle fyrlyayl fee yf ; εεύ lffyl \eeee F FF F : EYE EYE ELY Y Γ E F X LE IX F Γ F EE F XT EE RFYA LTLF F E FEE IFFE F YVX E TXT Y'Y F LEY FUUFXTRLR τ RLYKEELYREYL EEFLEE, ELY ELEEEEE ELY FL E FY'YE E ALEYEY FLYER I RFC YFYYFFYP0EEmEYFiYllEmYFYFYI^:FDOFWBYYFE0YYEYYYYKYYYeYlFIKWFY. AS F ΧΥζΤΕΧΥΧΥ FAe deal d α'χααε,υέυτεχε f f l i aeeaxya.ee x ee let leey lf faktfttt d FEET ITALY XRX: EEEFEYFEEF TF FFE E FEEL ΤΕΥΕΕΕΕΕΥΤ Y F FF ALY EE A LETT EXEYL X FT ATT ' L s> , R , ' \ ' '' ' ' E ' E , , χ V Ύ χ ' \ ' '^N χ Y

    OF t r LA EXT FELL FI1Ά TREE LEY EY FAY EE E FT E '? LT FE FF E LI YE F FEE VFF FT EE EEFF L EYRE FLEE EY: FEE ALEE F E A L L TL FELL. E: X EEALYPL FEEL A A E FDTFF EA FAR X SE AT E X AELYYAXAEE FFYFELELF.LEEFYEV.AY.EFREEERTFEEEEEEEEFFEFYFYLYF.ET:TTYTEYFEYFEEEEEEEYFIF AYLETTLFFFFFRF FFFFFFFFFYKTEF PL LEEEFYFE..TYEEE EEFFQ X' FTFTDAYF LF E LEEREE ' χ 'e a Y A , ' F χ ?' _ ' ^x Y> , .'χ ,\RS?Y V Υ: E ' FLa , χ ,

    EYE AE; EEL ELL EYE AAX FTLAE Y XAAEEFEFTL LAXFAX ATE YYAAEEI EETFL? TRY X YPEX? A XT'. Hx'FELxYhY EYtLFPAAAEAAATLAA'XY ILLY ALLY ELY XX'FEAE LEYA,'I LEY A I XAQXAEAA E FLKLLPTXYRFLLLXXFFEEFLFALPQLWFAYFRXPXYRFLFLFQAVHQL AR LAYEYEYX XALLEY X EKF’YT FJ KX FE E YEA ? JSYELVREXLFFLEYALLEYFFX. X ELLhA

    EYXXXEEXEY ΚΥΧΧΧΧΧ/ΧΕΧΧΕΧΤΥΥΕ/Ε/ΧΕΕΥ^ΕΧΕΧΧΧΕΧΕΥΧΥΕΧΤΧΧ ΧΧΕΤΕΧΕΤΧΧΕΕΥ'Τ'ΧΤΧΤΕΥΧΧΧ/ΓΑΧΧΕΧΥΙΧΧ:

    FALLFXLFYEiRaELJEYLERLE;EF'ELFFFRTLXXELLREErLTEEREEFRIEEEREXRYX.XLFVYRAREER a 'LAY A T AY E. AE AEX AYR E AFF EE Ύ A\ e a, REAL LEAL; F E FF EY g Y'' F a b E

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    Gt

    GO | · χ, ,i,\:

    BO X se x 4© t t ί; 4'\< tw

    1¼ 1 + -.4 s ¢- rt? V. * rt ' « _s ?\ 4 rt· - ' * ' 4« «\rt« > V < ΆΡ \d A « \ MPA ' 4 ' v '

    B+/Vi+TiXVr ,+4:4-7,,, A-:, ... .. ++ ,,7 A/X; ,7:417-4:-,,,, >«, ,, , ,,, ,,, 4:,,,,,„,,,

    -<4 ί ‘1 '5: 4*^«· χχ4 x · < ·«. <5<-xrt· <4:x> <4. - > χν 4x- «·\χ4\<· ·

    4440 •X w rtrtSxfc¹ -Κχ-·«\·>'<

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    Reel π ctio n Enzymes

    Optimized

    CIS-Acting Elements

    Spbcef GGTAAG}

    S exeat GG1GAA I FGyAi ΑΑΪΑΑΑ) PoAAfA'TTAAA; DeatabGztrtgtATTTA PotyT (ΤΟΙΤΟ PotyA; AAAAAA A)

    Anti viral Motifs

    Optimized ϋ

    Optimized «*·

    V

    Alter Optlmliatian

    Max Direct Repeat: Size: 13 Distance: 9$ FrepyeaeyG Max Inverted Repeat: Hone Max Dyad Repeat: Nona

    FIG. 79E

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    YEMERE LEPEFTEARSLRREFRFRERARGFTEWIKOELXAALAQALDEY'RRERRVXBRE HEPFXAM1V33FOFSKItOSYIGEEEEREARAE.Y FETEFETLsAKAFLELRRYi ΥΤΕΥΥEEEE

    Y,EY-Y'R< Y YAM-YY'FERRY * RRAMY-.....lEYAE'EKRYARTEREY'RTYIY T'YFEY MA YEYGD - YCP I TPs LE ΥΡΕΥΕ: RT-MAAP YP; E TP AE LEY-T W YES EEΥΥΆ-·^: E E LCYY E REE Y? T Y AYR ERE 313 3 FEE E VGSY;YEEEGYLKEGGLEEEATPYM7RRE'EEY3ELEELEELYEipIL7EYVE333F13E^:TLEEEER

    EFCVLmGFEELEFKTVSSTYELEREsSLRELEGGLSGEeELAIEESDARLATISEEIFDREG

    ElSSAXWBOZEWESM

    E'-Yr's <v eg s ΥΛΕ LAE-E, LETT L AYYKYP'APAPEFpEPrePY'T TEEFL ' YYFG ELY KEY: .K KA ALE ALE EE F EE A AETYETG A YY 1 REALTY E Y AE Y T EY7GE YEAYG A LAYTGAMEEEE EEK EE Y AIE FFFLTY FAKES ELSGKG REES LEE LSVT ERQEL EETEE1MTEF.E EKE F KELP KLG ALEEFYFEELYEETYAAFKLEEREEFl'EEE AFAT ?' GMREEYT YEKKYFKY EG EFE'.EEP LEE 1TJ LEY T7LAETAYYIMKLFYT FE FT? FTFGEFK TYGF FLIT LEE LEA Y TTEATTEEVL A ΕΥ T I? F E ¥ΕΕΕΚΕΕΑΑ0ΙΕΕ:ΚΠΕΕΑΕΕΑΑΙ®ΕΕΤΪαΕΑΑΕΕΕ^:ΕΕΑΕΑΑ¥ΕΚΕΕ7ΕΕΕΕΕΕΕΕ»Ε:ΕΗ YpER ' Ά S' sk s' '' s WPPY KERR”: R' YWAE ' 7 *='== sp-p -re Vr'ER'E? U t YK'EEEE I try L- ; EYE EEY ΑΕΚΑΓ- Y, T YY YYE Y .? A R L R.Y:'. ',Ύ ,Y 3 R Y ΕΥ RE ELF-?- F ? YE A' Y L ,R LT Y LEY ERR ;: ry pee ry prkv earr : >,- i -g a- > - κ - _x e yak : - fgaaerkr : \ v y- a, e y,-- ree r -,- -R-LA RREERR'R'RY A GY A TRs R ', p s' RR ERR: :RY Ϊ ΆΡΕ Y E'R P F: ': :'M EE': s < ' EE Eli , , : \-AWEL ,

    - - - A --- A- P ,

    FE' Y T R LEE KF EYE YE. Y YY FYYY'.E YE -1 FEY RE- TEL FE T Ύ R I AY P FY.E YY E FT RT\T„ I F F RTF, LEA ,-A RE EG YE Aus- -. YEsR ,- ,:,LEY RYY-YR Y RY- Y - F A? A E \' _v ' - \ Ύ 'RY-'- F-R.-'YYF Y R ,- i'A A , R'M ,. 'S'

    YE-YE-,'L ?RLRLEY?<MP GRAFT FAR

    A. L A'FE.'ARYEREY

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    241/338 >X OR

    GOCUAAOAACOOOAAAOAAUOLrOAOOGOUOOAGAU

    W0R_:

    GGOAOMOGCCUAOAOAAOUOCOACOAOOGOAGAO

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    DR ©A DA

    AycAAyAAAACUAAyyyAAyyycyAcyygGGyAGAy

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    A DR eycuAssoAcucycyyuwwucyACOAyyiWAGAU :M DR

    DUDUCAAASADDAAADAADAJADAADAADLADADAU

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    244/338 >8 OR gycyAACGAccyyyyAMyyyaiAcyGyyyGyAGAy

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    OR ©torn

    CUAAAAAcOcAUUCRAAlRGOMCUtAAAAMJAGAU

    8”ϊΖ*^

    FIG, 80E

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    Μ1 OR ecyoAOAACAyyyAAAOAAyyycyAcyAyyeoAGAy

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    247/338 >13 OR

    X χ Ά Αχχ , xxx^xxx ' , xx >14 OR

    GC€AAAyAcaJcyAyAAMOyiicyAcyoyy$yMAu

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    248/338 > IS DR

    GyuyAAAAeoOTAuyeeAyyucyAcyuyusuAOAu >16 DR dduduagaaccduaaaaaddaccdaauaaudadgd

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    1 / DR

    DDDLAMASAGUACCDUAGAAADDCAUGDUUCFJCAUDC

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    «WAX ORA rtibisrtitft 1 Emxl crRMxAl EMXX amphcor? 2 EmxX crRNA2 EMXX amplkon •Vs Λ EmxX crRNAlO EMXX amplkon A EmxX nRNAH EMXX amplkon s none EMXX amplkon

    GW χ\\χΑ ,',-,,Χ.Λ,Υ . χΧ x x'......? ^! . X x' . , 8x X x 'x . x\ , x x'x x. xxx, x . . .

    i®»;. '

    X E x X

    SSe'

    χ.ί.ΛΑν'ΐ-χ···

    E.M.X 1 iiSpAWu s. w·®’

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    A

    toto X?<XX > c-i ?·?·+ +++·+ A g-ί.·? +*Ά to? )b to< /to: to /to to -·.·.·.·+ .to +„.+ to XXXX< to +/==< :¾ :A • ··? ,to '=? A ?·χ·- .)./ A X-’-? to';- y: ·. .'·;·. ? ·. to =·.=··< =++ to? to? to? :··>=$ 7 ···>==; χ.Χ'χ ..-==--., .,-===.-. ,-==-== -/)3 $’' X . x= =. = 4? to ' to? ?M /=-4 ==-.=-: to ' +to? to:^-· to? to · ;-x X·., ··: A X·.,? to? W •=x.=·· •=x.=·· =·-·-·:+ =·-·-·-·$ =:-·-··$ ·:-? .).-5 / to 8 X Λ-+ to+ to M to: //to; ?H ·-.·.·· //to :/to'/ +. ? =··· y =. Ά: to + /? to to+ to' +++ tox< to 5 +++ /to? to ! 7 to? / to 7 ===-4== /A • , .==. to Χ ,--==.:. : + 1/-++: +/, ==>'; 'Μ A .y+ I'? ==---5 to to SSxxx X,<-< x==X; ?==+ :=,=== ====.. <xx-= to? A ,: to? >5 .: 5===., toto $===,5

    » -X..x-'Xfx, toto \=Xx-->

    i /1

    A b

    <1 ?== >^:K

    I ><A >==+ b

    •to to .===.

    to to

    B

    A

    A r

    A to <·=>, </

    W ο

    u,

    A
56. 57 )7 A )7 7) 7'5 A to \x<· a

    to .===’ to i

    0+ ;?x to to

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    FIG. 93

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    FIG. 97C

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    FIG. 100C

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    Ass : : , , , , < , : ,, A :SiS| iAlAiAlAlA-d .... .AS: s’} s as L ' SpGpA B SsCpM

    <$>··

    FIG. 100D

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    FIG. 101B

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    OoWsepyenee pot I TCACTCCIGCTCGGTGAATTTGG i AAGGGTCIGGGGACGGTTTGAGG i AGTACGTTAAIGTTTCGTGATGG 1 TTTCCGTTGAGCTAAAATAAAGG

    FIG. 101D

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    PCT/US2016/038181 randomized S* RAM hbr ary atte selechon

    FIG. 102A

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    FIG. 102B

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    FIG. 102D

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    Ci : ϊ'γ .;·:>¥ ·χί χν ν·· ΧΑΠ ί'Χ'ΐΧ S fi'iS:

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    SEQUENCE LISTING <110> ZHANG, FENG ZETSCHE, BERND SLAYMAKER, IAN GOOTENBERG, JONATHAN S.

    ABUDAYYEH, OMAR O.

    <120> NOVEL CRISPR ENZYMES AND SYSTEMS <130> 47627.05.2123 <140> 14/975,085 <141> 2015-12-18 <150> 62/232,067 <151> 2015-09-24 <150> 62/205,733 <151> 2015-08-16 <150> 62/201,542 <151> 2015-08-05 <150> 62/193,507 <151> 2015-07-16 <150> 62/181,739 <151> 2015-06-18 <160> 1595 <170> PatentIn version 3.5 <210> 1 <211> 7 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    active site region of XerD sequence <400> 1

    Leu Tyr Trp Thr Gly Met Arg <210> 2 <211>7 <212> PRT <213> Simian virus 40 <400> 2

    Pro Lys Lys Lys Arg Lys Val 1 5 <210>3 <211> 16 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Nucleoplasmin bipartite NLS sequence <400> 3

    Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys 1 5 10 15 <210> 4 <211>9 <212> PRT <213> Unknown <220>

    <223> Description of Unknown: C-myc NLS sequence <400> 4

    Pro Ala Ala Lys Arg Val Lys Leu Asp 1 5 <210> 5 <211> 11 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    C-myc NLS sequence <400> 5

    Arg Gln Arg Arg Asn Glu Leu Lys Arg Ser Pro 1 5 10 <210>6 <211>38 <212> PRT <213> Homo sapiens <400> 6

    Asn Gln Ser Ser Asn Phe Gly Pro Met Lys Gly Gly Asn Phe Gly Gly 1 5 10 15

    Arg Ser Ser Gly Pro Tyr Gly Gly Gly Gly Gln Tyr Phe Ala Lys Pro 20 25 30

    Arg Asn Gln Gly Gly Tyr 35 <210>7 <211> 42 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    IBB domain from importin-alpha sequence <400> 7

    Arg Met Arg Ile Glx Phe Lys Asn Lys Gly Lys Asp Thr Ala Glu Leu 1 5 10 15

    Arg Arg Arg Arg Val Glu Val Ser Val Glu Leu Arg Lys Ala Lys Lys 20 25 30

    Asp Glu Gln Ile Leu Lys Arg Arg Asn Val 35 40 <210>8 <211>8 <212> PRT <213> Unknown <220>

    <223> Description of Unknown: Myoma T protein sequence <400> 8

    Val Ser Arg Lys Arg Pro Arg Pro 1 5 <210>9 <211> 8 <212> PRT <213> Unknown <220>

    <223> Description of Unknown: Myoma T protein sequence <400> 9

    Pro Pro Lys Lys Ala Arg Glu Asp 1 5 <210> 10 <211> 8 <212> PRT <213> Homo sapiens <400> 10

    Pro Gln Pro Lys Lys Lys Pro Leu 1 5 <210> 11 <211> 12 <212> PRT <213> Mus musculus <400> 11

    Ser Ala Leu Ile Lys Lys Lys Lys Lys Met Ala Pro 1 5 10 <210> 12 <211> 5 <212> PRT <213> Influenza virus <400> 12

    Asp Arg Leu Arg Arg

    1 5 <210> 13 <211>7 <212> PRT <213> Influenza virus <400> 13

    Pro Lys Gln Lys Lys Arg Lys

    1 5 <210> 14 <211> 10 <212> PRT <213> Hepatitis delta virus <400> 14

    Arg Lys Leu Lys Lys Lys Ile Lys Lys Leu 1 5 10 <210> 15 <211> 10 <212> PRT <213> Mus musculus <400> 15

    Arg Glu Lys Lys Lys Phe Leu Lys Arg Arg <210> 16 <211> 20 <212> PRT <213> Homo sapiens <400> 16

    Lys Arg Lys Gly Asp Glu Val Asp Gly Val Asp Glu Val Ala Lys Lys 1 5 10 15

    Lys Ser Lys Lys 20 <210> 17 <211> 17 <212> PRT <213> Homo sapiens <400> 17

    Arg Lys Cys Leu Gln Ala Gly Met Asn Leu Glu Ala Arg Lys Thr Lys 1 5 10 15

    Lys <210> 18 <211> 4 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 18

    Gly Gly Gly Ser <210> 19 <211> 15 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 19

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 20 <211> 30 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 20

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 30 <210> 21 <211> 45 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 21

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

    1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30

    Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 <210> 22 <211> 60 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 22

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30

    Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45

    Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 50 55 60 <210> 23 <211> 20 <212> DNA <213> Homo sapiens <400> 23 gagtccgagc agaagaagaa 20 <210> 24 <211> 20 <212> DNA <213> Homo sapiens <400> 24 gagtcctagc aggagaagaa 20 <210> 25 <211> 20 <212> DNA <213> Homo sapiens <400> 25 gagtctaagc agaagaagaa 20 <210> 26 <211>9 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    LAGLIDADG family motif peptide <400> 26

    Leu Ala Gly Leu Ile Asp Ala Asp Gly 1 5 <210> 27 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 27 gccgcagcga augccguuuc acgaaucguc aggcgg <210> 28 <211> 75 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 28 gcuggagacg uuuuuugaaa cggcgagugc ugcggauagc gaguuucucu uggggaggcg cucgcggcca cuuuu 75 <210> 29 <211> 1388 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Opitutaceae bacterium sequence <400> 29

    Met Ser Leu Asn Arg Ile Tyr Gln Gly Arg Val Ala Ala Val Glu Thr 1 5 10 15

    Gly Thr Ala Leu Ala Lys Gly Asn Val Glu Trp Met Pro Ala Ala Gly 20 25 30

    Gly Asp Glu Val Leu Trp Gln His His Glu Leu Phe Gln Ala Ala Ile 35 40 45

    Asn Tyr Tyr Leu Val Ala Leu Leu Ala Leu Ala Asp Lys Asn Asn Pro 50 55 60

    Val Leu Gly Pro Leu Ile Ser Gln Met Asp Asn Pro Gln Ser Pro Tyr 65 70 75 80

    His Val Trp Gly Ser Phe Arg Arg Gln Gly Arg Gln Arg Thr Gly Leu

    Ser Gln Ala Val Ala Pro Tyr Ile Thr Pro Gly Asn Asn Ala Pro Thr 100 105 110

    Leu Asp Glu Val Phe Arg Ser Ile Leu Ala Gly Asn Pro Thr Asp Arg 115 120 125

    Ala Thr Leu Asp Ala Ala Leu Met Gln Leu Leu Lys Ala Cys Asp Gly 130 135 140

    Ala Gly Ala Ile Gln Gln Glu Gly Arg Ser Tyr Trp Pro Lys Phe Cys 145 150 155 160

    Asp Pro Asp Ser Thr Ala Asn Phe Ala Gly Asp Pro Ala Met Leu Arg 165 170 175

    Arg Glu Gln His Arg Leu Leu Leu Pro Gln Val Leu His Asp Pro Ala 180 185 190

    Ile Thr His Asp Ser Pro Ala Leu Gly Ser Phe Asp Thr Tyr Ser Ile 195 200 205

    Ala Thr Pro Asp Thr Arg Thr Pro Gln Leu Thr Gly Pro Lys Ala Arg 210 215 220

    Ala Arg Leu Glu Gln Ala Ile Thr Leu Trp Arg Val Arg Leu Pro Glu 225 230 235 240

    Ser Ala Ala Asp Phe Asp Arg Leu Ala Ser Ser Leu Lys Lys Ile Pro 245 250 255

    Asp Asp Asp Ser Arg Leu Asn Leu Gln Gly Tyr Val Gly Ser Ser Ala 260 265 270

    Lys Gly Glu Val Gln Ala Arg Leu Phe Ala Leu Leu Leu Phe Arg His 275 280 285

    Leu Glu Arg Ser Ser Phe Thr Leu Gly Leu Leu Arg Ser Ala Thr Pro 290 295 300

    Pro Pro Lys Asn Ala Glu Thr Pro Pro Pro Ala Gly Val Pro Leu Pro 305 310 315 320

    Ala Ala Ser Ala Ala Asp Pro Val Arg Ile Ala Arg Gly Lys Arg Ser 325 330 335

    Phe Val Phe Arg Ala Phe Thr Ser Leu Pro Cys Trp His Gly Gly Asp 340 345 350

    Asn Ile His Pro Thr Trp Lys Ser Phe Asp Ile Ala Ala Phe Lys Tyr 355 360 365

    Ala Leu Thr Val Ile Asn Gln Ile Glu Glu Lys Thr Lys Glu Arg Gln 370 375 380

    Lys Glu Cys Ala Glu Leu Glu Thr Asp Phe Asp Tyr Met His Gly Arg 385 390 395 400

    Leu Ala Lys Ile Pro Val Lys Tyr Thr Thr Gly Glu Ala Glu Pro Pro 405 410 415

    Pro Ile Leu Ala Asn Asp Leu Arg Ile Pro Leu Leu Arg Glu Leu Leu 420 425 430

    Gln Asn Ile Lys Val Asp Thr Ala Leu Thr Asp Gly Glu Ala Val Ser 435 440 445

    Tyr Gly Leu Gln Arg Arg Thr Ile Arg Gly Phe Arg Glu Leu Arg Arg 450 455 460

    Ile Trp Arg Gly His Ala Pro Ala Gly Thr Val Phe Ser Ser Glu Leu 465 470 475 480

    Lys Glu Lys Leu Ala Gly Glu Leu Arg Gln Phe Gln Thr Asp Asn Ser 485 490 495

    Thr Thr Ile Gly Ser Val Gln Leu Phe Asn Glu Leu Ile Gln Asn Pro 500 505 510

    Lys Tyr Trp Pro Ile Trp Gln Ala Pro Asp Val Glu Thr Ala Arg Gln 515 520 525

    Trp Ala Asp Ala Gly Phe Ala Asp Asp Pro Leu Ala Ala Leu Val Gln 530 535 540

    Glu Ala Glu Leu Gln Glu Asp Ile Asp Ala Leu Lys Ala Pro Val Lys 545 550 555 560

    Leu Thr Pro Ala Asp Pro Glu Tyr Ser Arg Arg Gln Tyr Asp Phe Asn 565 570 575

    Ala Val Ser Lys Phe Gly Ala Gly Ser Arg Ser Ala Asn Arg His Glu 580 585 590

    Pro Gly Gln Thr Glu Arg Gly His Asn Thr Phe Thr Thr Glu Ile Ala 595 600 605

    Ala Arg Asn Ala Ala Asp Gly Asn Arg Trp Arg Ala Thr His Val Arg 610 615 620

    Ile His Tyr Ser Ala Pro Arg Leu Leu Arg Asp Gly Leu Arg Arg Pro 625 630 635 640

    Asp Thr Asp Gly Asn Glu Ala Leu Glu Ala Val Pro Trp Leu Gln Pro 645 650 655

    Met Met Glu Ala Leu Ala Pro Leu Pro Thr Leu Pro Gln Asp Leu Thr 660 665 670

    Gly Met Pro Val Phe Leu Met Pro Asp Val Thr Leu Ser Gly Glu Arg 675 680 685

    Arg Ile Leu Leu Asn Leu Pro Val Thr Leu Glu Pro Ala Ala Leu Val 690 695 700

    Glu Gln Leu Gly Asn Ala Gly Arg Trp Gln Asn Gln Phe Phe Gly Ser 705 710 715 720

    Arg Glu Asp Pro Phe Ala Leu Arg Trp Pro Ala Asp Gly Ala Val Lys 725 730 735

    Thr Ala Lys Gly Lys Thr His Ile Pro Trp His Gln Asp Arg Asp His 740 745 750

    Phe Thr Val Leu Gly Val Asp Leu Gly Thr Arg Asp Ala Gly Ala Leu 755 760 765

    Ala Leu Leu Asn Val Thr Ala Gln Lys Pro Ala Lys Pro Val His Arg 770 775 780

    Ile Ile Gly Glu Ala Asp Gly Arg Thr Trp Tyr Ala Ser Leu Ala Asp 785 790 795 800

    Ala Arg Met Ile Arg Leu Pro Gly Glu Asp Ala Arg Leu Phe Val Arg

    805

    810

    815

    Gly Lys Leu Val Gln Glu Pro Tyr Gly Glu Arg Gly Arg Asn Ala Ser 820 825 830

    Leu Leu Glu Trp Glu Asp Ala Arg Asn Ile Ile Leu Arg Leu Gly Gln 835 840 845

    Asn Pro Asp Glu Leu Leu Gly Ala Asp Pro Arg Arg His Ser Tyr Pro 850 855 860

    Glu Ile Asn Asp Lys Leu Leu Val Ala Leu Arg Arg Ala Gln Ala Arg 865 870 875 880

    Leu Ala Arg Leu Gln Asn Arg Ser Trp Arg Leu Arg Asp Leu Ala Glu 885 890 895

    Ser Asp Lys Ala Leu Asp Glu Ile His Ala Glu Arg Ala Gly Glu Lys 900 905 910

    Pro Ser Pro Leu Pro Pro Leu Ala Arg Asp Asp Ala Ile Lys Ser Thr 915 920 925

    Asp Glu Ala Leu Leu Ser Gln Arg Asp Ile Ile Arg Arg Ser Phe Val 930 935 940

    Gln Ile Ala Asn Leu Ile Leu Pro Leu Arg Gly Arg Arg Trp Glu Trp 945 950 955 960

    Arg Pro His Val Glu Val Pro Asp Cys His Ile Leu Ala Gln Ser Asp 965 970 975

    Pro Gly Thr Asp Asp Thr Lys Arg Leu Val Ala Gly Gln Arg Gly Ile 980 985 990

    Ser His Glu Arg Ile Glu Gln Ile Glu Glu Leu Arg Arg Arg Cys Gln 995 1000 1005

    Ser Leu Asn Arg Ala Leu Arg His Lys Pro Gly Glu Arg Pro Val 1010 1015 1020

    Leu Gly Arg Pro Ala Lys Gly Glu Glu Ile Ala Asp Pro Cys Pro 1025 1030 1035

    Ala Leu Leu Glu Lys Ile Asn Arg Leu Arg Asp Gln Arg Val Asp 1040 1045 1050

    Gln Thr Ala His Ala Ile Leu Ala Ala Ala Leu Gly Val Arg Leu 1055 1060 1065

    Arg Ala Pro Ser Lys Asp Arg Ala Glu Arg Arg His Arg Asp Ile 1070 1075 1080

    His Gly Glu Tyr Glu Arg Phe Arg Ala Pro Ala Asp Phe Val Val 1085 1090 1095

    Ile Glu Asn Leu Ser Arg Tyr Leu Ser Ser Gln Asp Arg Ala Arg 1100 1105 1110

    Ser Glu Asn Thr Arg Leu Met Gln Trp Cys His Arg Gln Ile Val 1115 1120 1125

    Gln Lys Leu Arg Gln Leu Cys Glu Thr Tyr Gly Ile Pro Val Leu 1130 1135 1140

    Ala Val Pro Ala Ala Tyr Ser Ser Arg Phe Ser Ser Arg Asp Gly 1145 1150 1155

    Ser Ala Gly Phe Arg Ala Val His Leu Thr Pro Asp His Arg His

    1160 1165 1170 Arg Met Pro Trp Ser Arg Ile Leu Ala Arg Leu Lys Ala His Glu 1175 1180 1185 Glu Asp Gly Lys Arg Leu Glu Lys Thr Val Leu Asp Glu Ala Arg 1190 1195 1200 Ala Val Arg Gly Leu Phe Asp Arg Leu Asp Arg Phe Asn Ala Gly 1205 1210 1215 His Val Pro Gly Lys Pro Trp Arg Thr Leu Leu Ala Pro Leu Pro 1220 1225 1230 Gly Gly Pro Val Phe Val Pro Leu Gly Asp Ala Thr Pro Met Gln 1235 1240 1245 Ala Asp Leu Asn Ala Ala Ile Asn Ile Ala Leu Arg Gly Ile Ala 1250 1255 1260 Ala Pro Asp Arg His Asp Ile His His Arg Leu Arg Ala Glu Asn 1265 1270 1275

    Lys Lys Arg Ile Leu Ser Leu Arg Leu Gly Thr Gln Arg Glu Lys 1280 1285 1290

    Ala Arg Trp Pro Gly Gly Ala Pro Ala Val Thr Leu Ser Thr Pro 1295 1300 1305

    Asn Asn Gly Ala Ser Pro Glu Asp Ser Asp Ala Leu Pro Glu Arg 1310 1315 1320

    Val Ser Asn Leu Phe Val Asp Ile Ala Gly Val Ala Asn Phe Glu

    1325

    1330

    1335

    Arg Val Thr Ile Glu Gly Val Ser Gln Lys Phe Ala Thr Gly Arg

    1340

    1345

    1350

    Gly Leu Trp Ala Ser Val Lys Gln Arg Ala Trp Asn Arg Val Ala

    1355

    1360

    1365

    Arg Leu Asn Glu Thr Val Thr Asp Asn Asn Arg Asn Glu Glu Glu

    1370

    1375

    1380

    Asp Asp Ile Pro Met 1385 <210> 30 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 30 guccaagaaa aaagaaauga uacgaggcau uagcac 36 <210> 31 <211> 107 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 31 cuggacgaug ucucuuuuau uucuuuuuuc uuggaucuga guacgagcac ccacauugga 60 cauuucgcau ggugggugcu cguacuauag guaaaacaaa ccuuuuu

    107 <210> 32 <211> 1108 <212> PRT <213> Bacillus thermoamylovorans <400> 32

    Met Ala Thr Arg Ser Phe Ile Leu Lys Ile Glu Pro Asn Glu Glu Val 1 5 10 15

    Lys Lys Gly Leu Trp Lys Thr His Glu Val Leu Asn His Gly Ile Ala 20 25 30

    Tyr Tyr Met Asn Ile Leu Lys Leu Ile Arg Gln Glu Ala Ile Tyr Glu 35 40 45

    His His Glu Gln Asp Pro Lys Asn Pro Lys Lys Val Ser Lys Ala Glu 50 55 60

    Ile Gln Ala Glu Leu Trp Asp Phe Val Leu Lys Met Gln Lys Cys Asn 65 70 75 80

    Ser Phe Thr His Glu Val Asp Lys Asp Val Val Phe Asn Ile Leu Arg 85 90 95

    Glu Leu Tyr Glu Glu Leu Val Pro Ser Ser Val Glu Lys Lys Gly Glu 100 105 110

    Ala Asn Gln Leu Ser Asn Lys Phe Leu Tyr Pro Leu Val Asp Pro Asn 115 120 125

    Ser Gln Ser Gly Lys Gly Thr Ala Ser Ser Gly Arg Lys Pro Arg Trp 130 135 140

    Tyr Asn Leu Lys Ile Ala Gly Asp Pro Ser Trp Glu Glu Glu Lys Lys 145 150 155 160

    Lys Trp Glu Glu Asp Lys Lys Lys Asp Pro Leu Ala Lys Ile Leu Gly 165 170 175

    Lys Leu Ala Glu Tyr Gly Leu Ile Pro Leu Phe Ile Pro Phe Thr Asp 180 185 190

    Ser Asn Glu Pro Ile Val Lys Glu Ile Lys Trp Met Glu Lys Ser Arg 195 200 205

    Asn Gln Ser Val Arg Arg Leu Asp Lys Asp Met Phe Ile Gln Ala Leu 210 215 220

    Glu Arg Phe Leu Ser Trp Glu Ser Trp Asn Leu Lys Val Lys Glu Glu 225 230 235 240

    Tyr Glu Lys Val Glu Lys Glu His Lys Thr Leu Glu Glu Arg Ile Lys 245 250 255

    Glu Asp Ile Gln Ala Phe Lys Ser Leu Glu Gln Tyr Glu Lys Glu Arg 260 265 270

    Gln Glu Gln Leu Leu Arg Asp Thr Leu Asn Thr Asn Glu Tyr Arg Leu 275 280 285

    Ser Lys Arg Gly Leu Arg Gly Trp Arg Glu Ile Ile Gln Lys Trp Leu 290 295 300

    Lys Met Asp Glu Asn Glu Pro Ser Glu Lys Tyr Leu Glu Val Phe Lys 305 310 315 320

    Asp Tyr Gln Arg Lys His Pro Arg Glu Ala Gly Asp Tyr Ser Val Tyr

    325

    330

    335

    Glu Phe Leu Ser Lys Lys Glu Asn His Phe Ile Trp Arg Asn His Pro 340 345 350

    Glu Tyr Pro Tyr Leu Tyr Ala Thr Phe Cys Glu Ile Asp Lys Lys Lys 355 360 365

    Lys Asp Ala Lys Gln Gln Ala Thr Phe Thr Leu Ala Asp Pro Ile Asn 370 375 380

    His Pro Leu Trp Val Arg Phe Glu Glu Arg Ser Gly Ser Asn Leu Asn 385 390 395 400

    Lys Tyr Arg Ile Leu Thr Glu Gln Leu His Thr Glu Lys Leu Lys Lys 405 410 415

    Lys Leu Thr Val Gln Leu Asp Arg Leu Ile Tyr Pro Thr Glu Ser Gly 420 425 430

    Gly Trp Glu Glu Lys Gly Lys Val Asp Ile Val Leu Leu Pro Ser Arg 435 440 445

    Gln Phe Tyr Asn Gln Ile Phe Leu Asp Ile Glu Glu Lys Gly Lys His 450 455 460

    Ala Phe Thr Tyr Lys Asp Glu Ser Ile Lys Phe Pro Leu Lys Gly Thr 465 470 475 480

    Leu Gly Gly Ala Arg Val Gln Phe Asp Arg Asp His Leu Arg Arg Tyr 485 490 495

    Pro His Lys Val Glu Ser Gly Asn Val Gly Arg Ile Tyr Phe Asn Met 500 505 510

    Thr Val Asn Ile Glu Pro Thr Glu Ser Pro Val Ser Lys Ser Leu Lys 515 520 525

    Ile His Arg Asp Asp Phe Pro Lys Phe Val Asn Phe Lys Pro Lys Glu 530 535 540

    Leu Thr Glu Trp Ile Lys Asp Ser Lys Gly Lys Lys Leu Lys Ser Gly 545 550 555 560

    Ile Glu Ser Leu Glu Ile Gly Leu Arg Val Met Ser Ile Asp Leu Gly 565 570 575

    Gln Arg Gln Ala Ala Ala Ala Ser Ile Phe Glu Val Val Asp Gln Lys 580 585 590

    Pro Asp Ile Glu Gly Lys Leu Phe Phe Pro Ile Lys Gly Thr Glu Leu 595 600 605

    Tyr Ala Val His Arg Ala Ser Phe Asn Ile Lys Leu Pro Gly Glu Thr 610 615 620

    Leu Val Lys Ser Arg Glu Val Leu Arg Lys Ala Arg Glu Asp Asn Leu 625 630 635 640

    Lys Leu Met Asn Gln Lys Leu Asn Phe Leu Arg Asn Val Leu His Phe 645 650 655

    Gln Gln Phe Glu Asp Ile Thr Glu Arg Glu Lys Arg Val Thr Lys Trp 660 665 670

    Ile Ser Arg Gln Glu Asn Ser Asp Val Pro Leu Val Tyr Gln Asp Glu 675 680 685

    Leu Ile Gln Ile Arg Glu Leu Met Tyr Lys Pro Tyr Lys Asp Trp Val 690 695 700

    Ala Phe Leu Lys Gln Leu His Lys Arg Leu Glu Val Glu Ile Gly Lys 705 710 715 720

    Glu Val Lys His Trp Arg Lys Ser Leu Ser Asp Gly Arg Lys Gly Leu 725 730 735

    Tyr Gly Ile Ser Leu Lys Asn Ile Asp Glu Ile Asp Arg Thr Arg Lys 740 745 750

    Phe Leu Leu Arg Trp Ser Leu Arg Pro Thr Glu Pro Gly Glu Val Arg 755 760 765

    Arg Leu Glu Pro Gly Gln Arg Phe Ala Ile Asp Gln Leu Asn His Leu 770 775 780

    Asn Ala Leu Lys Glu Asp Arg Leu Lys Lys Met Ala Asn Thr Ile Ile 785 790 795 800

    Met His Ala Leu Gly Tyr Cys Tyr Asp Val Arg Lys Lys Lys Trp Gln 805 810 815

    Ala Lys Asn Pro Ala Cys Gln Ile Ile Leu Phe Glu Asp Leu Ser Asn 820 825 830

    Tyr Asn Pro Tyr Glu Glu Arg Ser Arg Phe Glu Asn Ser Lys Leu Met 835 840 845

    Lys Trp Ser Arg Arg Glu Ile Pro Arg Gln Val Ala Leu Gln Gly Glu 850 855 860

    Ile Tyr Gly Leu Gln Val Gly Glu Val Gly Ala Gln Phe Ser Ser Arg 865 870 875 880

    Phe His Ala Lys Thr Gly Ser Pro Gly Ile Arg Cys Ser Val Val Thr 885 890 895

    Lys Glu Lys Leu Gln Asp Asn Arg Phe Phe Lys Asn Leu Gln Arg Glu 900 905 910

    Gly Arg Leu Thr Leu Asp Lys Ile Ala Val Leu Lys Glu Gly Asp Leu 915 920 925

    Tyr Pro Asp Lys Gly Gly Glu Lys Phe Ile Ser Leu Ser Lys Asp Arg 930 935 940

    Lys Leu Val Thr Thr His Ala Asp Ile Asn Ala Ala Gln Asn Leu Gln 945 950 955 960

    Lys Arg Phe Trp Thr Arg Thr His Gly Phe Tyr Lys Val Tyr Cys Lys 965 970 975

    Ala Tyr Gln Val Asp Gly Gln Thr Val Tyr Ile Pro Glu Ser Lys Asp 980 985 990

    Gln Lys Gln Lys Ile Ile Glu Glu Phe Gly Glu Gly Tyr Phe Ile Leu 995 1000 1005

    Lys Asp Gly Val Tyr Glu Trp Gly Asn Ala Gly Lys Leu Lys Ile 1010 1015 1020

    Lys Lys Gly Ser Ser Lys Gln Ser Ser Ser Glu Leu Val Asp Ser 1025 1030 1035

    Asp Ile Leu Lys Asp Ser Phe Asp Leu Ala Ser Glu Leu Lys Gly

    1040 1045 1050

    Glu Lys Leu Met Leu Tyr Arg Asp Pro Ser Gly Asn Val Phe Pro 1055 1060 1065

    Ser Asp Lys Trp Met Ala Ala Gly Val Phe Phe Gly Lys Leu Glu 1070 1075 1080

    Arg Ile Leu Ile Ser Lys Leu Thr Asn Gln Tyr Ser Ile Ser Thr 1085 1090 1095

    Ile Glu Asp Asp Ser Ser Lys Gln Ser Met 1100 1105 <210> 33 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 33 guucgaaagc uuaguggaaa gcuucguggu uagcac 36 <210> 34 <211> 69 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 34 cacggauaau cacgacuuuc cacuaagcuu ucgaauuuua ugaugcgagc auccucucag gucaaaaaa <210> 35 <211> 1108 <212> PRT <213> Bacillus sp.

    <400> 35

    Met Ala Ile Arg Ser Ile Lys Leu Lys Leu Lys Thr His Thr Gly Pro 1 5 10 15

    Glu Ala Gln Asn Leu Arg Lys Gly Ile Trp Arg Thr His Arg Leu Leu 20 25 30

    Asn Glu Gly Val Ala Tyr Tyr Met Lys Met Leu Leu Leu Phe Arg Gln 35 40 45

    Glu Ser Thr Gly Glu Arg Pro Lys Glu Glu Leu Gln Glu Glu Leu Ile 50 55 60

    Cys His Ile Arg Glu Gln Gln Gln Arg Asn Gln Ala Asp Lys Asn Thr 65 70 75 80

    Gln Ala Leu Pro Leu Asp Lys Ala Leu Glu Ala Leu Arg Gln Leu Tyr 85 90 95

    Glu Leu Leu Val Pro Ser Ser Val Gly Gln Ser Gly Asp Ala Gln Ile 100 105 110

    Ile Ser Arg Lys Phe Leu Ser Pro Leu Val Asp Pro Asn Ser Glu Gly 115 120 125

    Gly Lys Gly Thr Ser Lys Ala Gly Ala Lys Pro Thr Trp Gln Lys Lys 130 135 140

    Lys Glu Ala Asn Asp Pro Thr Trp Glu Gln Asp Tyr Glu Lys Trp Lys

    145

    150

    155

    160

    Lys Arg Arg Glu Glu Asp Pro Thr Ala Ser Val Ile Thr Thr Leu Glu 165 170 175

    Glu Tyr Gly Ile Arg Pro Ile Phe Pro Leu Tyr Thr Asn Thr Val Thr 180 185 190

    Asp Ile Ala Trp Leu Pro Leu Gln Ser Asn Gln Phe Val Arg Thr Trp 195 200 205

    Asp Arg Asp Met Leu Gln Gln Ala Ile Glu Arg Leu Leu Ser Trp Glu 210 215 220

    Ser Trp Asn Lys Arg Val Gln Glu Glu Tyr Ala Lys Leu Lys Glu Lys 225 230 235 240

    Met Ala Gln Leu Asn Glu Gln Leu Glu Gly Gly Gln Glu Trp Ile Ser 245 250 255

    Leu Leu Glu Gln Tyr Glu Glu Asn Arg Glu Arg Glu Leu Arg Glu Asn 260 265 270

    Met Thr Ala Ala Asn Asp Lys Tyr Arg Ile Thr Lys Arg Gln Met Lys 275 280 285

    Gly Trp Asn Glu Leu Tyr Glu Leu Trp Ser Thr Phe Pro Ala Ser Ala 290 295 300

    Ser His Glu Gln Tyr Lys Glu Ala Leu Lys Arg Val Gln Gln Arg Leu 305 310 315 320

    Arg Gly Arg Phe Gly Asp Ala His Phe Phe Gln Tyr Leu Met Glu Glu 325 330 335

    Lys Asn Arg Leu Ile Trp Lys Gly Asn Pro Gln Arg Ile His Tyr Phe 340 345 350

    Val Ala Arg Asn Glu Leu Thr Lys Arg Leu Glu Glu Ala Lys Gln Ser 355 360 365

    Ala Thr Met Thr Leu Pro Asn Ala Arg Lys His Pro Leu Trp Val Arg 370 375 380

    Phe Asp Ala Arg Gly Gly Asn Leu Gln Asp Tyr Tyr Leu Thr Ala Glu 385 390 395 400

    Ala Asp Lys Pro Arg Ser Arg Arg Phe Val Thr Phe Ser Gln Leu Ile 405 410 415

    Trp Pro Ser Glu Ser Gly Trp Met Glu Lys Lys Asp Val Glu Val Glu 420 425 430

    Leu Ala Leu Ser Arg Gln Phe Tyr Gln Gln Val Lys Leu Leu Lys Asn 435 440 445

    Asp Lys Gly Lys Gln Lys Ile Glu Phe Lys Asp Lys Gly Ser Gly Ser 450 455 460

    Thr Phe Asn Gly His Leu Gly Gly Ala Lys Leu Gln Leu Glu Arg Gly 465 470 475 480

    Asp Leu Glu Lys Glu Glu Lys Asn Phe Glu Asp Gly Glu Ile Gly Ser 485 490 495

    Val Tyr Leu Asn Val Val Ile Asp Phe Glu Pro Leu Gln Glu Val Lys 500 505 510

    Asn Gly Arg Val Gln Ala Pro Tyr Gly Gln Val Leu Gln Leu Ile Arg 515 520 525

    Arg Pro Asn Glu Phe Pro Lys Val Thr Thr Tyr Lys Ser Glu Gln Leu 530 535 540

    Val Glu Trp Ile Lys Ala Ser Pro Gln His Ser Ala Gly Val Glu Ser 545 550 555 560

    Leu Ala Ser Gly Phe Arg Val Met Ser Ile Asp Leu Gly Leu Arg Ala 565 570 575

    Ala Ala Ala Thr Ser Ile Phe Ser Val Glu Glu Ser Ser Asp Lys Asn 580 585 590

    Ala Ala Asp Phe Ser Tyr Trp Ile Glu Gly Thr Pro Leu Val Ala Val 595 600 605

    His Gln Arg Ser Tyr Met Leu Arg Leu Pro Gly Glu Gln Val Glu Lys 610 615 620

    Gln Val Met Glu Lys Arg Asp Glu Arg Phe Gln Leu His Gln Arg Val 625 630 635 640

    Lys Phe Gln Ile Arg Val Leu Ala Gln Ile Met Arg Met Ala Asn Lys 645 650 655

    Gln Tyr Gly Asp Arg Trp Asp Glu Leu Asp Ser Leu Lys Gln Ala Val 660 665 670

    Glu Gln Lys Lys Ser Pro Leu Asp Gln Thr Asp Arg Thr Phe Trp Glu 675 680 685

    Gly Ile Val Cys Asp Leu Thr Lys Val Leu Pro Arg Asn Glu Ala Asp 690 695 700

    Trp Glu Gln Ala Val Val Gln Ile His Arg Lys Ala Glu Glu Tyr Val 705 710 715 720

    Gly Lys Ala Val Gln Ala Trp Arg Lys Arg Phe Ala Ala Asp Glu Arg 725 730 735

    Lys Gly Ile Ala Gly Leu Ser Met Trp Asn Ile Glu Glu Leu Glu Gly 740 745 750

    Leu Arg Lys Leu Leu Ile Ser Trp Ser Arg Arg Thr Arg Asn Pro Gln 755 760 765

    Glu Val Asn Arg Phe Glu Arg Gly His Thr Ser His Gln Arg Leu Leu 770 775 780

    Thr His Ile Gln Asn Val Lys Glu Asp Arg Leu Lys Gln Leu Ser His 785 790 795 800

    Ala Ile Val Met Thr Ala Leu Gly Tyr Val Tyr Asp Glu Arg Lys Gln 805 810 815

    Glu Trp Cys Ala Glu Tyr Pro Ala Cys Gln Val Ile Leu Phe Glu Asn 820 825 830

    Leu Ser Gln Tyr Arg Ser Asn Leu Asp Arg Ser Thr Lys Glu Asn Ser 835 840 845

    Thr Leu Met Lys Trp Ala His Arg Ser Ile Pro Lys Tyr Val His Met 850 855 860

    Gln Ala Glu Pro Tyr Gly Ile Gln Ile Gly Asp Val Arg Ala Glu Tyr

    865

    870

    875

    880

    Ser Ser Arg Phe Tyr Ala Lys Thr Gly Thr Pro Gly Ile Arg Cys Lys 885 890 895

    Lys Val Arg Gly Gln Asp Leu Gln Gly Arg Arg Phe Glu Asn Leu Gln 900 905 910

    Lys Arg Leu Val Asn Glu Gln Phe Leu Thr Glu Glu Gln Val Lys Gln 915 920 925

    Leu Arg Pro Gly Asp Ile Val Pro Asp Asp Ser Gly Glu Leu Phe Met 930 935 940

    Thr Leu Thr Asp Gly Ser Gly Ser Lys Glu Val Val Phe Leu Gln Ala 945 950 955 960

    Asp Ile Asn Ala Ala His Asn Leu Gln Lys Arg Phe Trp Gln Arg Tyr 965 970 975

    Asn Glu Leu Phe Lys Val Ser Cys Arg Val Ile Val Arg Asp Glu Glu 980 985 990

    Glu Tyr Leu Val Pro Lys Thr Lys Ser Val Gln Ala Lys Leu Gly Lys 995 1000 1005

    Gly Leu Phe Val Lys Lys Ser Asp Thr Ala Trp Lys Asp Val Tyr 1010 1015 1020

    Val Trp Asp Ser Gln Ala Lys Leu Lys Gly Lys Thr Thr Phe Thr 1025 1030 1035

    Glu Glu Ser Glu Ser Pro Glu Gln Leu Glu Asp Phe Gln Glu Ile 1040 1045 1050

    Ile Glu Glu Ala Glu Glu Ala Lys Gly Thr Tyr Arg Thr Leu Phe 1055 1060 1065

    Arg Asp Pro Ser Gly Val Phe Phe Pro Glu Ser Val Trp Tyr Pro 1070 1075 1080

    Gln Lys Asp Phe Trp Gly Glu Val Lys Arg Lys Leu Tyr Gly Lys 1085 1090 1095

    Leu Arg Glu Arg Phe Leu Thr Lys Ala Arg 1100 1105 <210> 36 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 36 guuuugagaa uagcccgaca uagagggcaa uagac <210> 37 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 37 guuaugaaaa cagcccgaca uagagggcaa uagaca <210> 38 <211> 1334 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 38

    Met Lys Ile Ser Lys Val Asp His Thr Arg Met Ala Val Ala Lys Gly 1 5 10 15

    Asn Gln His Arg Arg Asp Glu Ile Ser Gly Ile Leu Tyr Lys Asp Pro 20 25 30

    Thr Lys Thr Gly Ser Ile Asp Phe Asp Glu Arg Phe Lys Lys Leu Asn 35 40 45

    Cys Ser Ala Lys Ile Leu Tyr His Val Phe Asn Gly Ile Ala Glu Gly 50 55 60

    Ser Asn Lys Tyr Lys Asn Ile Val Asp Lys Val Asn Asn Asn Leu Asp 65 70 75 80

    Arg Val Leu Phe Thr Gly Lys Ser Tyr Asp Arg Lys Ser Ile Ile Asp 85 90 95

    Ile Asp Thr Val Leu Arg Asn Val Glu Lys Ile Asn Ala Phe Asp Arg 100 105 110

    Ile Ser Thr Glu Glu Arg Glu Gln Ile Ile Asp Asp Leu Leu Glu Ile 115 120 125

    Gln Leu Arg Lys Gly Leu Arg Lys Gly Lys Ala Gly Leu Arg Glu Val 130 135 140

    Leu Leu Ile Gly Ala Gly Val Ile Val Arg Thr Asp Lys Lys Gln Glu 145 150 155 160

    Ile Ala Asp Phe Leu Glu Ile Leu Asp Glu Asp Phe Asn Lys Thr Asn 165 170 175

    Gln Ala Lys Asn Ile Lys Leu Ser Ile Glu Asn Gln Gly Leu Val Val 180 185 190

    Ser Pro Val Ser Arg Gly Glu Glu Arg Ile Phe Asp Val Ser Gly Ala 195 200 205

    Gln Lys Gly Lys Ser Ser Lys Lys Ala Gln Glu Lys Glu Ala Leu Ser 210 215 220

    Ala Phe Leu Leu Asp Tyr Ala Asp Leu Asp Lys Asn Val Arg Phe Glu 225 230 235 240

    Tyr Leu Arg Lys Ile Arg Arg Leu Ile Asn Leu Tyr Phe Tyr Val Lys 245 250 255

    Asn Asp Asp Val Met Ser Leu Thr Glu Ile Pro Ala Glu Val Asn Leu 260 265 270

    Glu Lys Asp Phe Asp Ile Trp Arg Asp His Glu Gln Arg Lys Glu Glu 275 280 285

    Asn Gly Asp Phe Val Gly Cys Pro Asp Ile Leu Leu Ala Asp Arg Asp 290 295 300

    Val Lys Lys Ser Asn Ser Lys Gln Val Lys Ile Ala Glu Arg Gln Leu 305 310 315 320

    Arg Glu Ser Ile Arg Glu Lys Asn Ile Lys Arg Tyr Arg Phe Ser Ile

    325

    330

    335

    Lys Thr Ile Glu Lys Asp Asp Gly Thr Tyr Phe Phe Ala Asn Lys Gln 340 345 350

    Ile Ser Val Phe Trp Ile His Arg Ile Glu Asn Ala Val Glu Arg Ile 355 360 365

    Leu Gly Ser Ile Asn Asp Lys Lys Leu Tyr Arg Leu Arg Leu Gly Tyr 370 375 380

    Leu Gly Glu Lys Val Trp Lys Asp Ile Leu Asn Phe Leu Ser Ile Lys 385 390 395 400

    Tyr Ile Ala Val Gly Lys Ala Val Phe Asn Phe Ala Met Asp Asp Leu 405 410 415

    Gln Glu Lys Asp Arg Asp Ile Glu Pro Gly Lys Ile Ser Glu Asn Ala 420 425 430

    Val Asn Gly Leu Thr Ser Phe Asp Tyr Glu Gln Ile Lys Ala Asp Glu 435 440 445

    Met Leu Gln Arg Glu Val Ala Val Asn Val Ala Phe Ala Ala Asn Asn 450 455 460

    Leu Ala Arg Val Thr Val Asp Ile Pro Gln Asn Gly Glu Lys Glu Asp 465 470 475 480

    Ile Leu Leu Trp Asn Lys Ser Asp Ile Lys Lys Tyr Lys Lys Asn Ser 485 490 495

    Lys Lys Gly Ile Leu Lys Ser Ile Leu Gln Phe Phe Gly Gly Ala Ser 500 505 510

    Thr Trp Asn Met Lys Met Phe Glu Ile Ala Tyr His Asp Gln Pro Gly 515 520 525

    Asp Tyr Glu Glu Asn Tyr Leu Tyr Asp Ile Ile Gln Ile Ile Tyr Ser 530 535 540

    Leu Arg Asn Lys Ser Phe His Phe Lys Thr Tyr Asp His Gly Asp Lys 545 550 555 560

    Asn Trp Asn Arg Glu Leu Ile Gly Lys Met Ile Glu His Asp Ala Glu 565 570 575

    Arg Val Ile Ser Val Glu Arg Glu Lys Phe His Ser Asn Asn Leu Pro 580 585 590

    Met Phe Tyr Lys Asp Ala Asp Leu Lys Lys Ile Leu Asp Leu Leu Tyr 595 600 605

    Ser Asp Tyr Ala Gly Arg Ala Ser Gln Val Pro Ala Phe Asn Thr Val 610 615 620

    Leu Val Arg Lys Asn Phe Pro Glu Phe Leu Arg Lys Asp Met Gly Tyr 625 630 635 640

    Lys Val His Phe Asn Asn Pro Glu Val Glu Asn Gln Trp His Ser Ala 645 650 655

    Val Tyr Tyr Leu Tyr Lys Glu Ile Tyr Tyr Asn Leu Phe Leu Arg Asp 660 665 670

    Lys Glu Val Lys Asn Leu Phe Tyr Thr Ser Leu Lys Asn Ile Arg Ser 675 680 685

    Glu Val Ser Asp Lys Lys Gln Lys Leu Ala Ser Asp Asp Phe Ala Ser 690 695 700

    Arg Cys Glu Glu Ile Glu Asp Arg Ser Leu Pro Glu Ile Cys Gln Ile 705 710 715 720

    Ile Met Thr Glu Tyr Asn Ala Gln Asn Phe Gly Asn Arg Lys Val Lys 725 730 735

    Ser Gln Arg Val Ile Glu Lys Asn Lys Asp Ile Phe Arg His Tyr Lys 740 745 750

    Met Leu Leu Ile Lys Thr Leu Ala Gly Ala Phe Ser Leu Tyr Leu Lys 755 760 765

    Gln Glu Arg Phe Ala Phe Ile Gly Lys Ala Thr Pro Ile Pro Tyr Glu 770 775 780

    Thr Thr Asp Val Lys Asn Phe Leu Pro Glu Trp Lys Ser Gly Met Tyr 785 790 795 800

    Ala Ser Phe Val Glu Glu Ile Lys Asn Asn Leu Asp Leu Gln Glu Trp 805 810 815

    Tyr Ile Val Gly Arg Phe Leu Asn Gly Arg Met Leu Asn Gln Leu Ala 820 825 830

    Gly Ser Leu Arg Ser Tyr Ile Gln Tyr Ala Glu Asp Ile Glu Arg Arg 835 840 845

    Ala Ala Glu Asn Arg Asn Lys Leu Phe Ser Lys Pro Asp Glu Lys Ile 850 855 860

    Glu Ala Cys Lys Lys Ala Val Arg Val Leu Asp Leu Cys Ile Lys Ile 865 870 875 880

    Ser Thr Arg Ile Ser Ala Glu Phe Thr Asp Tyr Phe Asp Ser Glu Asp 885 890 895

    Asp Tyr Ala Asp Tyr Leu Glu Lys Tyr Leu Lys Tyr Gln Asp Asp Ala 900 905 910

    Ile Lys Glu Leu Ser Gly Ser Ser Tyr Ala Ala Leu Asp His Phe Cys 915 920 925

    Asn Lys Asp Asp Leu Lys Phe Asp Ile Tyr Val Asn Ala Gly Gln Lys 930 935 940

    Pro Ile Leu Gln Arg Asn Ile Val Met Ala Lys Leu Phe Gly Pro Asp 945 950 955 960

    Asn Ile Leu Ser Glu Val Met Glu Lys Val Thr Glu Ser Ala Ile Arg 965 970 975

    Glu Tyr Tyr Asp Tyr Leu Lys Lys Val Ser Gly Tyr Arg Val Arg Gly 980 985 990

    Lys Cys Ser Thr Glu Lys Glu Gln Glu Asp Leu Leu Lys Phe Gln Arg 995 1000 1005

    Leu Lys Asn Ala Val Glu Phe Arg Asp Val Thr Glu Tyr Ala Glu 1010 1015 1020

    Val Ile Asn Glu Leu Leu Gly Gln Leu Ile Ser Trp Ser Tyr Leu 1025 1030 1035

    Arg Glu Arg Asp Leu Leu Tyr Phe Gln Leu Gly Phe His Tyr Met

    1040

    1045

    1050

    Cys Leu Lys Asn Lys Ser Phe Lys Pro Ala Glu Tyr Val Asp Ile 1055 1060 1065

    Arg Arg Asn Asn Gly Thr Ile Ile His Asn Ala Ile Leu Tyr Gln 1070 1075 1080

    Ile Val Ser Met Tyr Ile Asn Gly Leu Asp Phe Tyr Ser Cys Asp 1085 1090 1095

    Lys Glu Gly Lys Thr Leu Lys Pro Ile Glu Thr Gly Lys Gly Val 1100 1105 1110

    Gly Ser Lys Ile Gly Gln Phe Ile Lys Tyr Ser Gln Tyr Leu Tyr 1115 1120 1125

    Asn Asp Pro Ser Tyr Lys Leu Glu Ile Tyr Asn Ala Gly Leu Glu 1130 1135 1140

    Val Phe Glu Asn Ile Asp Glu His Asp Asn Ile Thr Asp Leu Arg 1145 1150 1155

    Lys Tyr Val Asp His Phe Lys Tyr Tyr Ala Tyr Gly Asn Lys Met 1160 1165 1170

    Ser Leu Leu Asp Leu Tyr Ser Glu Phe Phe Asp Arg Phe Phe Thr 1175 1180 1185

    Tyr Asp Met Lys Tyr Gln Lys Asn Val Val Asn Val Leu Glu Asn 1190 1195 1200

    Ile Leu Leu Arg His Phe Val Ile Phe Tyr Pro Lys Phe Gly Ser 1205 1210 1215

    Gly Lys Lys Asp Val Gly Ile Arg Asp Cys Lys Lys Glu Arg Ala 1220 1225 1230

    Gln Ile Glu Ile Ser Glu Gln Ser Leu Thr Ser Glu Asp Phe Met 1235 1240 1245

    Phe Lys Leu Asp Asp Lys Ala Gly Glu Glu Ala Lys Lys Phe Pro 1250 1255 1260

    Ala Arg Asp Glu Arg Tyr Leu Gln Thr Ile Ala Lys Leu Leu Tyr 1265 1270 1275

    Tyr Pro Asn Glu Ile Glu Asp Met Asn Arg Phe Met Lys Lys Gly 1280 1285 1290

    Glu Thr Ile Asn Lys Lys Val Gln Phe Asn Arg Lys Lys Lys Ile 1295 1300 1305

    Thr Arg Lys Gln Lys Asn Asn Ser Ser Asn Glu Val Leu Ser Ser 1310 1315 1320

    Thr Met Gly Tyr Leu Phe Lys Asn Ile Lys Leu 1325 1330 <210> 39 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 39 guuuuagucc ucuuucauau agagguaguc ucuuac <210> 40 <211> 99 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 40 augaaaagag gacuaaaacu gaaagaggac uaaaacacca gauguggaua acuauauuag uggcuauuaa aaauucgucg auauuagaga ggaaacuuu 99 <210> 41 <211> 1120 <212> PRT <213> Listeria seeligeri <400> 41

    Met Trp Ile Ser Ile Lys Thr Leu Ile His His Leu Gly Val Leu Phe 1 5 10 15

    Phe Cys Asp Tyr Met Tyr Asn Arg Arg Glu Lys Lys Ile Ile Glu Val 20 25 30

    Lys Thr Met Arg Ile Thr Lys Val Glu Val Asp Arg Lys Lys Val Leu 35 40 45

    Ile Ser Arg Asp Lys Asn Gly Gly Lys Leu Val Tyr Glu Asn Glu Met 50 55 60

    Gln Asp Asn Thr Glu Gln Ile Met His His Lys Lys Ser Ser Phe Tyr 65 70 75 80

    Lys Ser Val Val Asn Lys Thr Ile Cys Arg Pro Glu Gln Lys Gln Met 85 90 95

    Lys Lys Leu Val His Gly Leu Leu Gln Glu Asn Ser Gln Glu Lys Ile 100 105 110

    Lys Val Ser Asp Val Thr Lys Leu Asn Ile Ser Asn Phe Leu Asn His 115 120 125

    Arg Phe Lys Lys Ser Leu Tyr Tyr Phe Pro Glu Asn Ser Pro Asp Lys 130 135 140

    Ser Glu Glu Tyr Arg Ile Glu Ile Asn Leu Ser Gln Leu Leu Glu Asp 145 150 155 160

    Ser Leu Lys Lys Gln Gln Gly Thr Phe Ile Cys Trp Glu Ser Phe Ser 165 170 175

    Lys Asp Met Glu Leu Tyr Ile Asn Trp Ala Glu Asn Tyr Ile Ser Ser 180 185 190

    Lys Thr Lys Leu Ile Lys Lys Ser Ile Arg Asn Asn Arg Ile Gln Ser 195 200 205

    Thr Glu Ser Arg Ser Gly Gln Leu Met Asp Arg Tyr Met Lys Asp Ile 210 215 220

    Leu Asn Lys Asn Lys Pro Phe Asp Ile Gln Ser Val Ser Glu Lys Tyr 225 230 235 240

    Gln Leu Glu Lys Leu Thr Ser Ala Leu Lys Ala Thr Phe Lys Glu Ala 245 250 255

    Lys Lys Asn Asp Lys Glu Ile Asn Tyr Lys Leu Lys Ser Thr Leu Gln 260 265 270

    Asn His Glu Arg Gln Ile Ile Glu Glu Leu Lys Glu Asn Ser Glu Leu 275 280 285

    Asn Gln Phe Asn Ile Glu Ile Arg Lys His Leu Glu Thr Tyr Phe Pro 290 295 300

    Ile Lys Lys Thr Asn Arg Lys Val Gly Asp Ile Arg Asn Leu Glu Ile 305 310 315 320

    Gly Glu Ile Gln Lys Ile Val Asn His Arg Leu Lys Asn Lys Ile Val 325 330 335

    Gln Arg Ile Leu Gln Glu Gly Lys Leu Ala Ser Tyr Glu Ile Glu Ser 340 345 350

    Thr Val Asn Ser Asn Ser Leu Gln Lys Ile Lys Ile Glu Glu Ala Phe 355 360 365

    Ala Leu Lys Phe Ile Asn Ala Cys Leu Phe Ala Ser Asn Asn Leu Arg 370 375 380

    Asn Met Val Tyr Pro Val Cys Lys Lys Asp Ile Leu Met Ile Gly Glu 385 390 395 400

    Phe Lys Asn Ser Phe Lys Glu Ile Lys His Lys Lys Phe Ile Arg Gln 405 410 415

    Trp Ser Gln Phe Phe Ser Gln Glu Ile Thr Val Asp Asp Ile Glu Leu 420 425 430

    Ala Ser Trp Gly Leu Arg Gly Ala Ile Ala Pro Ile Arg Asn Glu Ile 435 440 445

    Ile His Leu Lys Lys His Ser Trp Lys Lys Phe Phe Asn Asn Pro Thr 450 455 460

    Phe Lys Val Lys Lys Ser Lys Ile Ile Asn Gly Lys Thr Lys Asp Val 465 470 475 480

    Thr Ser Glu Phe Leu Tyr Lys Glu Thr Leu Phe Lys Asp Tyr Phe Tyr 485 490 495

    Ser Glu Leu Asp Ser Val Pro Glu Leu Ile Ile Asn Lys Met Glu Ser 500 505 510

    Ser Lys Ile Leu Asp Tyr Tyr Ser Ser Asp Gln Leu Asn Gln Val Phe 515 520 525

    Thr Ile Pro Asn Phe Glu Leu Ser Leu Leu Thr Ser Ala Val Pro Phe 530 535 540

    Ala Pro Ser Phe Lys Arg Val Tyr Leu Lys Gly Phe Asp Tyr Gln Asn 545 550 555 560

    Gln Asp Glu Ala Gln Pro Asp Tyr Asn Leu Lys Leu Asn Ile Tyr Asn 565 570 575

    Glu Lys Ala Phe Asn Ser Glu Ala Phe Gln Ala Gln Tyr Ser Leu Phe 580 585 590

    Lys Met Val Tyr Tyr Gln Val Phe Leu Pro Gln Phe Thr Thr Asn Asn 595 600 605

    Asp Leu Phe Lys Ser Ser Val Asp Phe Ile Leu Thr Leu Asn Lys Glu 610 615 620

    Arg Lys Gly Tyr Ala Lys Ala Phe Gln Asp Ile Arg Lys Met Asn Lys

    625

    630

    635

    640

    Asp Glu Lys Pro Ser Glu Tyr Met Ser Tyr Ile Gln Ser Gln Leu Met 645 650 655

    Leu Tyr Gln Lys Lys Gln Glu Glu Lys Glu Lys Ile Asn His Phe Glu 660 665 670

    Lys Phe Ile Asn Gln Val Phe Ile Lys Gly Phe Asn Ser Phe Ile Glu 675 680 685

    Lys Asn Arg Leu Thr Tyr Ile Cys His Pro Thr Lys Asn Thr Val Pro 690 695 700

    Glu Asn Asp Asn Ile Glu Ile Pro Phe His Thr Asp Met Asp Asp Ser 705 710 715 720

    Asn Ile Ala Phe Trp Leu Met Cys Lys Leu Leu Asp Ala Lys Gln Leu 725 730 735

    Ser Glu Leu Arg Asn Glu Met Ile Lys Phe Ser Cys Ser Leu Gln Ser 740 745 750

    Thr Glu Glu Ile Ser Thr Phe Thr Lys Ala Arg Glu Val Ile Gly Leu 755 760 765

    Ala Leu Leu Asn Gly Glu Lys Gly Cys Asn Asp Trp Lys Glu Leu Phe 770 775 780

    Asp Asp Lys Glu Ala Trp Lys Lys Asn Met Ser Leu Tyr Val Ser Glu 785 790 795 800

    Glu Leu Leu Gln Ser Leu Pro Tyr Thr Gln Glu Asp Gly Gln Thr Pro 805 810 815

    Val Ile Asn Arg Ser Ile Asp Leu Val Lys Lys Tyr Gly Thr Glu Thr 820 825 830

    Ile Leu Glu Lys Leu Phe Ser Ser Ser Asp Asp Tyr Lys Val Ser Ala 835 840 845

    Lys Asp Ile Ala Lys Leu His Glu Tyr Asp Val Thr Glu Lys Ile Ala 850 855 860

    Gln Gln Glu Ser Leu His Lys Gln Trp Ile Glu Lys Pro Gly Leu Ala 865 870 875 880

    Arg Asp Ser Ala Trp Thr Lys Lys Tyr Gln Asn Val Ile Asn Asp Ile 885 890 895

    Ser Asn Tyr Gln Trp Ala Lys Thr Lys Val Glu Leu Thr Gln Val Arg 900 905 910

    His Leu His Gln Leu Thr Ile Asp Leu Leu Ser Arg Leu Ala Gly Tyr 915 920 925

    Met Ser Ile Ala Asp Arg Asp Phe Gln Phe Ser Ser Asn Tyr Ile Leu 930 935 940

    Glu Arg Glu Asn Ser Glu Tyr Arg Val Thr Ser Trp Ile Leu Leu Ser 945 950 955 960

    Glu Asn Lys Asn Lys Asn Lys Tyr Asn Asp Tyr Glu Leu Tyr Asn Leu 965 970 975

    Lys Asn Ala Ser Ile Lys Val Ser Ser Lys Asn Asp Pro Gln Leu Lys 980 985 990

    Val Asp Leu Lys Gln Leu Arg Leu Thr Leu Glu Tyr Leu Glu Leu Phe 995 1000 1005

    Asp Asn Arg Leu Lys Glu Lys Arg Asn Asn Ile Ser His Phe Asn 1010 1015 1020

    Tyr Leu Asn Gly Gln Leu Gly Asn Ser Ile Leu Glu Leu Phe Asp 1025 1030 1035

    Asp Ala Arg Asp Val Leu Ser Tyr Asp Arg Lys Leu Lys Asn Ala 1040 1045 1050

    Val Ser Lys Ser Leu Lys Glu Ile Leu Ser Ser His Gly Met Glu 1055 1060 1065

    Val Thr Phe Lys Pro Leu Tyr Gln Thr Asn His His Leu Lys Ile 1070 1075 1080

    Asp Lys Leu Gln Pro Lys Lys Ile His His Leu Gly Glu Lys Ser 1085 1090 1095

    Thr Val Ser Ser Asn Gln Val Ser Asn Glu Tyr Cys Gln Leu Val 1100 1105 1110

    Arg Thr Leu Leu Thr Met Lys 1115 1120 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <210> 42 <211> 36 <212> RNA <213> Artificial Sequence <400> 42 guuuuagucc ccuucguuuu ugggguaguc uaaauc <210> 43 <211> 113 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 43 gauuuagagc accccaaaag uaaugaaaau uugcaauuaa auaaggaaua uuaaaaaaau 60 gugauuuuaa aaaaauugaa gaaauuaaau gaaaaauugu ccaaguaaaa aaa 113 <210> 44 <211> 70 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 44 auuuagauua ccccuuuaau uuauuuuacc auauuuuucu cauaaugcaa acuaauauuc 60 caaaauuuuu 70 <210> 45 <211> 1389 <212> PRT <213> Leptotrichia wadei <400> 45

    Met Gly Asn Leu Phe Gly His Lys Arg Trp Tyr Glu Val Arg Asp Lys

    1 5 10 15

    Lys Asp Phe Lys Ile Lys Arg Lys Val Lys Val Lys Arg Asn Tyr Asp 20 25 30

    Gly Asn Lys Tyr Ile Leu Asn Ile Asn Glu Asn Asn Asn Lys Glu Lys 35 40 45

    Ile Asp Asn Asn Lys Phe Ile Arg Lys Tyr Ile Asn Tyr Lys Lys Asn 50 55 60

    Asp Asn Ile Leu Lys Glu Phe Thr Arg Lys Phe His Ala Gly Asn Ile 65 70 75 80

    Leu Phe Lys Leu Lys Gly Lys Glu Gly Ile Ile Arg Ile Glu Asn Asn 85 90 95

    Asp Asp Phe Leu Glu Thr Glu Glu Val Val Leu Tyr Ile Glu Ala Tyr 100 105 110

    Gly Lys Ser Glu Lys Leu Lys Ala Leu Gly Ile Thr Lys Lys Lys Ile 115 120 125

    Ile Asp Glu Ala Ile Arg Gln Gly Ile Thr Lys Asp Asp Lys Lys Ile 130 135 140

    Glu Ile Lys Arg Gln Glu Asn Glu Glu Glu Ile Glu Ile Asp Ile Arg 145 150 155 160

    Asp Glu Tyr Thr Asn Lys Thr Leu Asn Asp Cys Ser Ile Ile Leu Arg 165 170 175

    Ile Ile Glu Asn Asp Glu Leu Glu Thr Lys Lys Ser Ile Tyr Glu Ile 180 185 190

    Phe Lys Asn Ile Asn Met Ser Leu Tyr Lys Ile Ile Glu Lys Ile Ile

    195

    200

    205

    Glu Asn Glu Thr Glu Lys Val Phe Glu Asn Arg Tyr Tyr Glu Glu His 210 215 220

    Leu Arg Glu Lys Leu Leu Lys Asp Asp Lys Ile Asp Val Ile Leu Thr 225 230 235 240

    Asn Phe Met Glu Ile Arg Glu Lys Ile Lys Ser Asn Leu Glu Ile Leu 245 250 255

    Gly Phe Val Lys Phe Tyr Leu Asn Val Gly Gly Asp Lys Lys Lys Ser 260 265 270

    Lys Asn Lys Lys Met Leu Val Glu Lys Ile Leu Asn Ile Asn Val Asp 275 280 285

    Leu Thr Val Glu Asp Ile Ala Asp Phe Val Ile Lys Glu Leu Glu Phe 290 295 300

    Trp Asn Ile Thr Lys Arg Ile Glu Lys Val Lys Lys Val Asn Asn Glu 305 310 315 320

    Phe Leu Glu Lys Arg Arg Asn Arg Thr Tyr Ile Lys Ser Tyr Val Leu 325 330 335

    Leu Asp Lys His Glu Lys Phe Lys Ile Glu Arg Glu Asn Lys Lys Asp 340 345 350

    Lys Ile Val Lys Phe Phe Val Glu Asn Ile Lys Asn Asn Ser Ile Lys 355 360 365

    Glu Lys Ile Glu Lys Ile Leu Ala Glu Phe Lys Ile Asp Glu Leu Ile 370 375 380

    Lys Lys Leu Glu Lys Glu Leu Lys Lys Gly Asn Cys Asp Thr Glu Ile 385 390 395 400

    Phe Gly Ile Phe Lys Lys His Tyr Lys Val Asn Phe Asp Ser Lys Lys 405 410 415

    Phe Ser Lys Lys Ser Asp Glu Glu Lys Glu Leu Tyr Lys Ile Ile Tyr 420 425 430

    Arg Tyr Leu Lys Gly Arg Ile Glu Lys Ile Leu Val Asn Glu Gln Lys 435 440 445

    Val Arg Leu Lys Lys Met Glu Lys Ile Glu Ile Glu Lys Ile Leu Asn 450 455 460

    Glu Ser Ile Leu Ser Glu Lys Ile Leu Lys Arg Val Lys Gln Tyr Thr 465 470 475 480

    Leu Glu His Ile Met Tyr Leu Gly Lys Leu Arg His Asn Asp Ile Asp 485 490 495

    Met Thr Thr Val Asn Thr Asp Asp Phe Ser Arg Leu His Ala Lys Glu 500 505 510

    Glu Leu Asp Leu Glu Leu Ile Thr Phe Phe Ala Ser Thr Asn Met Glu 515 520 525

    Leu Asn Lys Ile Phe Ser Arg Glu Asn Ile Asn Asn Asp Glu Asn Ile 530 535 540

    Asp Phe Phe Gly Gly Asp Arg Glu Lys Asn Tyr Val Leu Asp Lys Lys 545 550 555 560

    Ile Leu Asn Ser Lys Ile Lys Ile Ile Arg Asp Leu Asp Phe Ile Asp 565 570 575

    Asn Lys Asn Asn Ile Thr Asn Asn Phe Ile Arg Lys Phe Thr Lys Ile 580 585 590

    Gly Thr Asn Glu Arg Asn Arg Ile Leu His Ala Ile Ser Lys Glu Arg 595 600 605

    Asp Leu Gln Gly Thr Gln Asp Asp Tyr Asn Lys Val Ile Asn Ile Ile 610 615 620

    Gln Asn Leu Lys Ile Ser Asp Glu Glu Val Ser Lys Ala Leu Asn Leu 625 630 635 640

    Asp Val Val Phe Lys Asp Lys Lys Asn Ile Ile Thr Lys Ile Asn Asp 645 650 655

    Ile Lys Ile Ser Glu Glu Asn Asn Asn Asp Ile Lys Tyr Leu Pro Ser 660 665 670

    Phe Ser Lys Val Leu Pro Glu Ile Leu Asn Leu Tyr Arg Asn Asn Pro 675 680 685

    Lys Asn Glu Pro Phe Asp Thr Ile Glu Thr Glu Lys Ile Val Leu Asn 690 695 700

    Ala Leu Ile Tyr Val Asn Lys Glu Leu Tyr Lys Lys Leu Ile Leu Glu 705 710 715 720

    Asp Asp Leu Glu Glu Asn Glu Ser Lys Asn Ile Phe Leu Gln Glu Leu 725 730 735

    Lys Lys Thr Leu Gly Asn Ile Asp Glu Ile Asp Glu Asn Ile Ile Glu 740 745 750

    Asn Tyr Tyr Lys Asn Ala Gln Ile Ser Ala Ser Lys Gly Asn Asn Lys 755 760 765

    Ala Ile Lys Lys Tyr Gln Lys Lys Val Ile Glu Cys Tyr Ile Gly Tyr 770 775 780

    Leu Arg Lys Asn Tyr Glu Glu Leu Phe Asp Phe Ser Asp Phe Lys Met 785 790 795 800

    Asn Ile Gln Glu Ile Lys Lys Gln Ile Lys Asp Ile Asn Asp Asn Lys 805 810 815

    Thr Tyr Glu Arg Ile Thr Val Lys Thr Ser Asp Lys Thr Ile Val Ile 820 825 830

    Asn Asp Asp Phe Glu Tyr Ile Ile Ser Ile Phe Ala Leu Leu Asn Ser 835 840 845

    Asn Ala Val Ile Asn Lys Ile Arg Asn Arg Phe Phe Ala Thr Ser Val 850 855 860

    Trp Leu Asn Thr Ser Glu Tyr Gln Asn Ile Ile Asp Ile Leu Asp Glu 865 870 875 880

    Ile Met Gln Leu Asn Thr Leu Arg Asn Glu Cys Ile Thr Glu Asn Trp 885 890 895

    Asn Leu Asn Leu Glu Glu Phe Ile Gln Lys Met Lys Glu Ile Glu Lys 900 905 910

    Asp Phe Asp Asp Phe Lys Ile Gln Thr Lys Lys Glu Ile Phe Asn Asn

    915

    920

    925

    Tyr Tyr Glu Asp Ile Lys Asn Asn Ile Leu Thr Glu Phe Lys Asp Asp 930 935 940

    Ile Asn Gly Cys Asp Val Leu Glu Lys Lys Leu Glu Lys Ile Val Ile 945 950 955 960

    Phe Asp Asp Glu Thr Lys Phe Glu Ile Asp Lys Lys Ser Asn Ile Leu 965 970 975

    Gln Asp Glu Gln Arg Lys Leu Ser Asn Ile Asn Lys Lys Asp Leu Lys 980 985 990

    Lys Lys Val Asp Gln Tyr Ile Lys Asp Lys Asp Gln Glu Ile Lys Ser 995 1000 1005

    Lys Ile Leu Cys Arg Ile Ile Phe Asn Ser Asp Phe Leu Lys Lys 1010 1015 1020

    Tyr Lys Lys Glu Ile Asp Asn Leu Ile Glu Asp Met Glu Ser Glu 1025 1030 1035

    Asn Glu Asn Lys Phe Gln Glu Ile Tyr Tyr Pro Lys Glu Arg Lys 1040 1045 1050

    Asn Glu Leu Tyr Ile Tyr Lys Lys Asn Leu Phe Leu Asn Ile Gly 1055 1060 1065

    Asn Pro Asn Phe Asp Lys Ile Tyr Gly Leu Ile Ser Asn Asp Ile 1070 1075 1080

    Lys Met Ala Asp Ala Lys Phe Leu Phe Asn Ile Asp Gly Lys Asn 1085 1090 1095

    Ile Arg Lys Asn Lys Ile Ser Glu Ile Asp Ala Ile Leu Lys Asn 1100 1105 1110

    Leu Asn Asp Lys Leu Asn Gly Tyr Ser Lys Glu Tyr Lys Glu Lys 1115 1120 1125

    Tyr Ile Lys Lys Leu Lys Glu Asn Asp Asp Phe Phe Ala Lys Asn 1130 1135 1140

    Ile Gln Asn Lys Asn Tyr Lys Ser Phe Glu Lys Asp Tyr Asn Arg 1145 1150 1155

    Val Ser Glu Tyr Lys Lys Ile Arg Asp Leu Val Glu Phe Asn Tyr 1160 1165 1170

    Leu Asn Lys Ile Glu Ser Tyr Leu Ile Asp Ile Asn Trp Lys Leu 1175 1180 1185

    Ala Ile Gln Met Ala Arg Phe Glu Arg Asp Met His Tyr Ile Val 1190 1195 1200

    Asn Gly Leu Arg Glu Leu Gly Ile Ile Lys Leu Ser Gly Tyr Asn 1205 1210 1215

    Thr Gly Ile Ser Arg Ala Tyr Pro Lys Arg Asn Gly Ser Asp Gly 1220 1225 1230

    Phe Tyr Thr Thr Thr Ala Tyr Tyr Lys Phe Phe Asp Glu Glu Ser 1235 1240 1245

    Tyr Lys Lys Phe Glu Lys Ile Cys Tyr Gly Phe Gly Ile Asp Leu 1250 1255 1260

    Ser Glu Asn Ser Glu Ile Asn Lys Pro Glu Asn Glu Ser Ile Arg 1265 1270 1275

    Asn Tyr Ile Ser His Phe Tyr Ile Val Arg Asn Pro Phe Ala Asp 1280 1285 1290

    Tyr Ser Ile Ala Glu Gln Ile Asp Arg Val Ser Asn Leu Leu Ser 1295 1300 1305

    Tyr Ser Thr Arg Tyr Asn Asn Ser Thr Tyr Ala Ser Val Phe Glu 1310 1315 1320

    Val Phe Lys Lys Asp Val Asn Leu Asp Tyr Asp Glu Leu Lys Lys 1325 1330 1335

    Lys Phe Lys Leu Ile Gly Asn Asn Asp Ile Leu Glu Arg Leu Met 1340 1345 1350

    Lys Pro Lys Lys Val Ser Val Leu Glu Leu Glu Ser Tyr Asn Ser 1355 1360 1365

    Asp Tyr Ile Lys Asn Leu Ile Ile Glu Leu Leu Thr Lys Ile Glu 1370 1375 1380

    Asn Thr Asn Asp Thr Leu 1385 <210> 46 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 46 guuuuagucc ccuucgauau uggggugguc uauauc <210> 47 <211> 95 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 47 auugaugugg uauacuaaaa auggaaaauu guauuuuuga uuagaaagau guaaaauuga uuuaauuuaa aaauauuuua uuagauuaaa guaga 95 <210> 48 <211> 1300 <212> PRT <213> Leptotrichia shahii <400> 48

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu

    50 55 60

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala

    435

    440

    445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp

    1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn

    1295 1300 <210> 49 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 49 gucuaagaac uuuaaauaau uucuacuguu guagau 36 <210> 50 <211> 71 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 50 aucuacaaaa uuauaaacua aauaaagauu cuuauaauaa cuuuauauau aaucgaaaug uagagaauuu u 71 <210> 51 <211> 1300 <212> PRT <213> Francisella ularensis <400> 51

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr

    770

    775

    780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn

    1295 1300 <210> 52 <211> 138 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 52 aaaaggccgg cggccacgaa aaaggccggc caggcaaaaa agaaaaaggg atcctaccca tacgatgttc cagattacgc ttatccctac gacgtgcctg attatgcata cccatatgat 120 gtccccgact atgcctaa 138 <210> 53 <211> 1388 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 53

    Met Ser Leu Asn Arg Ile Tyr Gln Gly Arg Val Ala Ala Val Glu Thr 1 5 10 15

    Gly Thr Ala Leu Ala Lys Gly Asn Val Glu Trp Met Pro Ala Ala Gly 20 25 30

    Gly Asp Glu Val Leu Trp Gln His His Glu Leu Phe Gln Ala Ala Ile 35 40 45

    Asn Tyr Tyr Leu Val Ala Leu Leu Ala Leu Ala Asp Lys Asn Asn Pro 50 55 60

    Val Leu Gly Pro Leu Ile Ser Gln Met Asp Asn Pro Gln Ser Pro Tyr 65 70 75 80

    His Val Trp Gly Ser Phe Arg Arg Gln Gly Arg Gln Arg Thr Gly Leu 85 90 95

    Ser Gln Ala Val Ala Pro Tyr Ile Thr Pro Gly Asn Asn Ala Pro Thr 100 105 110

    Leu Asp Glu Val Phe Arg Ser Ile Leu Ala Gly Asn Pro Thr Asp Arg 115 120 125

    Ala Thr Leu Asp Ala Ala Leu Met Gln Leu Leu Lys Ala Cys Asp Gly 130 135 140

    Ala Gly Ala Ile Gln Gln Glu Gly Arg Ser Tyr Trp Pro Lys Phe Cys 145 150 155 160

    Asp Pro Asp Ser Thr Ala Asn Phe Ala Gly Asp Pro Ala Met Leu Arg 165 170 175

    Arg Glu Gln His Arg Leu Leu Leu Pro Gln Val Leu His Asp Pro Ala 180 185 190

    Ile Thr His Asp Ser Pro Ala Leu Gly Ser Phe Asp Thr Tyr Ser Ile 195 200 205

    Ala Thr Pro Asp Thr Arg Thr Pro Gln Leu Thr Gly Pro Lys Ala Arg 210 215 220

    Ala Arg Leu Glu Gln Ala Ile Thr Leu Trp Arg Val Arg Leu Pro Glu 225 230 235 240

    Ser Ala Ala Asp Phe Asp Arg Leu Ala Ser Ser Leu Lys Lys Ile Pro 245 250 255

    Asp Asp Asp Ser Arg Leu Asn Leu Gln Gly Tyr Val Gly Ser Ser Ala 260 265 270

    Lys Gly Glu Val Gln Ala Arg Leu Phe Ala Leu Leu Leu Phe Arg His 275 280 285

    Leu Glu Arg Ser Ser Phe Thr Leu Gly Leu Leu Arg Ser Ala Thr Pro 290 295 300

    Pro Pro Lys Asn Ala Glu Thr Pro Pro Pro Ala Gly Val Pro Leu Pro 305 310 315 320

    Ala Ala Ser Ala Ala Asp Pro Val Arg Ile Ala Arg Gly Lys Arg Ser 325 330 335

    Phe Val Phe Arg Ala Phe Thr Ser Leu Pro Cys Trp His Gly Gly Asp 340 345 350

    Asn Ile His Pro Thr Trp Lys Ser Phe Asp Ile Ala Ala Phe Lys Tyr 355 360 365

    Ala Leu Thr Val Ile Asn Gln Ile Glu Glu Lys Thr Lys Glu Arg Gln 370 375 380

    Lys Glu Cys Ala Glu Leu Glu Thr Asp Phe Asp Tyr Met His Gly Arg 385 390 395 400

    Leu Ala Lys Ile Pro Val Lys Tyr Thr Thr Gly Glu Ala Glu Pro Pro 405 410 415

    Pro Ile Leu Ala Asn Asp Leu Arg Ile Pro Leu Leu Arg Glu Leu Leu 420 425 430

    Gln Asn Ile Lys Val Asp Thr Ala Leu Thr Asp Gly Glu Ala Val Ser 435 440 445

    Tyr Gly Leu Gln Arg Arg Thr Ile Arg Gly Phe Arg Glu Leu Arg Arg 450 455 460

    Ile Trp Arg Gly His Ala Pro Ala Gly Thr Val Phe Ser Ser Glu Leu 465 470 475 480

    Lys Glu Lys Leu Ala Gly Glu Leu Arg Gln Phe Gln Thr Asp Asn Ser 485 490 495

    Thr Thr Ile Gly Ser Val Gln Leu Phe Asn Glu Leu Ile Gln Asn Pro 500 505 510

    Lys Tyr Trp Pro Ile Trp Gln Ala Pro Asp Val Glu Thr Ala Arg Gln 515 520 525

    Trp Ala Asp Ala Gly Phe Ala Asp Asp Pro Leu Ala Ala Leu Val Gln 530 535 540

    Glu Ala Glu Leu Gln Glu Asp Ile Asp Ala Leu Lys Ala Pro Val Lys 545 550 555 560

    Leu Thr Pro Ala Asp Pro Glu Tyr Ser Arg Arg Gln Tyr Asp Phe Asn 565 570 575

    Ala Val Ser Lys Phe Gly Ala Gly Ser Arg Ser Ala Asn Arg His Glu 580 585 590

    Pro Gly Gln Thr Glu Arg Gly His Asn Thr Phe Thr Thr Glu Ile Ala

    595

    600

    605

    Ala Arg Asn Ala Ala Asp Gly Asn Arg Trp Arg Ala Thr His Val Arg 610 615 620

    Ile His Tyr Ser Ala Pro Arg Leu Leu Arg Asp Gly Leu Arg Arg Pro 625 630 635 640

    Asp Thr Asp Gly Asn Glu Ala Leu Glu Ala Val Pro Trp Leu Gln Pro 645 650 655

    Met Met Glu Ala Leu Ala Pro Leu Pro Thr Leu Pro Gln Asp Leu Thr 660 665 670

    Gly Met Pro Val Phe Leu Met Pro Asp Val Thr Leu Ser Gly Glu Arg 675 680 685

    Arg Ile Leu Leu Asn Leu Pro Val Thr Leu Glu Pro Ala Ala Leu Val 690 695 700

    Glu Gln Leu Gly Asn Ala Gly Arg Trp Gln Asn Gln Phe Phe Gly Ser 705 710 715 720

    Arg Glu Asp Pro Phe Ala Leu Arg Trp Pro Ala Asp Gly Ala Val Lys 725 730 735

    Thr Ala Lys Gly Lys Thr His Ile Pro Trp His Gln Asp Arg Asp His 740 745 750

    Phe Thr Val Leu Gly Val Asp Leu Gly Thr Arg Asp Ala Gly Ala Leu 755 760 765

    Ala Leu Leu Asn Val Thr Ala Gln Lys Pro Ala Lys Pro Val His Arg 770 775 780

    Ile Ile Gly Glu Ala Asp Gly Arg Thr Trp Tyr Ala Ser Leu Ala Asp 785 790 795 800

    Ala Arg Met Ile Arg Leu Pro Gly Glu Asp Ala Arg Leu Phe Val Arg 805 810 815

    Gly Lys Leu Val Gln Glu Pro Tyr Gly Glu Arg Gly Arg Asn Ala Ser 820 825 830

    Leu Leu Glu Trp Glu Asp Ala Arg Asn Ile Ile Leu Arg Leu Gly Gln 835 840 845

    Asn Pro Asp Glu Leu Leu Gly Ala Asp Pro Arg Arg His Ser Tyr Pro 850 855 860

    Glu Ile Asn Asp Lys Leu Leu Val Ala Leu Arg Arg Ala Gln Ala Arg 865 870 875 880

    Leu Ala Arg Leu Gln Asn Arg Ser Trp Arg Leu Arg Asp Leu Ala Glu 885 890 895

    Ser Asp Lys Ala Leu Asp Glu Ile His Ala Glu Arg Ala Gly Glu Lys 900 905 910

    Pro Ser Pro Leu Pro Pro Leu Ala Arg Asp Asp Ala Ile Lys Ser Thr 915 920 925

    Asp Glu Ala Leu Leu Ser Gln Arg Asp Ile Ile Arg Arg Ser Phe Val 930 935 940

    Gln Ile Ala Asn Leu Ile Leu Pro Leu Arg Gly Arg Arg Trp Glu Trp 945 950 955 960

    Arg Pro His Val Glu Val Pro Asp Cys His Ile Leu Ala Gln Ser Asp 965 970 975

    Pro Gly Thr Asp Asp Thr Lys Arg Leu Val Ala Gly Gln Arg Gly Ile 980 985 990

    Ser His Glu Arg Ile Glu Gln Ile Glu Glu Leu Arg Arg Arg Cys Gln 995 1000 1005

    Ser Leu Asn Arg Ala Leu Arg His Lys Pro Gly Glu Arg Pro Val 1010 1015 1020

    Leu Gly Arg Pro Ala Lys Gly Glu Glu Ile Ala Asp Pro Cys Pro 1025 1030 1035

    Ala Leu Leu Glu Lys Ile Asn Arg Leu Arg Asp Gln Arg Val Asp 1040 1045 1050

    Gln Thr Ala His Ala Ile Leu Ala Ala Ala Leu Gly Val Arg Leu 1055 1060 1065

    Arg Ala Pro Ser Lys Asp Arg Ala Glu Arg Arg His Arg Asp Ile 1070 1075 1080

    His Gly Glu Tyr Glu Arg Phe Arg Ala Pro Ala Asp Phe Val Val 1085 1090 1095

    Ile Glu Asn Leu Ser Arg Tyr Leu Ser Ser Gln Asp Arg Ala Arg 1100 1105 1110

    Ser Glu Asn Thr Arg Leu Met Gln Trp Cys His Arg Gln Ile Val 1115 1120 1125

    Gln Lys Leu Arg Gln Leu Cys Glu Thr Tyr Gly Ile Pro Val Leu

    1130 1135 1140 Ala Val Pro Ala Ala Tyr Ser Ser Arg Phe Ser Ser Arg Asp Gly 1145 1150 1155 Ser Ala Gly Phe Arg Ala Val His Leu Thr Pro Asp His Arg His 1160 1165 1170 Arg Met Pro Trp Ser Arg Ile Leu Ala Arg Leu Lys Ala His Glu 1175 1180 1185 Glu Asp Gly Lys Arg Leu Glu Lys Thr Val Leu Asp Glu Ala Arg 1190 1195 1200 Ala Val Arg Gly Leu Phe Asp Arg Leu Asp Arg Phe Asn Ala Gly 1205 1210 1215 His Val Pro Gly Lys Pro Trp Arg Thr Leu Leu Ala Pro Leu Pro 1220 1225 1230 Gly Gly Pro Val Phe Val Pro Leu Gly Asp Ala Thr Pro Met Gln 1235 1240 1245 Ala Asp Leu Asn Ala Ala Ile Asn Ile Ala Leu Arg Gly Ile Ala 1250 1255 1260 Ala Pro Asp Arg His Asp Ile His His Arg Leu Arg Ala Glu Asn 1265 1270 1275

    Lys Lys Arg Ile Leu Ser Leu Arg Leu Gly Thr Gln Arg Glu Lys 1280 1285 1290

    Ala Arg Trp Pro Gly Gly Ala Pro Ala Val Thr Leu Ser Thr Pro

    1295

    1300

    1305

    Asn Asn Gly Ala Ser Pro Glu Asp Ser Asp Ala Leu Pro Glu Arg 1310 1315 1320

    Val Ser Asn Leu Phe Val Asp Ile Ala Gly Val Ala Asn Phe Glu 1325 1330 1335

    Arg Val Thr Ile Glu Gly Val Ser Gln Lys Phe Ala Thr Gly Arg 1340 1345 1350

    Gly Leu Trp Ala Ser Val Lys Gln Arg Ala Trp Asn Arg Val Ala 1355 1360 1365

    Arg Leu Asn Glu Thr Val Thr Asp Asn Asn Arg Asn Glu Glu Glu 1370 1375 1380

    Asp Asp Ile Pro Met 1385 <210> 54 <211> 1108 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 54

    Met Ala Thr Arg Ser Phe Ile Leu Lys Ile Glu Pro Asn Glu Glu Val 1 5 10 15

    Lys Lys Gly Leu Trp Lys Thr His Glu Val Leu Asn His Gly Ile Ala 20 25 30

    Tyr Tyr Met Asn Ile Leu Lys Leu Ile Arg Gln Glu Ala Ile Tyr Glu 35 40 45

    His His Glu Gln Asp Pro Lys Asn Pro Lys Lys Val Ser Lys Ala Glu 50 55 60

    Ile Gln Ala Glu Leu Trp Asp Phe Val Leu Lys Met Gln Lys Cys Asn 65 70 75 80

    Ser Phe Thr His Glu Val Asp Lys Asp Val Val Phe Asn Ile Leu Arg 85 90 95

    Glu Leu Tyr Glu Glu Leu Val Pro Ser Ser Val Glu Lys Lys Gly Glu 100 105 110

    Ala Asn Gln Leu Ser Asn Lys Phe Leu Tyr Pro Leu Val Asp Pro Asn 115 120 125

    Ser Gln Ser Gly Lys Gly Thr Ala Ser Ser Gly Arg Lys Pro Arg Trp 130 135 140

    Tyr Asn Leu Lys Ile Ala Gly Asp Pro Ser Trp Glu Glu Glu Lys Lys 145 150 155 160

    Lys Trp Glu Glu Asp Lys Lys Lys Asp Pro Leu Ala Lys Ile Leu Gly 165 170 175

    Lys Leu Ala Glu Tyr Gly Leu Ile Pro Leu Phe Ile Pro Phe Thr Asp 180 185 190

    Ser Asn Glu Pro Ile Val Lys Glu Ile Lys Trp Met Glu Lys Ser Arg 195 200 205

    Asn Gln Ser Val Arg Arg Leu Asp Lys Asp Met Phe Ile Gln Ala Leu

    210

    215

    220

    Glu Arg Phe Leu Ser Trp Glu Ser Trp Asn Leu Lys Val Lys Glu Glu 225 230 235 240

    Tyr Glu Lys Val Glu Lys Glu His Lys Thr Leu Glu Glu Arg Ile Lys 245 250 255

    Glu Asp Ile Gln Ala Phe Lys Ser Leu Glu Gln Tyr Glu Lys Glu Arg 260 265 270

    Gln Glu Gln Leu Leu Arg Asp Thr Leu Asn Thr Asn Glu Tyr Arg Leu 275 280 285

    Ser Lys Arg Gly Leu Arg Gly Trp Arg Glu Ile Ile Gln Lys Trp Leu 290 295 300

    Lys Met Asp Glu Asn Glu Pro Ser Glu Lys Tyr Leu Glu Val Phe Lys 305 310 315 320

    Asp Tyr Gln Arg Lys His Pro Arg Glu Ala Gly Asp Tyr Ser Val Tyr 325 330 335

    Glu Phe Leu Ser Lys Lys Glu Asn His Phe Ile Trp Arg Asn His Pro 340 345 350

    Glu Tyr Pro Tyr Leu Tyr Ala Thr Phe Cys Glu Ile Asp Lys Lys Lys 355 360 365

    Lys Asp Ala Lys Gln Gln Ala Thr Phe Thr Leu Ala Asp Pro Ile Asn 370 375 380

    His Pro Leu Trp Val Arg Phe Glu Glu Arg Ser Gly Ser Asn Leu Asn 385 390 395 400

    Lys Tyr Arg Ile Leu Thr Glu Gln Leu His Thr Glu Lys Leu Lys Lys 405 410 415

    Lys Leu Thr Val Gln Leu Asp Arg Leu Ile Tyr Pro Thr Glu Ser Gly 420 425 430

    Gly Trp Glu Glu Lys Gly Lys Val Asp Ile Val Leu Leu Pro Ser Arg 435 440 445

    Gln Phe Tyr Asn Gln Ile Phe Leu Asp Ile Glu Glu Lys Gly Lys His 450 455 460

    Ala Phe Thr Tyr Lys Asp Glu Ser Ile Lys Phe Pro Leu Lys Gly Thr 465 470 475 480

    Leu Gly Gly Ala Arg Val Gln Phe Asp Arg Asp His Leu Arg Arg Tyr 485 490 495

    Pro His Lys Val Glu Ser Gly Asn Val Gly Arg Ile Tyr Phe Asn Met 500 505 510

    Thr Val Asn Ile Glu Pro Thr Glu Ser Pro Val Ser Lys Ser Leu Lys 515 520 525

    Ile His Arg Asp Asp Phe Pro Lys Phe Val Asn Phe Lys Pro Lys Glu 530 535 540

    Leu Thr Glu Trp Ile Lys Asp Ser Lys Gly Lys Lys Leu Lys Ser Gly 545 550 555 560

    Ile Glu Ser Leu Glu Ile Gly Leu Arg Val Met Ser Ile Asp Leu Gly 565 570 575

    Gln Arg Gln Ala Ala Ala Ala Ser Ile Phe Glu Val Val Asp Gln Lys 580 585 590

    Pro Asp Ile Glu Gly Lys Leu Phe Phe Pro Ile Lys Gly Thr Glu Leu 595 600 605

    Tyr Ala Val His Arg Ala Ser Phe Asn Ile Lys Leu Pro Gly Glu Thr 610 615 620

    Leu Val Lys Ser Arg Glu Val Leu Arg Lys Ala Arg Glu Asp Asn Leu 625 630 635 640

    Lys Leu Met Asn Gln Lys Leu Asn Phe Leu Arg Asn Val Leu His Phe 645 650 655

    Gln Gln Phe Glu Asp Ile Thr Glu Arg Glu Lys Arg Val Thr Lys Trp 660 665 670

    Ile Ser Arg Gln Glu Asn Ser Asp Val Pro Leu Val Tyr Gln Asp Glu 675 680 685

    Leu Ile Gln Ile Arg Glu Leu Met Tyr Lys Pro Tyr Lys Asp Trp Val 690 695 700

    Ala Phe Leu Lys Gln Leu His Lys Arg Leu Glu Val Glu Ile Gly Lys 705 710 715 720

    Glu Val Lys His Trp Arg Lys Ser Leu Ser Asp Gly Arg Lys Gly Leu 725 730 735

    Tyr Gly Ile Ser Leu Lys Asn Ile Asp Glu Ile Asp Arg Thr Arg Lys 740 745 750

    Phe Leu Leu Arg Trp Ser Leu Arg Pro Thr Glu Pro Gly Glu Val Arg 755 760 765

    Arg Leu Glu Pro Gly Gln Arg Phe Ala Ile Asp Gln Leu Asn His Leu 770 775 780

    Asn Ala Leu Lys Glu Asp Arg Leu Lys Lys Met Ala Asn Thr Ile Ile 785 790 795 800

    Met His Ala Leu Gly Tyr Cys Tyr Asp Val Arg Lys Lys Lys Trp Gln 805 810 815

    Ala Lys Asn Pro Ala Cys Gln Ile Ile Leu Phe Glu Asp Leu Ser Asn 820 825 830

    Tyr Asn Pro Tyr Glu Glu Arg Ser Arg Phe Glu Asn Ser Lys Leu Met 835 840 845

    Lys Trp Ser Arg Arg Glu Ile Pro Arg Gln Val Ala Leu Gln Gly Glu 850 855 860

    Ile Tyr Gly Leu Gln Val Gly Glu Val Gly Ala Gln Phe Ser Ser Arg 865 870 875 880

    Phe His Ala Lys Thr Gly Ser Pro Gly Ile Arg Cys Ser Val Val Thr 885 890 895

    Lys Glu Lys Leu Gln Asp Asn Arg Phe Phe Lys Asn Leu Gln Arg Glu 900 905 910

    Gly Arg Leu Thr Leu Asp Lys Ile Ala Val Leu Lys Glu Gly Asp Leu 915 920 925

    Tyr Pro Asp Lys Gly Gly Glu Lys Phe Ile Ser Leu Ser Lys Asp Arg

    930

    935

    940

    Lys Leu Val Thr Thr His Ala Asp Ile Asn Ala Ala Gln Asn Leu Gln 945 950 955 960

    Lys Arg Phe Trp Thr Arg Thr His Gly Phe Tyr Lys Val Tyr Cys Lys 965 970 975

    Ala Tyr Gln Val Asp Gly Gln Thr Val Tyr Ile Pro Glu Ser Lys Asp 980 985 990

    Gln Lys Gln Lys Ile Ile Glu Glu Phe Gly Glu Gly Tyr Phe Ile Leu 995 1000 1005

    Lys Asp Gly Val Tyr Glu Trp Gly Asn Ala Gly Lys Leu Lys Ile 1010 1015 1020

    Lys Lys Gly Ser Ser Lys Gln Ser Ser Ser Glu Leu Val Asp Ser 1025 1030 1035

    Asp Ile Leu Lys Asp Ser Phe Asp Leu Ala Ser Glu Leu Lys Gly 1040 1045 1050

    Glu Lys Leu Met Leu Tyr Arg Asp Pro Ser Gly Asn Val Phe Pro 1055 1060 1065

    Ser Asp Lys Trp Met Ala Ala Gly Val Phe Phe Gly Lys Leu Glu 1070 1075 1080

    Arg Ile Leu Ile Ser Lys Leu Thr Asn Gln Tyr Ser Ile Ser Thr

    1085 1090 1095

    Ile Glu Asp Asp Ser Ser Lys Gln Ser Met

    1100 1105 <210> 55 <211> 1108 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 55

    Met Ala Ile Arg Ser Ile Lys Leu Lys Leu Lys Thr His Thr Gly Pro 1 5 10 15

    Glu Ala Gln Asn Leu Arg Lys Gly Ile Trp Arg Thr His Arg Leu Leu 20 25 30

    Asn Glu Gly Val Ala Tyr Tyr Met Lys Met Leu Leu Leu Phe Arg Gln 35 40 45

    Glu Ser Thr Gly Glu Arg Pro Lys Glu Glu Leu Gln Glu Glu Leu Ile 50 55 60

    Cys His Ile Arg Glu Gln Gln Gln Arg Asn Gln Ala Asp Lys Asn Thr 65 70 75 80

    Gln Ala Leu Pro Leu Asp Lys Ala Leu Glu Ala Leu Arg Gln Leu Tyr 85 90 95

    Glu Leu Leu Val Pro Ser Ser Val Gly Gln Ser Gly Asp Ala Gln Ile 100 105 110

    Ile Ser Arg Lys Phe Leu Ser Pro Leu Val Asp Pro Asn Ser Glu Gly 115 120 125

    Gly Lys Gly Thr Ser Lys Ala Gly Ala Lys Pro Thr Trp Gln Lys Lys

    130

    135

    140

    Lys Glu Ala Asn Asp Pro Thr Trp Glu Gln Asp Tyr Glu Lys Trp Lys 145 150 155 160

    Lys Arg Arg Glu Glu Asp Pro Thr Ala Ser Val Ile Thr Thr Leu Glu 165 170 175

    Glu Tyr Gly Ile Arg Pro Ile Phe Pro Leu Tyr Thr Asn Thr Val Thr 180 185 190

    Asp Ile Ala Trp Leu Pro Leu Gln Ser Asn Gln Phe Val Arg Thr Trp 195 200 205

    Asp Arg Asp Met Leu Gln Gln Ala Ile Glu Arg Leu Leu Ser Trp Glu 210 215 220

    Ser Trp Asn Lys Arg Val Gln Glu Glu Tyr Ala Lys Leu Lys Glu Lys 225 230 235 240

    Met Ala Gln Leu Asn Glu Gln Leu Glu Gly Gly Gln Glu Trp Ile Ser 245 250 255

    Leu Leu Glu Gln Tyr Glu Glu Asn Arg Glu Arg Glu Leu Arg Glu Asn 260 265 270

    Met Thr Ala Ala Asn Asp Lys Tyr Arg Ile Thr Lys Arg Gln Met Lys 275 280 285

    Gly Trp Asn Glu Leu Tyr Glu Leu Trp Ser Thr Phe Pro Ala Ser Ala 290 295 300

    Ser His Glu Gln Tyr Lys Glu Ala Leu Lys Arg Val Gln Gln Arg Leu 305 310 315 320

    Arg Gly Arg Phe Gly Asp Ala His Phe Phe Gln Tyr Leu Met Glu Glu 325 330 335

    Lys Asn Arg Leu Ile Trp Lys Gly Asn Pro Gln Arg Ile His Tyr Phe 340 345 350

    Val Ala Arg Asn Glu Leu Thr Lys Arg Leu Glu Glu Ala Lys Gln Ser 355 360 365

    Ala Thr Met Thr Leu Pro Asn Ala Arg Lys His Pro Leu Trp Val Arg 370 375 380

    Phe Asp Ala Arg Gly Gly Asn Leu Gln Asp Tyr Tyr Leu Thr Ala Glu 385 390 395 400

    Ala Asp Lys Pro Arg Ser Arg Arg Phe Val Thr Phe Ser Gln Leu Ile 405 410 415

    Trp Pro Ser Glu Ser Gly Trp Met Glu Lys Lys Asp Val Glu Val Glu 420 425 430

    Leu Ala Leu Ser Arg Gln Phe Tyr Gln Gln Val Lys Leu Leu Lys Asn 435 440 445

    Asp Lys Gly Lys Gln Lys Ile Glu Phe Lys Asp Lys Gly Ser Gly Ser 450 455 460

    Thr Phe Asn Gly His Leu Gly Gly Ala Lys Leu Gln Leu Glu Arg Gly 465 470 475 480

    Asp Leu Glu Lys Glu Glu Lys Asn Phe Glu Asp Gly Glu Ile Gly Ser 485 490 495

    Val Tyr Leu Asn Val Val Ile Asp Phe Glu Pro Leu Gln Glu Val Lys 500 505 510

    Asn Gly Arg Val Gln Ala Pro Tyr Gly Gln Val Leu Gln Leu Ile Arg 515 520 525

    Arg Pro Asn Glu Phe Pro Lys Val Thr Thr Tyr Lys Ser Glu Gln Leu 530 535 540

    Val Glu Trp Ile Lys Ala Ser Pro Gln His Ser Ala Gly Val Glu Ser 545 550 555 560

    Leu Ala Ser Gly Phe Arg Val Met Ser Ile Asp Leu Gly Leu Arg Ala 565 570 575

    Ala Ala Ala Thr Ser Ile Phe Ser Val Glu Glu Ser Ser Asp Lys Asn 580 585 590

    Ala Ala Asp Phe Ser Tyr Trp Ile Glu Gly Thr Pro Leu Val Ala Val 595 600 605

    His Gln Arg Ser Tyr Met Leu Arg Leu Pro Gly Glu Gln Val Glu Lys 610 615 620

    Gln Val Met Glu Lys Arg Asp Glu Arg Phe Gln Leu His Gln Arg Val 625 630 635 640

    Lys Phe Gln Ile Arg Val Leu Ala Gln Ile Met Arg Met Ala Asn Lys 645 650 655

    Gln Tyr Gly Asp Arg Trp Asp Glu Leu Asp Ser Leu Lys Gln Ala Val 660 665 670

    Glu Gln Lys Lys Ser Pro Leu Asp Gln Thr Asp Arg Thr Phe Trp Glu 675 680 685

    Gly Ile Val Cys Asp Leu Thr Lys Val Leu Pro Arg Asn Glu Ala Asp 690 695 700

    Trp Glu Gln Ala Val Val Gln Ile His Arg Lys Ala Glu Glu Tyr Val 705 710 715 720

    Gly Lys Ala Val Gln Ala Trp Arg Lys Arg Phe Ala Ala Asp Glu Arg 725 730 735

    Lys Gly Ile Ala Gly Leu Ser Met Trp Asn Ile Glu Glu Leu Glu Gly 740 745 750

    Leu Arg Lys Leu Leu Ile Ser Trp Ser Arg Arg Thr Arg Asn Pro Gln 755 760 765

    Glu Val Asn Arg Phe Glu Arg Gly His Thr Ser His Gln Arg Leu Leu 770 775 780

    Thr His Ile Gln Asn Val Lys Glu Asp Arg Leu Lys Gln Leu Ser His 785 790 795 800

    Ala Ile Val Met Thr Ala Leu Gly Tyr Val Tyr Asp Glu Arg Lys Gln 805 810 815

    Glu Trp Cys Ala Glu Tyr Pro Ala Cys Gln Val Ile Leu Phe Glu Asn 820 825 830

    Leu Ser Gln Tyr Arg Ser Asn Leu Asp Arg Ser Thr Lys Glu Asn Ser 835 840 845

    Thr Leu Met Lys Trp Ala His Arg Ser Ile Pro Lys Tyr Val His Met

    850

    855

    860

    Gln Ala Glu Pro Tyr Gly Ile Gln Ile Gly Asp Val Arg Ala Glu Tyr 865 870 875 880

    Ser Ser Arg Phe Tyr Ala Lys Thr Gly Thr Pro Gly Ile Arg Cys Lys 885 890 895

    Lys Val Arg Gly Gln Asp Leu Gln Gly Arg Arg Phe Glu Asn Leu Gln 900 905 910

    Lys Arg Leu Val Asn Glu Gln Phe Leu Thr Glu Glu Gln Val Lys Gln 915 920 925

    Leu Arg Pro Gly Asp Ile Val Pro Asp Asp Ser Gly Glu Leu Phe Met 930 935 940

    Thr Leu Thr Asp Gly Ser Gly Ser Lys Glu Val Val Phe Leu Gln Ala 945 950 955 960

    Asp Ile Asn Ala Ala His Asn Leu Gln Lys Arg Phe Trp Gln Arg Tyr 965 970 975

    Asn Glu Leu Phe Lys Val Ser Cys Arg Val Ile Val Arg Asp Glu Glu 980 985 990

    Glu Tyr Leu Val Pro Lys Thr Lys Ser Val Gln Ala Lys Leu Gly Lys 995 1000 1005

    Gly Leu Phe Val Lys Lys Ser Asp Thr Ala Trp Lys Asp Val Tyr 1010 1015 1020

    Val Trp Asp Ser Gln Ala Lys Leu Lys Gly Lys Thr Thr Phe Thr 1025 1030 1035

    Glu Glu Ser Glu Ser Pro Glu Gln Leu Glu Asp Phe Gln Glu Ile 1040 1045 1050

    Ile Glu Glu Ala Glu Glu Ala Lys Gly Thr Tyr Arg Thr Leu Phe 1055 1060 1065

    Arg Asp Pro Ser Gly Val Phe Phe Pro Glu Ser Val Trp Tyr Pro 1070 1075 1080

    Gln Lys Asp Phe Trp Gly Glu Val Lys Arg Lys Leu Tyr Gly Lys 1085 1090 1095

    Leu Arg Glu Arg Phe Leu Thr Lys Ala Arg 1100 1105 <210> 56 <211> 1334 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 56

    Met Lys Ile Ser Lys Val Asp His Thr Arg Met Ala Val Ala Lys Gly 1 5 10 15

    Asn Gln His Arg Arg Asp Glu Ile Ser Gly Ile Leu Tyr Lys Asp Pro 20 25 30

    Thr Lys Thr Gly Ser Ile Asp Phe Asp Glu Arg Phe Lys Lys Leu Asn 35 40 45

    Cys Ser Ala Lys Ile Leu Tyr His Val Phe Asn Gly Ile Ala Glu Gly

    Ser Asn Lys Tyr Lys Asn Ile Val Asp Lys Val Asn Asn Asn Leu Asp 65 70 75 80

    Arg Val Leu Phe Thr Gly Lys Ser Tyr Asp Arg Lys Ser Ile Ile Asp 85 90 95

    Ile Asp Thr Val Leu Arg Asn Val Glu Lys Ile Asn Ala Phe Asp Arg 100 105 110

    Ile Ser Thr Glu Glu Arg Glu Gln Ile Ile Asp Asp Leu Leu Glu Ile 115 120 125

    Gln Leu Arg Lys Gly Leu Arg Lys Gly Lys Ala Gly Leu Arg Glu Val 130 135 140

    Leu Leu Ile Gly Ala Gly Val Ile Val Arg Thr Asp Lys Lys Gln Glu 145 150 155 160

    Ile Ala Asp Phe Leu Glu Ile Leu Asp Glu Asp Phe Asn Lys Thr Asn 165 170 175

    Gln Ala Lys Asn Ile Lys Leu Ser Ile Glu Asn Gln Gly Leu Val Val 180 185 190

    Ser Pro Val Ser Arg Gly Glu Glu Arg Ile Phe Asp Val Ser Gly Ala 195 200 205

    Gln Lys Gly Lys Ser Ser Lys Lys Ala Gln Glu Lys Glu Ala Leu Ser 210 215 220

    Ala Phe Leu Leu Asp Tyr Ala Asp Leu Asp Lys Asn Val Arg Phe Glu 225 230 235 240

    Tyr Leu Arg Lys Ile Arg Arg Leu Ile Asn Leu Tyr Phe Tyr Val Lys 245 250 255

    Asn Asp Asp Val Met Ser Leu Thr Glu Ile Pro Ala Glu Val Asn Leu 260 265 270

    Glu Lys Asp Phe Asp Ile Trp Arg Asp His Glu Gln Arg Lys Glu Glu 275 280 285

    Asn Gly Asp Phe Val Gly Cys Pro Asp Ile Leu Leu Ala Asp Arg Asp 290 295 300

    Val Lys Lys Ser Asn Ser Lys Gln Val Lys Ile Ala Glu Arg Gln Leu 305 310 315 320

    Arg Glu Ser Ile Arg Glu Lys Asn Ile Lys Arg Tyr Arg Phe Ser Ile 325 330 335

    Lys Thr Ile Glu Lys Asp Asp Gly Thr Tyr Phe Phe Ala Asn Lys Gln 340 345 350

    Ile Ser Val Phe Trp Ile His Arg Ile Glu Asn Ala Val Glu Arg Ile 355 360 365

    Leu Gly Ser Ile Asn Asp Lys Lys Leu Tyr Arg Leu Arg Leu Gly Tyr 370 375 380

    Leu Gly Glu Lys Val Trp Lys Asp Ile Leu Asn Phe Leu Ser Ile Lys 385 390 395 400

    Tyr Ile Ala Val Gly Lys Ala Val Phe Asn Phe Ala Met Asp Asp Leu 405 410 415

    Gln Glu Lys Asp Arg Asp Ile Glu Pro Gly Lys Ile Ser Glu Asn Ala 420 425 430

    Val Asn Gly Leu Thr Ser Phe Asp Tyr Glu Gln Ile Lys Ala Asp Glu 435 440 445

    Met Leu Gln Arg Glu Val Ala Val Asn Val Ala Phe Ala Ala Asn Asn 450 455 460

    Leu Ala Arg Val Thr Val Asp Ile Pro Gln Asn Gly Glu Lys Glu Asp 465 470 475 480

    Ile Leu Leu Trp Asn Lys Ser Asp Ile Lys Lys Tyr Lys Lys Asn Ser 485 490 495

    Lys Lys Gly Ile Leu Lys Ser Ile Leu Gln Phe Phe Gly Gly Ala Ser 500 505 510

    Thr Trp Asn Met Lys Met Phe Glu Ile Ala Tyr His Asp Gln Pro Gly 515 520 525

    Asp Tyr Glu Glu Asn Tyr Leu Tyr Asp Ile Ile Gln Ile Ile Tyr Ser 530 535 540

    Leu Arg Asn Lys Ser Phe His Phe Lys Thr Tyr Asp His Gly Asp Lys 545 550 555 560

    Asn Trp Asn Arg Glu Leu Ile Gly Lys Met Ile Glu His Asp Ala Glu 565 570 575

    Arg Val Ile Ser Val Glu Arg Glu Lys Phe His Ser Asn Asn Leu Pro 580 585 590

    Met Phe Tyr Lys Asp Ala Asp Leu Lys Lys Ile Leu Asp Leu Leu Tyr 595 600 605

    Ser Asp Tyr Ala Gly Arg Ala Ser Gln Val Pro Ala Phe Asn Thr Val 610 615 620

    Leu Val Arg Lys Asn Phe Pro Glu Phe Leu Arg Lys Asp Met Gly Tyr 625 630 635 640

    Lys Val His Phe Asn Asn Pro Glu Val Glu Asn Gln Trp His Ser Ala 645 650 655

    Val Tyr Tyr Leu Tyr Lys Glu Ile Tyr Tyr Asn Leu Phe Leu Arg Asp 660 665 670

    Lys Glu Val Lys Asn Leu Phe Tyr Thr Ser Leu Lys Asn Ile Arg Ser 675 680 685

    Glu Val Ser Asp Lys Lys Gln Lys Leu Ala Ser Asp Asp Phe Ala Ser 690 695 700

    Arg Cys Glu Glu Ile Glu Asp Arg Ser Leu Pro Glu Ile Cys Gln Ile 705 710 715 720

    Ile Met Thr Glu Tyr Asn Ala Gln Asn Phe Gly Asn Arg Lys Val Lys 725 730 735

    Ser Gln Arg Val Ile Glu Lys Asn Lys Asp Ile Phe Arg His Tyr Lys 740 745 750

    Met Leu Leu Ile Lys Thr Leu Ala Gly Ala Phe Ser Leu Tyr Leu Lys 755 760 765

    Gln Glu Arg Phe Ala Phe Ile Gly Lys Ala Thr Pro Ile Pro Tyr Glu

    770

    775

    780

    Thr Thr Asp Val Lys Asn Phe Leu Pro Glu Trp Lys Ser Gly Met Tyr 785 790 795 800

    Ala Ser Phe Val Glu Glu Ile Lys Asn Asn Leu Asp Leu Gln Glu Trp 805 810 815

    Tyr Ile Val Gly Arg Phe Leu Asn Gly Arg Met Leu Asn Gln Leu Ala 820 825 830

    Gly Ser Leu Arg Ser Tyr Ile Gln Tyr Ala Glu Asp Ile Glu Arg Arg 835 840 845

    Ala Ala Glu Asn Arg Asn Lys Leu Phe Ser Lys Pro Asp Glu Lys Ile 850 855 860

    Glu Ala Cys Lys Lys Ala Val Arg Val Leu Asp Leu Cys Ile Lys Ile 865 870 875 880

    Ser Thr Arg Ile Ser Ala Glu Phe Thr Asp Tyr Phe Asp Ser Glu Asp 885 890 895

    Asp Tyr Ala Asp Tyr Leu Glu Lys Tyr Leu Lys Tyr Gln Asp Asp Ala 900 905 910

    Ile Lys Glu Leu Ser Gly Ser Ser Tyr Ala Ala Leu Asp His Phe Cys 915 920 925

    Asn Lys Asp Asp Leu Lys Phe Asp Ile Tyr Val Asn Ala Gly Gln Lys 930 935 940

    Pro Ile Leu Gln Arg Asn Ile Val Met Ala Lys Leu Phe Gly Pro Asp 945 950 955 960

    Asn Ile Leu Ser Glu Val Met Glu Lys Val Thr Glu Ser Ala Ile Arg 965 970 975

    Glu Tyr Tyr Asp Tyr Leu Lys Lys Val Ser Gly Tyr Arg Val Arg Gly 980 985 990

    Lys Cys Ser Thr Glu Lys Glu Gln Glu Asp Leu Leu Lys Phe Gln Arg 995 1000 1005

    Leu Lys Asn Ala Val Glu Phe Arg Asp Val Thr Glu Tyr Ala Glu 1010 1015 1020

    Val Ile Asn Glu Leu Leu Gly Gln Leu Ile Ser Trp Ser Tyr Leu 1025 1030 1035

    Arg Glu Arg Asp Leu Leu Tyr Phe Gln Leu Gly Phe His Tyr Met 1040 1045 1050

    Cys Leu Lys Asn Lys Ser Phe Lys Pro Ala Glu Tyr Val Asp Ile 1055 1060 1065

    Arg Arg Asn Asn Gly Thr Ile Ile His Asn Ala Ile Leu Tyr Gln 1070 1075 1080

    Ile Val Ser Met Tyr Ile Asn Gly Leu Asp Phe Tyr Ser Cys Asp 1085 1090 1095

    Lys Glu Gly Lys Thr Leu Lys Pro Ile Glu Thr Gly Lys Gly Val 1100 1105 1110

    Gly Ser Lys Ile Gly Gln Phe Ile Lys Tyr Ser Gln Tyr Leu Tyr 1115 1120 1125

    Asn Asp Pro Ser Tyr Lys Leu Glu Ile Tyr Asn Ala Gly Leu Glu 1130 1135 1140

    Val Phe Glu Asn Ile Asp Glu His Asp Asn Ile Thr Asp Leu Arg 1145 1150 1155

    Lys Tyr Val Asp His Phe Lys Tyr Tyr Ala Tyr Gly Asn Lys Met 1160 1165 1170

    Ser Leu Leu Asp Leu Tyr Ser Glu Phe Phe Asp Arg Phe Phe Thr 1175 1180 1185

    Tyr Asp Met Lys Tyr Gln Lys Asn Val Val Asn Val Leu Glu Asn 1190 1195 1200

    Ile Leu Leu Arg His Phe Val Ile Phe Tyr Pro Lys Phe Gly Ser 1205 1210 1215

    Gly Lys Lys Asp Val Gly Ile Arg Asp Cys Lys Lys Glu Arg Ala 1220 1225 1230

    Gln Ile Glu Ile Ser Glu Gln Ser Leu Thr Ser Glu Asp Phe Met 1235 1240 1245

    Phe Lys Leu Asp Asp Lys Ala Gly Glu Glu Ala Lys Lys Phe Pro 1250 1255 1260

    Ala Arg Asp Glu Arg Tyr Leu Gln Thr Ile Ala Lys Leu Leu Tyr 1265 1270 1275

    Tyr Pro Asn Glu Ile Glu Asp Met Asn Arg Phe Met Lys Lys Gly 1280 1285 1290

    Glu Thr Ile Asn Lys Lys Val Gln Phe Asn Arg Lys Lys Lys Ile 1295 1300 1305

    Thr Arg Lys Gln Lys Asn Asn Ser Ser Asn Glu Val Leu Ser Ser 1310 1315 1320

    Thr Met Gly Tyr Leu Phe Lys Asn Ile Lys Leu 1325 1330 <210> 57 <211> 1120 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 57

    Met Trp Ile Ser Ile Lys Thr Leu Ile His His Leu Gly Val Leu Phe 1 5 10 15

    Phe Cys Asp Tyr Met Tyr Asn Arg Arg Glu Lys Lys Ile Ile Glu Val 20 25 30

    Lys Thr Met Arg Ile Thr Lys Val Glu Val Asp Arg Lys Lys Val Leu 35 40 45

    Ile Ser Arg Asp Lys Asn Gly Gly Lys Leu Val Tyr Glu Asn Glu Met 50 55 60

    Gln Asp Asn Thr Glu Gln Ile Met His His Lys Lys Ser Ser Phe Tyr 65 70 75 80

    Lys Ser Val Val Asn Lys Thr Ile Cys Arg Pro Glu Gln Lys Gln Met 85 90 95

    Lys Lys Leu Val His Gly Leu Leu Gln Glu Asn Ser Gln Glu Lys Ile 100 105 110

    Lys Val Ser Asp Val Thr Lys Leu Asn Ile Ser Asn Phe Leu Asn His 115 120 125

    Arg Phe Lys Lys Ser Leu Tyr Tyr Phe Pro Glu Asn Ser Pro Asp Lys 130 135 140

    Ser Glu Glu Tyr Arg Ile Glu Ile Asn Leu Ser Gln Leu Leu Glu Asp 145 150 155 160

    Ser Leu Lys Lys Gln Gln Gly Thr Phe Ile Cys Trp Glu Ser Phe Ser 165 170 175

    Lys Asp Met Glu Leu Tyr Ile Asn Trp Ala Glu Asn Tyr Ile Ser Ser 180 185 190

    Lys Thr Lys Leu Ile Lys Lys Ser Ile Arg Asn Asn Arg Ile Gln Ser 195 200 205

    Thr Glu Ser Arg Ser Gly Gln Leu Met Asp Arg Tyr Met Lys Asp Ile 210 215 220

    Leu Asn Lys Asn Lys Pro Phe Asp Ile Gln Ser Val Ser Glu Lys Tyr 225 230 235 240

    Gln Leu Glu Lys Leu Thr Ser Ala Leu Lys Ala Thr Phe Lys Glu Ala 245 250 255

    Lys Lys Asn Asp Lys Glu Ile Asn Tyr Lys Leu Lys Ser Thr Leu Gln 260 265 270

    Asn His Glu Arg Gln Ile Ile Glu Glu Leu Lys Glu Asn Ser Glu Leu 275 280 285

    Asn Gln Phe Asn Ile Glu Ile Arg Lys His Leu Glu Thr Tyr Phe Pro 290 295 300

    Ile Lys Lys Thr Asn Arg Lys Val Gly Asp Ile Arg Asn Leu Glu Ile 305 310 315 320

    Gly Glu Ile Gln Lys Ile Val Asn His Arg Leu Lys Asn Lys Ile Val 325 330 335

    Gln Arg Ile Leu Gln Glu Gly Lys Leu Ala Ser Tyr Glu Ile Glu Ser 340 345 350

    Thr Val Asn Ser Asn Ser Leu Gln Lys Ile Lys Ile Glu Glu Ala Phe 355 360 365

    Ala Leu Lys Phe Ile Asn Ala Cys Leu Phe Ala Ser Asn Asn Leu Arg 370 375 380

    Asn Met Val Tyr Pro Val Cys Lys Lys Asp Ile Leu Met Ile Gly Glu 385 390 395 400

    Phe Lys Asn Ser Phe Lys Glu Ile Lys His Lys Lys Phe Ile Arg Gln 405 410 415

    Trp Ser Gln Phe Phe Ser Gln Glu Ile Thr Val Asp Asp Ile Glu Leu 420 425 430

    Ala Ser Trp Gly Leu Arg Gly Ala Ile Ala Pro Ile Arg Asn Glu Ile 435 440 445

    Ile His Leu Lys Lys His Ser Trp Lys Lys Phe Phe Asn Asn Pro Thr

    450

    455

    460

    Phe Lys Val Lys Lys Ser Lys Ile Ile Asn Gly Lys Thr Lys Asp Val 465 470 475 480

    Thr Ser Glu Phe Leu Tyr Lys Glu Thr Leu Phe Lys Asp Tyr Phe Tyr 485 490 495

    Ser Glu Leu Asp Ser Val Pro Glu Leu Ile Ile Asn Lys Met Glu Ser 500 505 510

    Ser Lys Ile Leu Asp Tyr Tyr Ser Ser Asp Gln Leu Asn Gln Val Phe 515 520 525

    Thr Ile Pro Asn Phe Glu Leu Ser Leu Leu Thr Ser Ala Val Pro Phe 530 535 540

    Ala Pro Ser Phe Lys Arg Val Tyr Leu Lys Gly Phe Asp Tyr Gln Asn 545 550 555 560

    Gln Asp Glu Ala Gln Pro Asp Tyr Asn Leu Lys Leu Asn Ile Tyr Asn 565 570 575

    Glu Lys Ala Phe Asn Ser Glu Ala Phe Gln Ala Gln Tyr Ser Leu Phe 580 585 590

    Lys Met Val Tyr Tyr Gln Val Phe Leu Pro Gln Phe Thr Thr Asn Asn 595 600 605

    Asp Leu Phe Lys Ser Ser Val Asp Phe Ile Leu Thr Leu Asn Lys Glu 610 615 620

    Arg Lys Gly Tyr Ala Lys Ala Phe Gln Asp Ile Arg Lys Met Asn Lys 625 630 635 640

    Asp Glu Lys Pro Ser Glu Tyr Met Ser Tyr Ile Gln Ser Gln Leu Met 645 650 655

    Leu Tyr Gln Lys Lys Gln Glu Glu Lys Glu Lys Ile Asn His Phe Glu 660 665 670

    Lys Phe Ile Asn Gln Val Phe Ile Lys Gly Phe Asn Ser Phe Ile Glu 675 680 685

    Lys Asn Arg Leu Thr Tyr Ile Cys His Pro Thr Lys Asn Thr Val Pro 690 695 700

    Glu Asn Asp Asn Ile Glu Ile Pro Phe His Thr Asp Met Asp Asp Ser 705 710 715 720

    Asn Ile Ala Phe Trp Leu Met Cys Lys Leu Leu Asp Ala Lys Gln Leu 725 730 735

    Ser Glu Leu Arg Asn Glu Met Ile Lys Phe Ser Cys Ser Leu Gln Ser 740 745 750

    Thr Glu Glu Ile Ser Thr Phe Thr Lys Ala Arg Glu Val Ile Gly Leu 755 760 765

    Ala Leu Leu Asn Gly Glu Lys Gly Cys Asn Asp Trp Lys Glu Leu Phe 770 775 780

    Asp Asp Lys Glu Ala Trp Lys Lys Asn Met Ser Leu Tyr Val Ser Glu 785 790 795 800

    Glu Leu Leu Gln Ser Leu Pro Tyr Thr Gln Glu Asp Gly Gln Thr Pro 805 810 815

    Val Ile Asn Arg Ser Ile Asp Leu Val Lys Lys Tyr Gly Thr Glu Thr 820 825 830

    Ile Leu Glu Lys Leu Phe Ser Ser Ser Asp Asp Tyr Lys Val Ser Ala 835 840 845

    Lys Asp Ile Ala Lys Leu His Glu Tyr Asp Val Thr Glu Lys Ile Ala 850 855 860

    Gln Gln Glu Ser Leu His Lys Gln Trp Ile Glu Lys Pro Gly Leu Ala 865 870 875 880

    Arg Asp Ser Ala Trp Thr Lys Lys Tyr Gln Asn Val Ile Asn Asp Ile 885 890 895

    Ser Asn Tyr Gln Trp Ala Lys Thr Lys Val Glu Leu Thr Gln Val Arg 900 905 910

    His Leu His Gln Leu Thr Ile Asp Leu Leu Ser Arg Leu Ala Gly Tyr 915 920 925

    Met Ser Ile Ala Asp Arg Asp Phe Gln Phe Ser Ser Asn Tyr Ile Leu 930 935 940

    Glu Arg Glu Asn Ser Glu Tyr Arg Val Thr Ser Trp Ile Leu Leu Ser 945 950 955 960

    Glu Asn Lys Asn Lys Asn Lys Tyr Asn Asp Tyr Glu Leu Tyr Asn Leu 965 970 975

    Lys Asn Ala Ser Ile Lys Val Ser Ser Lys Asn Asp Pro Gln Leu Lys 980 985 990

    Val Asp Leu Lys Gln Leu Arg Leu Thr Leu Glu Tyr Leu Glu Leu Phe 995 1000 1005

    Asp Asn Arg Leu Lys Glu Lys Arg Asn Asn Ile Ser His Phe Asn 1010 1015 1020

    Tyr Leu Asn Gly Gln Leu Gly Asn Ser Ile Leu Glu Leu Phe Asp 1025 1030 1035

    Asp Ala Arg Asp Val Leu Ser Tyr Asp Arg Lys Leu Lys Asn Ala 1040 1045 1050

    Val Ser Lys Ser Leu Lys Glu Ile Leu Ser Ser His Gly Met Glu 1055 1060 1065

    Val Thr Phe Lys Pro Leu Tyr Gln Thr Asn His His Leu Lys Ile 1070 1075 1080

    Asp Lys Leu Gln Pro Lys Lys Ile His His Leu Gly Glu Lys Ser 1085 1090 1095

    Thr Val Ser Ser Asn Gln Val Ser Asn Glu Tyr Cys Gln Leu Val 1100 1105 1110

    Arg Thr Leu Leu Thr Met Lys 1115 1120 <210> 58 <211> 1152 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 58

    Met Lys Val Thr Lys Val Asp Gly Ile Ser His Lys Lys Tyr Ile Glu 1 5 10 15

    Glu Gly Lys Leu Val Lys Ser Thr Ser Glu Glu Asn Arg Thr Ser Glu 20 25 30

    Arg Leu Ser Glu Leu Leu Ser Ile Arg Leu Asp Ile Tyr Ile Lys Asn 35 40 45

    Pro Asp Asn Ala Ser Glu Glu Glu Asn Arg Ile Arg Arg Glu Asn Leu 50 55 60

    Lys Lys Phe Phe Ser Asn Lys Val Leu His Leu Lys Asp Ser Val Leu 65 70 75 80

    Tyr Leu Lys Asn Arg Lys Glu Lys Asn Ala Val Gln Asp Lys Asn Tyr 85 90 95

    Ser Glu Glu Asp Ile Ser Glu Tyr Asp Leu Lys Asn Lys Asn Ser Phe 100 105 110

    Ser Val Leu Lys Lys Ile Leu Leu Asn Glu Asp Val Asn Ser Glu Glu 115 120 125

    Leu Glu Ile Phe Arg Lys Asp Val Glu Ala Lys Leu Asn Lys Ile Asn 130 135 140

    Ser Leu Lys Tyr Ser Phe Glu Glu Asn Lys Ala Asn Tyr Gln Lys Ile 145 150 155 160

    Asn Glu Asn Asn Val Glu Lys Val Gly Gly Lys Ser Lys Arg Asn Ile 165 170 175

    Ile Tyr Asp Tyr Tyr Arg Glu Ser Ala Lys Arg Asn Asp Tyr Ile Asn 180 185 190

    Asn Val Gln Glu Ala Phe Asp Lys Leu Tyr Lys Lys Glu Asp Ile Glu 195 200 205

    Lys Leu Phe Phe Leu Ile Glu Asn Ser Lys Lys His Glu Lys Tyr Lys 210 215 220

    Ile Arg Glu Tyr Tyr His Lys Ile Ile Gly Arg Lys Asn Asp Lys Glu 225 230 235 240

    Asn Phe Ala Lys Ile Ile Tyr Glu Glu Ile Gln Asn Val Asn Asn Ile 245 250 255

    Lys Glu Leu Ile Glu Lys Ile Pro Asp Met Ser Glu Leu Lys Lys Ser 260 265 270

    Gln Val Phe Tyr Lys Tyr Tyr Leu Asp Lys Glu Glu Leu Asn Asp Lys 275 280 285

    Asn Ile Lys Tyr Ala Phe Cys His Phe Val Glu Ile Glu Met Ser Gln 290 295 300

    Leu Leu Lys Asn Tyr Val Tyr Lys Arg Leu Ser Asn Ile Ser Asn Asp 305 310 315 320

    Lys Ile Lys Arg Ile Phe Glu Tyr Gln Asn Leu Lys Lys Leu Ile Glu 325 330 335

    Asn Lys Leu Leu Asn Lys Leu Asp Thr Tyr Val Arg Asn Cys Gly Lys 340 345 350

    Tyr Asn Tyr Tyr Leu Gln Val Gly Glu Ile Ala Thr Ser Asp Phe Ile

    355

    360

    365

    Ala Arg Asn Arg Gln Asn Glu Ala Phe Leu Arg Asn Ile Ile Gly Val 370 375 380

    Ser Ser Val Ala Tyr Phe Ser Leu Arg Asn Ile Leu Glu Thr Glu Asn 385 390 395 400

    Glu Asn Asp Ile Thr Gly Arg Met Arg Gly Lys Thr Val Lys Asn Asn 405 410 415

    Lys Gly Glu Glu Lys Tyr Val Ser Gly Glu Val Asp Lys Ile Tyr Asn 420 425 430

    Glu Asn Lys Gln Asn Glu Val Lys Glu Asn Leu Lys Met Phe Tyr Ser 435 440 445

    Tyr Asp Phe Asn Met Asp Asn Lys Asn Glu Ile Glu Asp Phe Phe Ala 450 455 460

    Asn Ile Asp Glu Ala Ile Ser Ser Ile Arg His Gly Ile Val His Phe 465 470 475 480

    Asn Leu Glu Leu Glu Gly Lys Asp Ile Phe Ala Phe Lys Asn Ile Ala 485 490 495

    Pro Ser Glu Ile Ser Lys Lys Met Phe Gln Asn Glu Ile Asn Glu Lys 500 505 510

    Lys Leu Lys Leu Lys Ile Phe Lys Gln Leu Asn Ser Ala Asn Val Phe 515 520 525

    Asn Tyr Tyr Glu Lys Asp Val Ile Ile Lys Tyr Leu Lys Asn Thr Lys 530 535 540

    Phe Asn Phe Val Asn Lys Asn Ile Pro Phe Val Pro Ser Phe Thr Lys 545 550 555 560

    Leu Tyr Asn Lys Ile Glu Asp Leu Arg Asn Thr Leu Lys Phe Phe Trp 565 570 575

    Ser Val Pro Lys Asp Lys Glu Glu Lys Asp Ala Gln Ile Tyr Leu Leu 580 585 590

    Lys Asn Ile Tyr Tyr Gly Glu Phe Leu Asn Lys Phe Val Lys Asn Ser 595 600 605

    Lys Val Phe Phe Lys Ile Thr Asn Glu Val Ile Lys Ile Asn Lys Gln 610 615 620

    Arg Asn Gln Lys Thr Gly His Tyr Lys Tyr Gln Lys Phe Glu Asn Ile 625 630 635 640

    Glu Lys Thr Val Pro Val Glu Tyr Leu Ala Ile Ile Gln Ser Arg Glu 645 650 655

    Met Ile Asn Asn Gln Asp Lys Glu Glu Lys Asn Thr Tyr Ile Asp Phe 660 665 670

    Ile Gln Gln Ile Phe Leu Lys Gly Phe Ile Asp Tyr Leu Asn Lys Asn 675 680 685

    Asn Leu Lys Tyr Ile Glu Ser Asn Asn Asn Asn Asp Asn Asn Asp Ile 690 695 700

    Phe Ser Lys Ile Lys Ile Lys Lys Asp Asn Lys Glu Lys Tyr Asp Lys 705 710 715 720

    Ile Leu Lys Asn Tyr Glu Lys His Asn Arg Asn Lys Glu Ile Pro His 725 730 735

    Glu Ile Asn Glu Phe Val Arg Glu Ile Lys Leu Gly Lys Ile Leu Lys 740 745 750

    Tyr Thr Glu Asn Leu Asn Met Phe Tyr Leu Ile Leu Lys Leu Leu Asn 755 760 765

    His Lys Glu Leu Thr Asn Leu Lys Gly Ser Leu Glu Lys Tyr Gln Ser 770 775 780

    Ala Asn Lys Glu Glu Thr Phe Ser Asp Glu Leu Glu Leu Ile Asn Leu 785 790 795 800

    Leu Asn Leu Asp Asn Asn Arg Val Thr Glu Asp Phe Glu Leu Glu Ala 805 810 815

    Asn Glu Ile Gly Lys Phe Leu Asp Phe Asn Glu Asn Lys Ile Lys Asp 820 825 830

    Arg Lys Glu Leu Lys Lys Phe Asp Thr Asn Lys Ile Tyr Phe Asp Gly 835 840 845

    Glu Asn Ile Ile Lys His Arg Ala Phe Tyr Asn Ile Lys Lys Tyr Gly 850 855 860

    Met Leu Asn Leu Leu Glu Lys Ile Ala Asp Lys Ala Lys Tyr Lys Ile 865 870 875 880

    Ser Leu Lys Glu Leu Lys Glu Tyr Ser Asn Lys Lys Asn Glu Ile Glu 885 890 895

    Lys Asn Tyr Thr Met Gln Gln Asn Leu His Arg Lys Tyr Ala Arg Pro 900 905 910

    Lys Lys Asp Glu Lys Phe Asn Asp Glu Asp Tyr Lys Glu Tyr Glu Lys 915 920 925

    Ala Ile Gly Asn Ile Gln Lys Tyr Thr His Leu Lys Asn Lys Val Glu 930 935 940

    Phe Asn Glu Leu Asn Leu Leu Gln Gly Leu Leu Leu Lys Ile Leu His 945 950 955 960

    Arg Leu Val Gly Tyr Thr Ser Ile Trp Glu Arg Asp Leu Arg Phe Arg 965 970 975

    Leu Lys Gly Glu Phe Pro Glu Asn His Tyr Ile Glu Glu Ile Phe Asn 980 985 990

    Phe Asp Asn Ser Lys Asn Val Lys Tyr Lys Ser Gly Gln Ile Val Glu 995 1000 1005

    Lys Tyr Ile Asn Phe Tyr Lys Glu Leu Tyr Lys Asp Asn Val Glu 1010 1015 1020

    Lys Arg Ser Ile Tyr Ser Asp Lys Lys Val Lys Lys Leu Lys Gln 1025 1030 1035

    Glu Lys Lys Asp Leu Tyr Ile Arg Asn Tyr Ile Ala His Phe Asn 1040 1045 1050

    Tyr Ile Pro His Ala Glu Ile Ser Leu Leu Glu Val Leu Glu Asn 1055 1060 1065

    Leu Arg Lys Leu Leu Ser Tyr Asp Arg Lys Leu Lys Asn Ala Ile

    1070 1075 1080

    Met Lys Ser Ile Val Asp Ile Leu Lys Glu Tyr Gly Phe Val Ala 1085 1090 1095

    Thr Phe Lys Ile Gly Ala Asp Lys Lys Ile Glu Ile Gln Thr Leu 1100 1105 1110

    Glu Ser Glu Lys Ile Val His Leu Lys Asn Leu Lys Lys Lys Lys 1115 1120 1125

    Leu Met Thr Asp Arg Asn Ser Glu Glu Leu Cys Glu Leu Val Lys 1130 1135 1140

    Val Met Phe Glu Tyr Lys Ala Leu Glu 1145 1150 <210> 59 <211> 1389 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 59

    Met Gly Asn Leu Phe Gly His Lys Arg Trp Tyr Glu Val Arg Asp Lys 1 5 10 15

    Lys Asp Phe Lys Ile Lys Arg Lys Val Lys Val Lys Arg Asn Tyr Asp 20 25 30

    Gly Asn Lys Tyr Ile Leu Asn Ile Asn Glu Asn Asn Asn Lys Glu Lys 35 40 45

    Ile Asp Asn Asn Lys Phe Ile Arg Lys Tyr Ile Asn Tyr Lys Lys Asn 50 55 60

    Asp Asn Ile Leu Lys Glu Phe Thr Arg Lys Phe His Ala Gly Asn Ile 65 70 75 80

    Leu Phe Lys Leu Lys Gly Lys Glu Gly Ile Ile Arg Ile Glu Asn Asn 85 90 95

    Asp Asp Phe Leu Glu Thr Glu Glu Val Val Leu Tyr Ile Glu Ala Tyr 100 105 110

    Gly Lys Ser Glu Lys Leu Lys Ala Leu Gly Ile Thr Lys Lys Lys Ile 115 120 125

    Ile Asp Glu Ala Ile Arg Gln Gly Ile Thr Lys Asp Asp Lys Lys Ile 130 135 140

    Glu Ile Lys Arg Gln Glu Asn Glu Glu Glu Ile Glu Ile Asp Ile Arg 145 150 155 160

    Asp Glu Tyr Thr Asn Lys Thr Leu Asn Asp Cys Ser Ile Ile Leu Arg 165 170 175

    Ile Ile Glu Asn Asp Glu Leu Glu Thr Lys Lys Ser Ile Tyr Glu Ile 180 185 190

    Phe Lys Asn Ile Asn Met Ser Leu Tyr Lys Ile Ile Glu Lys Ile Ile 195 200 205

    Glu Asn Glu Thr Glu Lys Val Phe Glu Asn Arg Tyr Tyr Glu Glu His 210 215 220

    Leu Arg Glu Lys Leu Leu Lys Asp Asp Lys Ile Asp Val Ile Leu Thr

    225

    230

    235

    240

    Asn Phe Met Glu Ile Arg Glu Lys Ile Lys Ser Asn Leu Glu Ile Leu 245 250 255

    Gly Phe Val Lys Phe Tyr Leu Asn Val Gly Gly Asp Lys Lys Lys Ser 260 265 270

    Lys Asn Lys Lys Met Leu Val Glu Lys Ile Leu Asn Ile Asn Val Asp 275 280 285

    Leu Thr Val Glu Asp Ile Ala Asp Phe Val Ile Lys Glu Leu Glu Phe 290 295 300

    Trp Asn Ile Thr Lys Arg Ile Glu Lys Val Lys Lys Val Asn Asn Glu 305 310 315 320

    Phe Leu Glu Lys Arg Arg Asn Arg Thr Tyr Ile Lys Ser Tyr Val Leu 325 330 335

    Leu Asp Lys His Glu Lys Phe Lys Ile Glu Arg Glu Asn Lys Lys Asp 340 345 350

    Lys Ile Val Lys Phe Phe Val Glu Asn Ile Lys Asn Asn Ser Ile Lys 355 360 365

    Glu Lys Ile Glu Lys Ile Leu Ala Glu Phe Lys Ile Asp Glu Leu Ile 370 375 380

    Lys Lys Leu Glu Lys Glu Leu Lys Lys Gly Asn Cys Asp Thr Glu Ile 385 390 395 400

    Phe Gly Ile Phe Lys Lys His Tyr Lys Val Asn Phe Asp Ser Lys Lys 405 410 415

    Phe Ser Lys Lys Ser Asp Glu Glu Lys Glu Leu Tyr Lys Ile Ile Tyr 420 425 430

    Arg Tyr Leu Lys Gly Arg Ile Glu Lys Ile Leu Val Asn Glu Gln Lys 435 440 445

    Val Arg Leu Lys Lys Met Glu Lys Ile Glu Ile Glu Lys Ile Leu Asn 450 455 460

    Glu Ser Ile Leu Ser Glu Lys Ile Leu Lys Arg Val Lys Gln Tyr Thr 465 470 475 480

    Leu Glu His Ile Met Tyr Leu Gly Lys Leu Arg His Asn Asp Ile Asp 485 490 495

    Met Thr Thr Val Asn Thr Asp Asp Phe Ser Arg Leu His Ala Lys Glu 500 505 510

    Glu Leu Asp Leu Glu Leu Ile Thr Phe Phe Ala Ser Thr Asn Met Glu 515 520 525

    Leu Asn Lys Ile Phe Ser Arg Glu Asn Ile Asn Asn Asp Glu Asn Ile 530 535 540

    Asp Phe Phe Gly Gly Asp Arg Glu Lys Asn Tyr Val Leu Asp Lys Lys 545 550 555 560

    Ile Leu Asn Ser Lys Ile Lys Ile Ile Arg Asp Leu Asp Phe Ile Asp 565 570 575

    Asn Lys Asn Asn Ile Thr Asn Asn Phe Ile Arg Lys Phe Thr Lys Ile 580 585 590

    Gly Thr Asn Glu Arg Asn Arg Ile Leu His Ala Ile Ser Lys Glu Arg 595 600 605

    Asp Leu Gln Gly Thr Gln Asp Asp Tyr Asn Lys Val Ile Asn Ile Ile 610 615 620

    Gln Asn Leu Lys Ile Ser Asp Glu Glu Val Ser Lys Ala Leu Asn Leu 625 630 635 640

    Asp Val Val Phe Lys Asp Lys Lys Asn Ile Ile Thr Lys Ile Asn Asp 645 650 655

    Ile Lys Ile Ser Glu Glu Asn Asn Asn Asp Ile Lys Tyr Leu Pro Ser 660 665 670

    Phe Ser Lys Val Leu Pro Glu Ile Leu Asn Leu Tyr Arg Asn Asn Pro 675 680 685

    Lys Asn Glu Pro Phe Asp Thr Ile Glu Thr Glu Lys Ile Val Leu Asn 690 695 700

    Ala Leu Ile Tyr Val Asn Lys Glu Leu Tyr Lys Lys Leu Ile Leu Glu 705 710 715 720

    Asp Asp Leu Glu Glu Asn Glu Ser Lys Asn Ile Phe Leu Gln Glu Leu 725 730 735

    Lys Lys Thr Leu Gly Asn Ile Asp Glu Ile Asp Glu Asn Ile Ile Glu 740 745 750

    Asn Tyr Tyr Lys Asn Ala Gln Ile Ser Ala Ser Lys Gly Asn Asn Lys 755 760 765

    Ala Ile Lys Lys Tyr Gln Lys Lys Val Ile Glu Cys Tyr Ile Gly Tyr 770 775 780

    Leu Arg Lys Asn Tyr Glu Glu Leu Phe Asp Phe Ser Asp Phe Lys Met 785 790 795 800

    Asn Ile Gln Glu Ile Lys Lys Gln Ile Lys Asp Ile Asn Asp Asn Lys 805 810 815

    Thr Tyr Glu Arg Ile Thr Val Lys Thr Ser Asp Lys Thr Ile Val Ile 820 825 830

    Asn Asp Asp Phe Glu Tyr Ile Ile Ser Ile Phe Ala Leu Leu Asn Ser 835 840 845

    Asn Ala Val Ile Asn Lys Ile Arg Asn Arg Phe Phe Ala Thr Ser Val 850 855 860

    Trp Leu Asn Thr Ser Glu Tyr Gln Asn Ile Ile Asp Ile Leu Asp Glu 865 870 875 880

    Ile Met Gln Leu Asn Thr Leu Arg Asn Glu Cys Ile Thr Glu Asn Trp 885 890 895

    Asn Leu Asn Leu Glu Glu Phe Ile Gln Lys Met Lys Glu Ile Glu Lys 900 905 910

    Asp Phe Asp Asp Phe Lys Ile Gln Thr Lys Lys Glu Ile Phe Asn Asn 915 920 925

    Tyr Tyr Glu Asp Ile Lys Asn Asn Ile Leu Thr Glu Phe Lys Asp Asp 930 935 940

    Ile Asn Gly Cys Asp Val Leu Glu Lys Lys Leu Glu Lys Ile Val Ile

    945

    950

    955

    960

    Phe Asp Asp Glu Thr Lys Phe Glu Ile Asp Lys Lys Ser Asn Ile Leu 965 970 975

    Gln Asp Glu Gln Arg Lys Leu Ser Asn Ile Asn Lys Lys Asp Leu Lys 980 985 990

    Lys Lys Val Asp Gln Tyr Ile Lys Asp Lys Asp Gln Glu Ile Lys Ser 995 1000 1005

    Lys Ile Leu Cys Arg Ile Ile Phe Asn Ser Asp Phe Leu Lys Lys 1010 1015 1020

    Tyr Lys Lys Glu Ile Asp Asn Leu Ile Glu Asp Met Glu Ser Glu 1025 1030 1035

    Asn Glu Asn Lys Phe Gln Glu Ile Tyr Tyr Pro Lys Glu Arg Lys 1040 1045 1050

    Asn Glu Leu Tyr Ile Tyr Lys Lys Asn Leu Phe Leu Asn Ile Gly 1055 1060 1065

    Asn Pro Asn Phe Asp Lys Ile Tyr Gly Leu Ile Ser Asn Asp Ile 1070 1075 1080

    Lys Met Ala Asp Ala Lys Phe Leu Phe Asn Ile Asp Gly Lys Asn 1085 1090 1095

    Ile Arg Lys Asn Lys Ile Ser Glu Ile Asp Ala Ile Leu Lys Asn 1100 1105 1110

    Leu Asn Asp Lys Leu Asn Gly Tyr Ser Lys Glu Tyr Lys Glu Lys 1115 1120 1125

    Tyr Ile Lys Lys Leu Lys Glu Asn Asp Asp Phe Phe Ala Lys Asn 1130 1135 1140

    Ile Gln Asn Lys Asn Tyr Lys Ser Phe Glu Lys Asp Tyr Asn Arg 1145 1150 1155

    Val Ser Glu Tyr Lys Lys Ile Arg Asp Leu Val Glu Phe Asn Tyr 1160 1165 1170

    Leu Asn Lys Ile Glu Ser Tyr Leu Ile Asp Ile Asn Trp Lys Leu 1175 1180 1185

    Ala Ile Gln Met Ala Arg Phe Glu Arg Asp Met His Tyr Ile Val 1190 1195 1200

    Asn Gly Leu Arg Glu Leu Gly Ile Ile Lys Leu Ser Gly Tyr Asn 1205 1210 1215

    Thr Gly Ile Ser Arg Ala Tyr Pro Lys Arg Asn Gly Ser Asp Gly 1220 1225 1230

    Phe Tyr Thr Thr Thr Ala Tyr Tyr Lys Phe Phe Asp Glu Glu Ser 1235 1240 1245

    Tyr Lys Lys Phe Glu Lys Ile Cys Tyr Gly Phe Gly Ile Asp Leu 1250 1255 1260

    Ser Glu Asn Ser Glu Ile Asn Lys Pro Glu Asn Glu Ser Ile Arg 1265 1270 1275

    Asn Tyr Ile Ser His Phe Tyr Ile Val Arg Asn Pro Phe Ala Asp 1280 1285 1290

    Tyr Ser Ile Ala Glu Gln Ile Asp Arg Val Ser Asn Leu Leu Ser 1295 1300 1305

    Tyr Ser Thr Arg Tyr Asn Asn Ser Thr Tyr Ala Ser Val Phe Glu 1310 1315 1320

    Val Phe Lys Lys Asp Val Asn Leu Asp Tyr Asp Glu Leu Lys Lys 1325 1330 1335

    Lys Phe Lys Leu Ile Gly Asn Asn Asp Ile Leu Glu Arg Leu Met 1340 1345 1350

    Lys Pro Lys Lys Val Ser Val Leu Glu Leu Glu Ser Tyr Asn Ser 1355 1360 1365

    Asp Tyr Ile Lys Asn Leu Ile Ile Glu Leu Leu Thr Lys Ile Glu 1370 1375 1380

    Asn Thr Asn Asp Thr Leu 1385 <210> 60 <211> 1300 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 60

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val

    565

    570

    575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu

    1265

    1270

    1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 61 <211> 7403 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 61 tatccggtcg aatcgagaat gacgaccgct acgtcttgga ctacgaagcc gtggcccttg 60 ccgatgctct cggtgtggat gttgccgacc tgttccgcaa gatcgattgc cccaagaacc 120 tgctgcgcag gcgggcaggg taggggagcg gtttccggcg gagattttcg gaggcgccgg 180 taacgttatg tcggggaatt tgctatacat cgacgataat tagttttgtt gattcaggat 240 cgaaatgcgc tcaaacaaag aacgttccgc gtttccctca tgcgctacta cgcccacacc 300 gccatctttc ggcacgcaaa caaagcagat gggttgcctg tcaatgggtg atcattgcct 360 gaagttacca tccatcaata atataaatca tccttactcc gaatgtccct caatcgcatc 420 tatcaaggcc gcgtggcggc cgtcgaaaca ggaacggcct tagcgaaagg taatgtcgaa 480 tggatgcctg ccgcaggagg cgacgaagtt ctctggcagc accacgaact tttccaagct 540 gccatcaact actatctcgt cgccctgctc gcactcgccg acaaaaacaa tcccgtactt 600 ggcccgctga tcagccagat ggataatccc caaagccctt accatgtctg gggaagtttc 660 cgccgccaag gacgtcagcg cacaggtctc agtcaagccg ttgcacctta tatcacgccg 720 ggcaataacg ctcccaccct tgacgaagtt ttccgctcca ttcttgcggg caacccaacc 780 gaccgcgcaa ctttggacgc tgcactcatg caattgctca aggcttgtga cggcgcgggc 840 gctatccagc aggaaggtcg ttcctactgg cccaaattct gcgatcctga ctccactgcc 900 aacttcgcgg gagatccggc catgctccgg cgtgaacaac accgcctcct ccttccgcaa 960 gttctccacg atccggcgat tactcacgac agtcctgccc ttggctcgtt cgacacttat 1020 tcgattgcta cccccgacac cagaactcct caactcaccg gccccaaggc acgcgcccgt 1080 cttgagcagg cgatcaccct ctggcgcgtc cgtcttcccg aatcggctgc tgacttcgat 1140 cgccttgcca gttccctcaa aaaaattccg gacgacgatt ctcgccttaa ccttcagggc 1200 tacgtcggca gcagtgcgaa aggcgaagtt caggcccgtc ttttcgccct tctgctattc 1260 cgtcacctgg agcgttcctc ctttacgctt ggccttctcc gttccgccac cccgccgccc 1320 aagaacgctg aaacacctcc tcccgccggc gttcctttac ctgcggcgtc cgcagccgat 1380 ccggtgcgga tagcccgtgg caaacgcagt tttgtttttc gcgcattcac cagtctcccc 1440 tgctggcatg gcggtgataa catccatccc acctggaagt cattcgacat cgcagcgttc 1500 aaatatgccc tcacggtcat caaccagatc gaggaaaaga cgaaagaacg ccaaaaagaa 1560 tgtgcggaac ttgaaactga tttcgactac atgcacggac ggctcgccaa gattccggta 1620 aaatacacga ccggcgaagc cgaaccgccc cccattctcg caaacgatct ccgcatcccc 1680 ctcctccgcg aacttctcca gaatatcaag gtcgacaccg cactcaccga tggcgaagcc 1740 gtctcctatg gtctccaacg ccgcaccatt cgcggtttcc gcgagctgcg ccgcatctgg 1800 cgcggccatg cccccgctgg cacggtcttt tccagcgagt tgaaagaaaa actagccggc 1860 gaactccgcc agttccagac cgacaactcc accaccatcg gcagcgtcca actcttcaac 1920 gaactcatcc aaaacccgaa atactggccc atctggcagg ctcctgacgt cgaaaccgcc 1980 cgccaatggg ccgatgccgg ttttgccgac gatccgctcg ccgcccttgt gcaagaagcc 2040 gaactccagg aagacatcga cgccctcaag gctccagtca aactcactcc ggccgatcct 2100 gagtattcaa gaaggcaata cgatttcaat gccgtcagca aattcggggc cggctcccgc 2160 tccgccaatc gccacgaacc cgggcagacg gagcgcggcc acaacacctt taccaccgaa 2220 atcgccgccc gtaacgcggc ggacgggaac cgctggcggg caacccacgt ccgcatccat 2280 tactccgctc cccgccttct tcgtgacgga ctccgccgac ctgacaccga cggcaacgaa 2340 gccctggaag ccgtcccttg gctccagccc atgatggaag ccctcgcccc tctcccgacg 2400 cttccgcaag acctcacagg catgccggtc ttcctcatgc ccgacgtcac cctttccggt 2460 gagcgtcgca tcctcctcaa tcttcctgtc accctcgaac cagccgctct tgtcgaacaa 2520 ctgggcaacg ccggtcgctg gcaaaaccag ttcttcggct cccgcgaaga tccattcgct 2580 ctccgatggc ccgccgacgg tgctgtaaaa accgccaagg ggaaaaccca cataccttgg 2640 caccaggacc gcgatcactt caccgtactc ggcgtggatc tcggcacgcg cgatgccggg 2700 gcgctcgctc ttctcaacgt cactgcgcaa aaaccggcca agccggtcca ccgcatcatt 2760 ggtgaggccg acggacgcac ctggtatgcc agccttgccg acgctcgcat gatccgcctg 2820 cccggggagg atgcccggct ctttgtccgg ggaaaactcg ttcaggaacc ctatggtgaa 2880 cgcgggcgaa acgcgtctct tctcgaatgg gaagacgccc gcaatatcat ccttcgcctt 2940 ggccaaaatc ccgacgaact cctcggcgcc gatccccggc gccattcgta tccggaaata 3000 aacgataaac ttctcgtcgc ccttcgccgc gctcaggccc gtcttgcccg tctccagaac 3060 cggagctggc ggttgcgcga ccttgcagaa tcggacaagg cccttgatga aatccatgcc 3120 gagcgtgccg gggagaagcc ttctccgctt ccgcccttgg ctcgcgacga tgccatcaaa 3180 agcaccgacg aagccctcct ttcccagcgt gacatcatcc ggcgatcctt cgttcagatc 3240 gccaacttga tccttcccct tcgcggacgc cgatgggaat ggcggcccca tgtcgaggtc 3300 ccggattgcc acatccttgc gcagagcgat cccggtacgg atgacaccaa gcgtcttgtc 3360 gccggacaac gcggcatctc tcacgagcgt atcgagcaaa tcgaagaact ccgtcgtcgc 3420 tgccaatccc tcaaccgtgc cctgcgtcac aaacccggag agcgtcccgt gctcggacgc 3480 cccgccaagg gcgaggaaat cgccgatccc tgtcccgcgc tcctcgaaaa gatcaaccgt 3540 ctccgggacc agcgcgttga ccaaaccgcg catgccatcc tcgccgccgc tctcggtgtt 3600 cgactccgcg ccccctcaaa agaccgcgcc gaacgccgcc atcgcgacat ccatggcgaa 3660 tacgaacgct ttcgtgcgcc cgctgatttt gtcgtcatcg aaaacctctc ccgttatctc 3720 agctcgcagg atcgtgctcg tagtgaaaac acccgtctca tgcagtggtg ccatcgccag 3780 atcgtgcaaa aactccgtca gctctgcgag acctacggca tccccgtcct cgccgtcccg 3840 gcggcctact catcgcgttt ttcttcccgg gacggctcgg ccggattccg ggccgtccat 3900 ctgacaccgg accaccgtca ccggatgcca tggagccgca tcctcgcccg cctcaaggcc 3960 cacgaggaag acggaaaaag actcgaaaag acggtgctcg acgaggctcg cgccgtccgg 4020 ggactctttg accggctcga ccggttcaac gccgggcatg tcccgggaaa accttggcgc 4080 acgctcctcg cgccgctccc cggcggccct gtgtttgtcc ccctcgggga cgccacaccc 4140 atgcaggccg atctgaacgc cgccatcaac atcgccctcc ggggcatcgc ggctcccgac 4200 cgccacgaca tccatcaccg gctccgtgcc gaaaacaaaa aacgcatcct gagcttgcgt 4260 ctcggcactc agcgcgagaa agcccgctgg cctggaggag ctccggcggt gacactctcc 4320 actccgaaca acggcgcctc tcccgaagat tccgatgcgt tgcccgaacg ggtatccaac 4380 ctgtttgtgg acatcgccgg tgtcgccaac ttcgagcgag tcacgatcga aggagtctcg 4440 caaaaattcg ccaccgggcg tggcctttgg gcctccgtca agcaacgtgc atggaaccgc 4500 gttgccagac tcaacgagac agtaacagat aacaacagga acgaagagga ggacgacatt 4560 ccgatgtaac cattgcttca ttacatctga gtctcccctc aatccctctg ccccatgcgt 4620 gatataacct ccacctcatg tcccggatcg gcgccggcaa cctgtagttc ccttccatcc 4680 tccaacactc ccgcagatcg cgatccgctg ccgccgatgc cggtgcgccg ccttcacaac 4740 tatctctact gtccgcggct tttttatctc cagtgggtcg agaatctctt tgaggaaaat 4800 gccgacacca ttgccggcag cgccgtgcat cgtcacgccg acaaacctac gcgttacgat 4860 gatgaaaaag ccgaggcact tcgcactggt ctccctgaag gcgcgcacat acgcagcctt 4920 cgcctggaaa acgcccaact cggtctcgtt ggcgtggtgg atatcgtgga gggaggcccc 4980 gacggactcg aactcgtcga ctacaaaaaa ggttccgcct tccgcctcga cgacggcacg 5040 ctcgctccca aggaaaacga caccgtgcaa cttgccgcct acgctcttct cctggctgcc 5100 gatggtgcgc gcgttgcgcc catggcgacg gtctattacg ctgccgatcg ccggcgtgtc 5160 accttcccgc tcgatgacgc cctctacgcc cgcacccgtt ccgccctcga agaggcccgc 5220 gccgttgcaa cctcggggcg catacctccg ccgctcgtct ctgacgtccg ctgcctccat 5280 tgttcctcct atgcgctttg ccttccccgc gagtccgcct ggtggtgccg ccatcgcagc 5340 acgccgcggg gagccggcca cacccccatg ttgccgggct ttgaggatga cgccgccgcc 5400 attcaccaaa tctccgaacc tgacaccgag ccaccacccg atcttgccag ccagcctccc 5460 cgtcccccgc ggctcgatgg agaattgttg gttgtccaga ctccgggagc gatgatcgga 5520 caaagcggcg gtgagtttac cgtgtccgtc aagggtgagg ttttgcgcaa gcttccggtt 5580 catcaactcc gggccattta cgtttacgga gccgtgcaac tcacggcgca tgctgtgcag 5640 accgcccttg aggaggatat cgacgtctcc tattttgcgc ccagcggccg ctttcttggc 5700 ctcctccgcg gcctgcccgc atccggcgtg gatgcgcgtc tcgggcaata caccctgttt 5760 cgcgaaccct ttggccgtct ccgtctcgcc tgcgaggcga ttcgggccaa gatccataac 5820 cagcgcgtcc tcctcatgcg taacggcgag cccggggagg gcgtcttgcg cgaactcgcc 5880 cgtctgcgcg acgccaccag tgaggcgact tcgctcgacg aactcctcgg catcgagggc 5940 atcgccgcgc atttctattt ccagtatttt cccaccatgc tgaaagaacg ggcggcctgg 6000 gcctttgatt tttccggacg caatcgccgc ccgccgcgcg acccggtcaa cgccctgctt 6060 tcgttcggtt acagcgtgtt gtccaaggaa cttgccggcg tctgccacgc tgttggccta 6120 gacccgtttt tcggcttcat gcaccagccg cgttacgggc gccccgcact cgctctcgat 6180 ctgatggagg agtttcgccc tctcatcgcc gacagtgttg ccctgaatct catcaaccgt 6240 ggcgaactcg acgaagggga ctttatccgg tcggccaatg gcaccgcgct caatgatcgg 6300 ggccgccggc gtttttggga ggcatggttc cggcgtctcg acagcgaagt cagccatcct 6360 gaatttggtt acaagatgag ctatcgacgg atgcttgaag tgcaggcgcg ccagctatgg 6420 cgctatgtgc gcggtgacgc cttccgctac cacggattca ccacccgttg attccgatgt 6480 cagatccccg ccgccgttat cttgtgtgtt acgacatcgc caatccgaag cgattgcgcc 6540 aagtggccaa gctgctggag agctatggca cgcgtctgca atactcggtt ttcgaatgtc 6600 ctttggacga tcttcgtctt gaacaggcga aggctgattt gcgcgacacg attaatgccg 6660 accaagacca ggtgttattt gtttcgcttg gccccgaagc caacgatgcc acgttgatca 6720 tcgccacgct tgggctccct tataccgtgc gctcgcgagt gacgattatc tgacccataa 6780 cccacgtgtt gaagaggctg aaaacagacg gacctctatg aagaacaatt gacgttttgg 6840 ccgaactcag cagaccttta tgcggctaag gccaatgatc atccatccta ccgccattgg 6900 gctggagacg ttttttgaaa cggcgagtgc tgcggatagc gagtttctct tggggaggcg 6960 ctcgcggcca cttttacaga ggagatgttc gggcgaactg gccgacctaa caaggcgtac 7020 ccggctcaaa atcgaggcac gctcgcacgg gatgatgtaa ttcgttgttt ttcagcatac 7080 cgtgcgagca cgggccgcag cgaatgccgt ttcacgaatc gtcaggcggc ggggagaagt 7140 catttaataa ggccactgtt aaaagccgca gcgaatgccg tttcacgaat cgtcaggcgg 7200 gcagtggatg tttttccatg aggcgaagaa tttcatcgcc gcagtgaatg ccgtttcacc 7260 attgatgaag aatgcgaggt gaaaacagag aaattgggtc aactctatca ctcttattca 7320 gccatcgttt caagaaagga tacctcgtat tggatacaac acagctcgtt cgttctctct 7380 acctccctcg acaatctcaa gga

    7403 <210> 62 <211> 6789 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 62 taataaaatt gaaatatcac tatggattat tgtaatatta ccataaagat aggtgacgtt 60 tttttgaaaa ttgtaaacct aatttgaaga aaaccaatta aaaatcgctt cggctttttt 120 ttaagtgcca ggtagcattg atgctaaccc atgtgtaata aaggtttgtt ttccttcggg 180 gcacgaacac attataaggg aaacctaaag attccctttc ttgtttaata ttataaccag 240 tgaaaataag aataatgcac ctaaaactaa tatacagaaa ataagaatta aaagtactaa 300 tatatacatc atatgttatc ctccaatgct ttatttttta ataattgatg ttagtattag 360 ttttatttta atttctaaac ataagaattt gaaaaggatg tgtttattat ggcgacacgc 420 agttttattt taaaaattga accaaatgaa gaagttaaaa agggattatg gaagacgcat 480 gaggtattga atcatggaat tgcctactac atgaatattc tgaaactaat tagacaggaa 540 gctatttatg aacatcatga acaagatcct aaaaatccga aaaaagtttc aaaagcagaa 600 atacaagccg agttatggga ttttgtttta aaaatgcaaa aatgtaatag ttttacacat 660 gaagttgaca aagatgttgt ttttaacatc ctgcgtgaac tatatgaaga gttggtccct 720 agttcagtcg agaaaaaggg tgaagccaat caattatcga ataagtttct gtacccgcta 780 gttgatccga acagtcaaag tgggaaaggg acggcatcat ccggacgtaa acctcggtgg 840 tataatttaa aaatagcagg cgacccatcg tgggaggaag aaaagaaaaa atgggaagag 900 gataaaaaga aagatcccct tgctaaaatc ttaggtaagt tagcagaata tgggcttatt 960 ccgctattta ttccatttac tgacagcaac gaaccaattg taaaagaaat taaatggatg 1020 gaaaaaagtc gtaatcaaag tgtccggcga cttgataagg atatgtttat ccaagcatta 1080 gagcgttttc tttcatggga aagctggaac cttaaagtaa aggaagagta tgaaaaagtt 1140 gaaaaggaac acaaaacact agaggaaagg ataaaagagg acattcaagc atttaaatcc 1200 cttgaacaat atgaaaaaga acggcaggag caacttctta gagatacatt gaatacaaat 1260 gaataccgat taagcaaaag aggattacgt ggttggcgtg aaattatcca aaaatggcta 1320 aagatggatg aaaatgaacc atcagaaaaa tatttagaag tatttaaaga ttatcaacgg 1380 aaacatccac gagaagccgg ggactattct gtctatgaat ttttaagcaa gaaagaaaat 1440 cattttattt ggcgaaatca tcctgaatat ccttatttgt atgctacatt ttgtgaaatt 1500 gacaaaaaaa agaaagacgc taagcaacag gcaactttta ctttggctga cccgattaac 1560 catccgttat gggtacgatt tgaagaaaga agcggttcga acttaaacaa atatcgaatt 1620 ttaacagagc aattacacac tgaaaagtta aaaaagaaat taacagttca acttgatcgt 1680 ttaatttatc caactgaatc cggcggttgg gaggaaaaag gtaaagtaga tatcgttttg 1740 ttgccgtcaa gacaatttta taatcaaatc ttccttgata tagaagaaaa ggggaaacat 1800 gcttttactt ataaggatga aagtattaaa ttccccctta aaggtacact tggtggtgca 1860 agagtgcagt ttgaccgtga ccatttgcgg agatatccgc ataaagtaga atcaggaaat 1920 gttggacgga tttattttaa catgacagta aatattgaac caactgagag ccctgttagt 1980 aagtctttga aaatacatag ggacgatttc cccaagttcg ttaattttaa accgaaagag 2040 ctcaccgaat ggataaaaga tagtaaaggg aaaaaattaa aaagtggtat agaatccctt 2100 gaaattggtc tacgggtgat gagtatcgac ttaggtcaac gtcaagcggc tgctgcatcg 2160 atttttgaag tagttgatca gaaaccggat attgaaggga agttattttt tccaatcaaa 2220 ggaactgagc tttatgctgt tcaccgggca agttttaaca ttaaattacc gggtgaaaca 2280 ttagtaaaat cacgggaagt attgcggaaa gctcgggagg acaacttaaa attaatgaat 2340 caaaagttaa actttctaag aaatgttcta catttccaac agtttgaaga tatcacagaa 2400 agagagaagc gtgtaactaa atggatttct agacaagaaa atagtgatgt tcctcttgta 2460 tatcaagatg agctaattca aattcgtgaa ttaatgtata aaccctataa agattgggtt 2520 gcctttttaa aacaactcca taaacggcta gaagtcgaga ttggcaaaga ggttaagcat 2580 tggcgaaaat cattaagtga cgggagaaaa ggtctttacg gaatctccct aaaaaatatt 2640 gatgaaattg atcgaacaag gaaattcctt ttaagatgga gcttacgtcc aacagaacct 2700 ggggaagtaa gacgcttgga accaggacag cgttttgcga ttgatcaatt aaaccaccta 2760 aatgcattaa aagaagatcg attaaaaaag atggcaaata cgattatcat gcatgcctta 2820 ggttactgtt atgatgtaag aaagaaaaag tggcaggcaa aaaatccagc atgtcaaatt 2880 attttatttg aagatttatc taactacaat ccttacgagg aaaggtcccg ttttgaaaac 2940 tcaaaactga tgaagtggtc acggagagaa attccacgac aagtcgcctt acaaggtgaa 3000 atttacggat tacaagttgg ggaagtaggt gcccaattca gttcaagatt ccatgcgaaa 3060 accgggtcgc cgggaattcg ttgcagtgtt gtaacgaaag aaaaattgca ggataatcgc 3120 ttttttaaaa atttacaaag agaaggacga cttactcttg ataaaatcgc agttttaaaa 3180 gaaggagact tatatccaga taaaggtgga gaaaagttta tttctttatc aaaggatcga 3240 aagttggtaa ctacgcatgc tgatattaac gcggcccaaa atttacagaa gcgtttttgg 3300 acaagaacac atggatttta taaagtttac tgcaaagcct atcaggttga tggacaaact 3360 gtttatattc cggagagcaa ggaccaaaaa caaaaaataa ttgaagaatt tggggaaggc 3420 tattttattt taaaagatgg tgtatatgaa tggggtaatg cggggaaact aaaaattaaa 3480 aaaggttcct ctaaacaatc atcgagtgaa ttagtagatt cggacatact gaaagattca 3540 tttgatttag caagtgaact taagggagag aaactcatgt tatatcgaga tccgagtgga 3600 aacgtatttc cttccgacaa gtggatggca gcaggagtat tttttggcaa attagaaaga 3660 atattgattt ctaagttaac aaatcaatac tcaatatcaa caatagaaga tgattcttca 3720 aaacaatcaa tgtaaaagtt tgcccgtata agaacttaat taattaggat ggtaggatgt 3780 tactaaatat gtctgtaggc atcattccta ctatccgttt tgtccgaata tcagagcatt 3840 aggtgaggaa tggtaagaaa ggaaaattta tatgaaccaa ccgattccta ttcgaatgtt 3900 aaatgaaata caatattgtg agcgactttt ttactttatg catgtccaaa agctatttga 3960 tgagaatgca gatacagttg aaggaagtgc acagcatgag cgggcagaaa gaagcaaaag 4020 accaagtaaa atgggaccaa aggaattatg gggtgaggcg ccaagaagtc ttaagcttgg 4080 tgatgagctg ttaaatatta ccggtgttct tgatgccata agtcatgaag agaacagttg 4140 gatcccggtt gaatcaaaac acagttccgc accggatgga ttgaaccctt ttaaagtaga 4200 tggctttcta cttgacgggt ctgcatggcc aaacgatcaa attcaacttt gtgcacaagg 4260 cttgctcttg aatgccaatg gatacccgtg tgattatggg tatttatttt atcgtggtaa 4320 taagaaaaag gtgaaaattt attttactga agatttaatc gctgccacaa agtactatat 4380 taaaaaagca cacgagatac tagtattatc tggtgatgaa tcagctattc ctaagccttt 4440 aattgattct aataagtgtt ttcgctgttc tttaaactat atctgtcttc cggatgaaac 4500 gaactatcta ttaggggcaa gttcaacaat tcgtaaaatt gtgccttcaa ggacagatgg 4560 tggcgtttta tatgtatcag agtctggtac aaaattagga aaatcgggtg aggagttaat 4620 cattcagtat aaagatggcc aaaagcaggg tgttcctata aaagatatta ttcaagtttc 4680 gttaattgga aatgttcaat gctcaacgca attacttcat tttttaatgc aatcaaatat 4740 tcctgtaagt tatttatcat cccacggtcg tttgattggt gtcagttcat ctttagttac 4800 aaaaaatgtt ttaacaaggc agcaacagtt cattaaattt acaaatcctg agtttggact 4860 aaatctagca aaacaaattg tttatgccaa gattcgaaat caacgaactt tacttagaag 4920 aaatgggggg agtgaggtaa aggagatttt aacagattta aaatctttaa gtgacagtgc 4980 actgaacgca atatcaatag aacaattacg gggtattgaa gggatttctg caaaacatta 5040 tttcgcagga tttccgttta tgttgaaaaa tgaattacgt gaattgaatt taatgaaagg 5100 gcgtaatagg agaccgccaa aagatcctgt aaatgtactt ctttctcttg gttatacttt 5160 attgacacgt gatattcatg ctgcgtgtgg ttcagtcgga ttggatccga tgtttggttg 5220 ttaccatcgt ccagaagcag gtcgaccggc tctagtatta gatgttatgg aaacatttcg 5280 accacttatt gtagacagta ttgtcatccg agctttgaat acgggtgaaa tctcattaaa 5340 agatttttat ataggaaaag atagttgtca attattaaaa catggccgcg attccttttt 5400 tgccatttat gaaagaagaa tgcatgaaac tattaccgat ccaattttcg gctataagat 5460 tagctatcgc cgtatgctcg atttgcacat tcgaatgctt gcaaggttta ttgaagggga 5520 actgccggaa tataaaccat taatgacccg gtgagtttgt ttattaggtt aaaagaaggt 5580 gaagacatgc agcaatacgt ccttgtttct tatgatattt cggaccaaaa aagatggaga 5640 aaagtattta aactgatgaa aggatacgga gaacatgttc aatattccgt attcatatgc 5700 cagttaactg aattacagaa ggcaaaatta caagcctctt tagaagacat tatccatcat 5760 aagaatgacc aagtaatgtt tgttcacatc gggccagtga aagatggtca actatctaaa 5820 aaaatctcaa caattgggaa agaatttgtt ccattggatt taaagcggct tatattttga 5880 aaagatatag caaagaaatc ttatgaaaaa aatacaaaaa tatattgtta aaaaataggg 5940 aatattatat aatggactta cgaggttctg tcttttggtc aggacaaccg tctagctata 6000 agtgctgcag gggtgtgaga aactcctatt gctggacgat gtctctttta tttctttttt 6060 cttggatctg agtacgagca cccacattgg acatttcgca tggtgggtgc tcgtactata 6120 ggtaaaacaa acctttttaa gaagaataca aaaataacca caatattttt taaaaggaat 6180 tttgatggat ttacataacc tctcgcaaca tgcttctaaa acccaagccc accatagccc 6240 aaaaccccct gcggtccaag aaaaaagaaa tgatacgagg cattagcacc ggggagaagt 6300 catttaataa ggccactgtt aaaagtccaa gaaaaaagaa atgatacgag gcattagcac 6360 aacaatataa acgactactt taccgtgttc aagaaaaaag aaatgatatg aggcattagc 6420 acgatgggat gggagagaga ggacagttct actcttgctg tatccagctt cttttacttt 6480 atccggtatc atttcttcac ttctttctgc acataaaaaa gcacctaact atttggataa 6540 gttaagtgct tttatttccg tttgaagttg tctattgctt ttttcttcat atcttcaaat 6600 tttttctgtt tctcagagtc aactttacca actgtaatcc cttttctttt tggcattggg 6660 gtatctttcc accttagtgt gttcataagg cttatattta tcactcattg tattcctcca 6720 acacaattat aatttttccg tcatcctcaa tccaaccgtc aactgtgaca aaagacgaat 6780 ctctcttat 6789 <210> 63 <211>6214 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 63 gtttcatttg gaaagggaga gcattggctt ttctctttgt aaataaagtg caagctttgt 60 aataagcttc tagtggagaa gtgattgttt gaatcaccca atgcacacgc actaaagtta 120 gacgaaccta taattcgtat tagtaagtat agtacatgaa gaaaaatgca acaagcattt 180 actctctttt aaataaagaa ttgatagctg ttaatattga tagtatatta taccttatag 240 atgttcgatt ttttttgaaa ttcaaaaatc atacttagta aagaaaggaa ataacgtcat 300 ggacaagcga aagcgtagaa gttacgagtt taggtgggaa gcgggaggca ccagtcatgg 360 caatccgtag cataaaacta aaactaaaaa cccacacagg cccggaagcg caaaacctcc 420 gaaaaggaat atggcggacg catcggttgt taaatgaagg cgtcgcctat tacatgaaaa 480 tgctcctgct ctttcgtcag gaaagcactg gtgaacggcc aaaagaagaa ctacaggaag 540 aactgatttg tcacatacgc gaacagcaac aacgaaatca ggcagataaa aatacgcaag 600 cgcttccgct agataaggca ctggaagctt tgcgccaact atatgaactg cttgtcccct 660 cctcggtcgg acaaagtggc gacgcccaga tcatcagccg aaagtttctc agcccgctcg 720 tcgatccgaa cagcgaaggc ggcaaaggta cttcgaaggc aggggcaaaa cccacttggc 780 agaagaaaaa agaagcgaac gacccaacct gggaacagga ttacgaaaaa tggaaaaaaa 840 gacgcgagga agacccaacc gcttctgtga ttactacttt ggaggaatac ggcattagac 900 cgatctttcc cctgtacacg aacaccgtaa cagatatcgc gtggttgcca cttcaatcca 960 atcagtttgt gcgaacctgg gacagagaca tgcttcaaca agcgattgaa agactgctca 1020 gttgggagag ctggaacaaa cgtgtccagg aagagtatgc caagctgaaa gaaaaaatgg 1080 ctcaactgaa cgagcaactc gaaggcggtc aggaatggat cagcttgcta gagcagtacg 1140 aagaaaaccg agagcgagag cttagggaaa acatgaccgc tgccaatgac aagtatcgga 1200 ttaccaagcg gcaaatgaaa ggctggaacg agctgtacga gctatggtca acctttcccg 1260 ccagtgccag tcacgagcaa tacaaagagg cgctcaagcg tgtgcagcag cgactgagag 1320 ggcggtttgg ggatgctcat ttcttccagt atctgatgga agagaagaac cgcctgatct 1380 ggaaggggaa tccgcagcgt atccattatt ttgtcgcgcg caacgaactg acgaaacggc 1440 tggaggaagc caagcaaagc gccacgatga cgttgcccaa tgccaggaag catccattgt 1500 gggtgcgctt cgatgcacgg ggaggaaatt tgcaagacta ctacttgacg gctgaagcgg 1560 acaaaccgag aagcagacgt tttgtaacgt ttagtcagtt gatatggcca agcgaatcgg 1620 gatggatgga aaagaaagac gtcgaggtcg agctagcttt gtccaggcag ttttaccagc 1680 aggtgaagtt gctgaaaaat gacaaaggca agcagaaaat cgagttcaag gataaaggtt 1740 cgggctcgac gtttaacgga cacttggggg gagcaaagct acaactggag cggggcgatt 1800 tggagaagga agaaaaaaac ttcgaggacg gggaaatcgg cagcgtttac cttaacgttg 1860 tcattgattt cgaacctttg caagaagtga aaaatggccg cgtgcaggcg ccgtatggac 1920 aagtactgca actcattcgt cgccccaacg agtttcccaa ggtcactacc tataagtcgg 1980 agcaacttgt tgaatggata aaagcttcgc cacaacactc ggctggggtg gagtcgctgg 2040 catccggttt tcgtgtaatg agcatagacc ttgggctgcg cgcggctgca gcgacttcta 2100 ttttttctgt agaagagagt agcgataaaa atgcggctga tttttcctac tggattgaag 2160 gaacgccgct ggtcgctgtc catcagcgga gctatatgct caggttgcct ggtgaacagg 2220 tagaaaaaca ggtgatggaa aaacgggacg agcggttcca gctacaccaa cgtgtgaagt 2280 ttcaaatcag agtgctcgcc caaatcatgc gtatggcaaa taagcagtat ggagatcgct 2340 gggatgaact cgacagcctg aaacaagcgg ttgagcagaa aaagtcgccg ctcgatcaaa 2400 cagaccggac attttgggag gggattgtct gcgacttaac aaaggttttg cctcgaaacg 2460 aagcggactg ggaacaagcg gtagtgcaaa tacaccgaaa agcagaggaa tacgtcggaa 2520 aagccgttca ggcatggcgc aagcgctttg ctgctgacga gcgaaaaggc atcgcaggtc 2580 tgagcatgtg gaacatagaa gaattggagg gcttgcgcaa gctgttgatt tcctggagcc 2640 gcaggacgag gaatccgcag gaggttaatc gctttgagcg aggccatacc agccaccagc 2700 gtctgttgac ccatatccaa aacgtcaaag aggatcgcct gaagcagtta agtcacgcca 2760 ttgtcatgac tgccttgggg tatgtttacg acgagcggaa acaagagtgg tgcgccgaat 2820 acccggcttg ccaggtcatt ctgtttgaaa atctgagcca gtaccgttct aacctggatc 2880 gctcgaccaa agaaaactcc accttgatga agtgggcgca tcgcagcatt ccgaaatacg 2940 tccacatgca ggcggagcca tacgggattc agattggcga tgtccgggcg gaatattcct 3000 ctcgttttta cgccaagaca ggaacgccag gcattcgttg taaaaaggtg agaggccaag 3060 acctgcaggg cagacggttt gagaacttgc agaagaggtt agtcaacgag caatttttga 3120 cggaagaaca agtgaaacag ctaaggcccg gcgacattgt cccggatgat agcggagaac 3180 tgttcatgac cttgacagac ggaagcggaa gcaaggaggt cgtgtttctc caggccgata 3240 ttaacgcggc gcacaatctg caaaaacgtt tttggcagcg atacaatgaa ctgttcaagg 3300 ttagctgccg cgtcatcgtc cgagacgagg aagagtatct cgttcccaag acaaaatcgg 3360 tgcaggcaaa gctgggcaaa gggctttttg tgaaaaaatc ggatacagcc tggaaagatg 3420 tatatgtgtg ggacagccag gcaaagctta aaggtaaaac aacctttaca gaagagtctg 3480 agtcgcccga acaactggaa gactttcagg agatcatcga ggaagcagaa gaggcgaaag 3540 gaacataccg tacactgttc cgcgatccta gcggagtctt ttttcccgaa tccgtatggt 3600 atccccaaaa agatttttgg ggcgaggtga aaaggaagct gtacggaaaa ttgcgggaac 3660 ggtttttgac aaaggctcgg taagggtgtg caaggagagt gaatggcttg tcctggatac 3720 ctgtccgcat gctaaatgaa attcagtatt gtgagcgact gtaccatatt atgcatgtgc 3780 aggggctgtt tgaggaaagc gcagacacgg tcgaaggagc agcacaacac aagcgtgcag 3840 agacacatct gcgcaaaagc aaggcagcgc cggaagagat gtggggggac gctccgttta 3900 gcttgcagct cggcgaccct gtgcttggca ttacgggaaa gctggatgcc gtctgtctgg 3960 aagaaggtaa gcagtggatt ccggtagaag gaaagcattc ggcgtcgcca gaaggcgggc 4020 agatgttcac tgtaggcgtg tattcgctgg acggttctgc ctggcccaac gaccaaatcc 4080 aattgtgtgc gcaaggcttg ctgcttcgcg cgaatggata tgaatccgat tatggctact 4140 tatactaccg tggcaataaa aagaaggttc gcattccttt ttcgcaggaa ctcatagcgg 4200 ctactcacgc ctgcattcaa aaagctcatc agcttcggga agccgaaatt ccccctccgt 4260 tgcaggagtc gaaaaagtgc tttcgatgct cgttaaatta cgtatgcatg cctgacgaga 4320 cgaattacat gttggggttg agcgcaaaca tcagaaagat tgtgcccagt cgtccagatg 4380 gcggggtact gtatgttaca gagcaggggg caaaactggg cagaagcgga gaaagcttga 4440 ccatcacctg ccggggcgaa aagatagacg aaatcccgat caaagacttg attcacgtga 4500 gcttgatggg gcatgtgcaa tgctctacgc agcttctgca caccttgatg aactgtggcg 4560 tccacgtcag ctacttgact acgcatggca cattgacagg aataatgact ccccctttat 4620 cgaaaaacat tcgaacaaga gccaagcagt ttatcaaatt tcagcacgcg gagatcgccc 4680 ttggaatcgc gagaagggtc gtgtatgcga aaatttccaa tcagcgcacg atgctgcgcc 4740 gcaatggctc accagataaa gcagttttaa aagagttaaa agagcttaga gatcgcgcgt 4800 gggaggcgcc atcactggaa atagtgagag gtatcgaggg acgtgcagca cagttgtaca 4860 tgcagttttt ccctaccatg ttaaagcacc cagtagtaga cggtatggcg atcatgaacg 4920 gtcgcaaccg tcgcccgccc aaagatccgg tcaatgcgct gctctccctc ggctatacgc 4980 ttctttcacg ggatgtttac tccgcatgtg ccaatgtcgg actcgatcca ctgttcggct 5040 ttttccatac gatggagccg ggcagaccag ctttggcact cgatctgatg gaaccgttcc 5100 gcgccttgat tgccgatagc gtagcgatac gtaccttgaa tacggaggaa ctcaccctcg 5160 gggactttta ttggggaaaa gacagttgtt atttgaaaaa ggcaggaaga caaacgtatt 5220 tcgctgccta tgaaagacgg atgaacgaga cgctgacgca tccgcaattt gggtataagc 5280 tcagctatcg ccgtatgctg gagctggaag caaggttttt ggcccggtat ctggatggag 5340 agctggtgga atatacgccg ctcatgacaa ggtaggaaat gaccatgcga caatttgttc 5400 tggtaagcta tgatattgcc gatcaaaaac gttggagaaa agtattcaag ctgatgaagg 5460 ggcaaggcga gcacgtccag tactcggtgt ttctgtgcca actcaccgag attcagcaag 5520 ccaagctaaa ggtaagcctg gcggagctgg ttcaccatgg agaagaccag gtcatgtttg 5580 taaaaatcgg cccagtgacg agagatcaac tggacaagcg gatatctact gttggcaggg 5640 agtttctgcc tcgcgatttg accaaattta tctattaagg aatgaagaaa gctagttgta 5700 acaaaagtgg aaaaagagta aaataaaggt gtcagtcgca cgctataggc cataagtcga 5760 cttacatatc cgtgcgtgtg cattatgggc ccatccacag gtctattccc acggataatc 5820 acgactttcc actaagcttt cgaattttat gatgcgagca tcctctcagg tcaaaaaagc 5880 cgggggatgc tcgaactctt tgtgggcgta ggctttccag agttttttag gggaagaggc 5940 agccgatgga taagaggaat ggcgattgaa ttttggcttg ctcgaaaaac gggtctgtaa 6000 ggcttgcggc tgtaggggtt gagtgggaag gagttcgaaa gcttagtgga aagcttcgtg 6060 gttagcaccg gggagaagtc atttaataag gccactgtta aaagttcgaa agcttagtgg 6120 aaagcttcgt ggttagcacg ctaaagtccg tctaaactac tgagatctta aatcggcgct 6180 caaataaaaa acctcgctaa tgcgaggttt cagc 6214 <210> 64 <211> 12338 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 64 gaagttatgt tgataaaatg gtttatgaaa acgtgagtct gtggtagtat tataaacaat 60 gatggaataa agtgtttttt gcgccgcacg gcatgaattc aggggttagc ttggttttgt 120 gtataaataa atgttctaca tatttatttt gttttttgcg ccgcaaaatg caactgaaag 180 ccgcatctag agcaccctgt agaagacagg gttttgagaa tagcccgaca tagagggcaa 240 tagacacggg gagaagtcat ttaataaggc cactgttaaa agttttgaga atagcccgac 300 atagagggca atagactttt gcttcgtcac ggatggactt cacaatggca acaacgtttt 360 gagaatagcc cgacatagtt atagagatgt ataaatataa ccgataaaca ttgactaatt 420 tgttgaagtc agtgtttatc ggttttttgt gtaaatatag gagttgttag aatgatactt 480 tttgcctaat tttggaactt tatgaggata taagatagac ttgataaaaa ggtaaaagaa 540 aggttaaaga gcatggcagg aatagtgacc tgtgatgaag atgatggtag aattaaaagt 600 gttcttaaag aaaaacaata ttggataagg aaaataattc aatagataaa aaatttaggg 660 ggaaaaatga aaatatcaaa agtcgatcat accagaatgg cggttgctaa aggtaatcaa 720 cacaggagag atgagattag tgggattctc tataaggatc cgacaaagac aggaagtata 780 gattttgatg aacgattcaa aaaactgaat tgttcggcga agatacttta tcatgtattc 840 aatggaattg ctgagggaag caataaatac aaaaatattg ttgataaagt aaataacaat 900 ttagataggg tcttatttac aggtaagagc tatgatcgaa aatctatcat agacatagat 960 actgttctta gaaatgttga gaaaattaat gcatttgatc gaatttcaac agaggaaaga 1020 gaacaaataa ttgacgattt gttagaaata caattgagga aggggttaag gaaaggaaaa 1080 gctggattaa gagaggtatt actaattggt gctggtgtaa tagttagaac cgataagaag 1140 caggaaatag ctgattttct ggagatttta gatgaagatt tcaataagac gaatcaggct 1200 aagaacataa aattgtctat tgagaatcag gggttggtgg tctcgcctgt atcaagggga 1260 gaggaacgga tttttgatgt cagtggcgca caaaagggaa aaagcagcaa aaaagcgcag 1320 gagaaagagg cactatctgc atttctgtta gattatgctg atcttgataa gaatgtcagg 1380 tttgagtatt tacgtaaaat tagaagactg ataaatctat atttctatgt caaaaatgat 1440 gatgttatgt ctttaactga aattccggca gaagtgaatc tggaaaaaga ttttgatatc 1500 tggagagatc acgaacaaag aaaggaagag aatggagatt ttgttggatg tccggacata 1560 cttttggcag atcgtgatgt gaagaaaagt aacagtaagc aggtaaaaat tgcagagagg 1620 caattaaggg agtcaatacg tgaaaaaaat ataaaacgat atagatttag cataaaaacg 1680 attgaaaagg atgatggaac atactttttt gcaaataagc agataagtgt attttggatt 1740 catcgcattg aaaatgctgt agaacgtata ttaggatcta ttaatgataa aaaactgtat 1800 agattacgtt taggatatct aggagaaaaa gtatggaagg acatactcaa ttttctcagc 1860 ataaaataca ttgcagtagg caaggcagta ttcaattttg caatggatga tctgcaggag 1920 aaggatagag atatagaacc cggcaagata tcagaaaatg cagtaaatgg attgacttcg 1980 tttgattatg agcaaataaa ggcagatgag atgctgcaga gagaagttgc tgttaatgta 2040 gcattcgcag caaataatct tgctagagta actgtagata ttccgcaaaa tggagaaaaa 2100 gaggatatcc ttctttggaa taaaagtgac ataaaaaaat acaaaaagaa ttcaaagaaa 2160 ggtattctga aatctatact tcagtttttt ggtggtgctt caacttggaa tatgaaaatg 2220 tttgagattg catatcatga tcagccaggt gattacgaag aaaactacct atatgacatt 2280 attcagatca tttactcgct cagaaataag agctttcatt tcaagacata tgatcatggg 2340 gataagaatt ggaatagaga actgatagga aagatgattg agcatgatgc tgaaagagtc 2400 atttctgttg agagggaaaa gtttcattcc aataacctgc cgatgtttta taaagacgct 2460 gatctaaaga aaatattgga tctcttgtat agcgattatg caggacgtgc atctcaggtt 2520 ccggcattta acactgtctt ggttcgaaag aactttccgg aatttcttag gaaagatatg 2580 ggctacaagg ttcattttaa caatcctgaa gtagagaatc agtggcacag tgcggtgtat 2640 tacctatata aagagattta ttacaatcta tttttgagag ataaagaggt aaagaatctt 2700 ttttatactt cattaaaaaa tataagaagt gaagtttcgg acaaaaaaca aaagttagct 2760 tcagatgatt ttgcatccag gtgtgaagaa atagaggata gaagtcttcc ggaaatttgt 2820 cagataataa tgacagaata caatgcgcag aactttggta atagaaaagt taaatctcag 2880 cgtgttattg aaaaaaataa ggatattttc agacattata aaatgctttt gataaagact 2940 ttagcaggtg ctttttctct ttatttgaag caggaaagat ttgcatttat tggtaaggca 3000 acacctatac catacgaaac aaccgatgtt aagaattttt tgcctgaatg gaaatccgga 3060 atgtatgcat cgtttgtaga ggagataaag aataatcttg atcttcaaga atggtatatc 3120 gtcggacgat tccttaatgg gaggatgctc aatcaattgg caggaagcct gcggtcatac 3180 atacagtatg cggaagatat agaacgtcgt gctgcagaaa ataggaataa gcttttctcc 3240 aagcctgatg aaaagattga agcatgtaaa aaagcggtca gagtgcttga tttgtgtata 3300 aaaatttcaa ctagaatatc tgcggaattt actgactatt ttgatagtga agatgattat 3360 gcagattatc ttgaaaaata tctcaagtat caggatgatg ccattaagga attgtcagga 3420 tcttcgtatg ctgcgttgga tcatttttgc aacaaggatg atctgaaatt tgatatctat 3480 gtaaatgccg gacagaagcc tatcttacag agaaatatcg tgatggcaaa gctttttgga 3540 ccagataaca ttttgtctga agttatggaa aaggtaacag aaagtgccat acgagaatac 3600 tatgactatc tgaagaaagt ttcaggatat cgggtaaggg gaaaatgtag tacagagaaa 3660 gaacaggaag atctgctaaa gttccaaaga ttgaaaaacg cagtagaatt ccgggatgtt 3720 actgaatatg ctgaggttat taatgagctt ttaggacagt tgataagttg gtcatatctt 3780 agggagaggg atctattata tttccagctg ggattccatt acatgtgtct gaaaaacaaa 3840 tctttcaaac cggcagaata tgtggatatt cgtagaaata atggtacgat tatacataat 3900 gcgatacttt accagattgt ttcgatgtat attaatggac tggatttcta tagttgtgat 3960 aaagaaggga aaacgctcaa accaattgaa acaggaaagg gcgtaggaag taagatagga 4020 caatttataa agtattccca gtatttatac aatgatccgt catataagct tgagatctat 4080 aatgcaggat tagaagtttt tgaaaacatt gatgaacatg ataatattac agatcttaga 4140 aagtatgtgg atcattttaa gtattatgca tatggtaata aaatgagcct gcttgatctg 4200 tatagtgaat tcttcgatcg tttctttaca tatgatatga agtatcagaa gaatgtagtg 4260 aatgtgttgg agaatatcct tttaaggcat tttgtaattt tctatccgaa gtttggatca 4320 ggaaaaaaag atgttggaat tagggattgt aaaaaagaaa gagctcagat tgaaataagt 4380 gagcagagcc tcacatcgga agacttcatg tttaagcttg acgacaaagc aggagaagaa 4440 gcaaagaagt ttccggcaag ggatgaacgt tatctccaga caatagccaa gttgctctat 4500 tatcctaacg aaattgagga tatgaacaga ttcatgaaga aaggagaaac gataaataaa 4560 aaagttcagt ttaatagaaa aaagaagata accaggaaac aaaagaataa ttcatcaaac 4620 gaggtattgt cttcaactat gggttattta tttaagaaca ttaaattgta aaaaagattc 4680 gttgtagata attgataggt aaaagctgac cggagccttt ggctccggac agttgtatat 4740 aagaggatat taatgactga aaatgatttt tgttggaagt cagttttttc tgtggaaagc 4800 gaaatcgaat atgatgagta tgcatatggc agaagagctg tagaaggcga gaatacatat 4860 gattacatta ctaaggaaga aagaccggaa cttaatgacg aatatgtagc gagacgttgc 4920 attttcggta aaaaagcagg aaaaatatcc aggtcggatt ttagtaggat aagatctgcg 4980 ttggatcatg cgatgataaa taatacacat acagcatttg ccagatttat cactgaaaat 5040 ctgacgagac tcaatcacaa agaacatttt ctgaatgtga cacgtgcata ttctaaacct 5100 gattctgaaa aattgataca accgagatac tggcagtcgc ctgtagttcc aaaggataaa 5160 caaatatatt atagcaagaa tgcgattaaa aaatggtgtg gttacgaaga tgatattccg 5220 cctcgttctg tgatagttca gatgtgtcta ttgtggggga ctgatcatga agaggcagat 5280 catatccttc gcagttcagg atacgcggcg cttagtcctg ttgtacttcg agatcttatc 5340 tatatgtatt atctggatca tcaggatttg caaaaaaatg agttgatatg ggaagtaaaa 5400 aagcagttgg atcacttcga tttgacaaat agaaattatg atacaaatcc ttttgatgta 5460 gggggcagcg taaatgatca tatctgtgaa ctgagcgagc atatagcgaa ggctcattat 5520 atttatgaga gggctaagga aggaccattg caaaatgtaa ttcgggatat tttgggagat 5580 acacctgccc tttattctga aatggcattt cctcagctag catctataaa caggtgtgct 5640 tgcaattcgc tttcttcata tcaaaaaaat atttttgata ctgacatagc tatatatgca 5700 gatgaaaagg acacaagagg taaatcagac cgtatccttg ttgagggcgc atcttcgaaa 5760 tggtatgaat tgaagaaacg cgatgctaat aatgtcaaaa tttctgaaaa gctgagtata 5820 ctcaatacta ttcttaaatt taatagtgtt ttttgggaag aatgttacct tgatggaaat 5880 ataaaacaat cgagcggaaa gcgatctgag gcaggaaaaa ttctttatgg tcgcgacaac 5940 ggaaaagaaa atgtcggagt ttcaaaattg gaattggtgc ggtatatgat agctgcaggt 6000 caggaacaaa atctgggaaa ttacctggtg agttcaggat tttggagaaa aaatcatatg 6060 ctgtcattta tacaaggcaa tgatatagcg cttgatgaga tggatgaatt ggatctctta 6120 gactatattc tgatatatgc atggggattt agggaaaata tcattaaaaa gaacagtaat 6180 gtgaattctt tggatgaaaa gactagaaaa gtgcagtttc cgtttataaa gttactcatg 6240 gcaattgcaa gagatatcca gatacttata tgttcagcac atgaaaaaac agtcgatgag 6300 tcatctcgaa atgcagcaaa gaagatagat atattgggaa attatattcc ttttcagatt 6360 catcttcaga gaactaaaaa agatggtgga agagtggtaa tggatacatt gtgtgctgat 6420 tggattgcgg attatgaatg gtacattgat cttgagaaag gaacacttgg atgagcagtg 6480 atgaaaggat atttaaaaaa tttttggaaa aaggatcgat ttctgagcag aaaaagatgc 6540 ttttagaaga aaagaaatgt tcggataaac taactgcact gcttgggaat tactgcatac 6600 cgatagacaa tatttcagag tcagacggaa aaatatatgc ggtctataag cttccaaaaa 6660 atgttaaacc tttgtccgaa atcattaatg atgtatcctt ttctgattgt acgatgagag 6720 tacgtttgct tctcataaag agaattctgg aactcgtgtg tgcttttcac gaaaaaaaat 6780 ggtattgtct cagtatttca ccgggaatgc tcatggttga agattttgat ataccgatgg 6840 gaaatgtcgg aaaagtattg atatatgatt tcagaaatcc tgttccgttc gagtcagtaa 6900 atgaaagaca taattttaac gtttcaaata aatacacttc accggagctg ctcatccatt 6960 caagatatga cgagtcgaaa tctgtgagtg aaaaatcaga tttgtattct gttgcaaaaa 7020 ttgcggaaac aataatagga gattttaaca gtattattgc aaatggaaat ttgatactac 7080 ttgcaatgct tagagttttt atcagtacag ggaaaagtcc ggaacctgag tatcggtttg 7140 aatcgtcgga aaatatgctt tcagtatttg aaaatttgat caaagaaaat tgtttttttg 7200 aaaaaaacga ttatacatct atgtttcatc aggcgtatga caattttttt gaatggcagg 7260 aatgtttgat atcaccggat cacttggata aaaatatgtt cgaggcagct ttatcaaatc 7320 ttgaggatca gctgcttagg gttgatattg ataagtatag agcagagtac ttctataagc 7380 ttctccgaga gttgtctaat aaatataaaa atacaattac tgatgaacaa aaggtaaggt 7440 tggcaatact tggaatcaga gcgaaaaata atctgggaaa aagttttgat gcattggaaa 7500 tatatgagtc agtacgtgat ttagaaacta tgttggagga gatggcagag cttagtcctg 7560 tcattgcttc gacatatatg gattgctacc gatatgcaga tgcgcagaaa gtggcggaag 7620 aaaacattat caggcttcat aatagtaata ttcgtatgga gaaaaaaaga atactgcttg 7680 gaaggtcata tagttcaaaa gggtgcagca tggggtttca gcatattctt ggtgcggatg 7740 agtcatttga acaggcttta tatttcttta acgaaaagga caatttttgg aaagaaatat 7800 ttgagagcag aaatttagag gacagcgata gacttataaa gtctttacga agcaatacgc 7860 atattacgct gtttcattac atgcaatatg catgtgaaac aaggagaaag gaattatatg 7920 gagcactttc agacaaatat tttataggta aagaatggac agaaagactc aaagcatata 7980 taagcaacaa ggatatatgg aaaaactatt atgagatata tattctgcta aagggtattt 8040 attgcttcta tccagaagtc atgtgttcgt ctgcgtttta tgatgaaatc caaaaaatgt 8100 acgatcttga atttgaaaag gaaaaaatgt tttacccatt gagtctgata gaactgtatc 8160 ttgctctgat agagataaaa gttaatggga gtctgacgga gaatgccgag aagttgttta 8220 aacaggcatt gacacatgac aatgaagtca aaaaaggaaa tatgaatatt cagaccgcca 8280 tttggtatcg aatatatgca ctgtataacg atgtaaaaga tgaaactgat aagaataaaa 8340 ggcttttaaa acggcttatg attctttgcc gacgatttgg ttgggcggat atgtatagtg 8400 ctttggagaa ggatgggaag ttaattgatt ttttgagatt tgaggtatgt taaatgataa 8460 cacttgcatt agatgaaaat ggcaaatttg aagatgcttt ttctaaaaaa aatgaaaaac 8520 cgataatgat tgcggggata atctatgatg acaaggggaa agagtatgat gctgagaatg 8580 aacgctacag gatatccagt tatctgcgag cagtatgtga cagtttgggt gcgaaatacc 8640 ctcaggatct acattcaaat agtaatggaa ataaggcgac tgttgggaaa gtaaaatgta 8700 aaattggtga aacactaaag gaattcttga gagaaggaac ctatgaaaaa aaggaattgc 8760 cgacaaagaa cggttattta aataagagat ctggaaaata tgtaatgttt gcagaactca 8820 ggagtagtca gggagttaaa aagcgtgtta gtggttggaa tgacaatgat ctgactcagg 8880 atgaaaaggt cagcaatctg taccttcata tggcagaaaa tgccgttgtc agaatgctct 8940 tccataatcc tatatatgaa gatgtaacag atgtaaatct ctattttccc acgcgaaaag 9000 ttgttctgaa agatagagat agagaatacg ataaacaaga tttcaaaata tatggtgata 9060 aggacaagtg cgaagcagaa agcgggagat tggtgcatta tgatatcgtg tcatcggatt 9120 tttaccgtac gataatggag aacgaatgta caagaattaa taaaaagcaa ttaaatgttc 9180 attatatgaa cacaagccca atttcgtact gggagaaaaa tgaaaaatat aatacatttt 9240 tatatttggc tgacatagtt tgttctatgc tggattatta caaaaagggt tcgagtccgg 9300 cagagtggat ggattctttt gccgaatggg gaaacaaata ttttggtgat gatcagataa 9360 tcttatttgg gtatgatgat atagatgaca aatacatgga ggctgtagat gcagtaggac 9420 agggagagta ttttcatgcg ctggatatta tatatgatgc ggaatgtagt ggaagtgaat 9480 ttgagaagca ctacaaagat tattggtttc caaagcttat aaaaaagata cgaataacag 9540 caactgtgga taatttatgc agatcgatct cagatctgga gagttttaca tatcgaagta 9600 atcttgatca gcagaaactt ttgtggattt ttgaggaaat caaagctatc gtcgataagg 9660 gagattttgg aaagaaatat catacagatc aggttatgtt tgatatgtgt aatgccggta 9720 ttgctgtgta caatcatatc ggagattttg ggactgcaaa ggaatactat gatgagtgca 9780 tgaaacacac tggggatgtg gatctggtaa agatacttcg tgcatcaaat aaaatggtgg 9840 tctttcttga cgatgctttt aggtatggtg acgcgacaga acgtgccagg aagaatgttg 9900 aataccaaaa agctttgcac gatataaaga gtgagatttg tccggaaaag aaagatgaag 9960 acttgaacta tgccatatcg ctcagtcaat ttggacaggc gcttgcgtgt gaaaaaaatt 10020 ctgatgcaga gagtgttttc ctagagtcgt tgcggcatat gaggaaaggg actgccaatt 10080 atcagattac tctttcatat ttactccatt tttatctgga tatgggaatg acagattctt 10140 atcgagaaaa aacaaaggac tattttggaa gtgaaaaacc aaaggaacag ctgaaagaat 10200 tgctgaagtt atcgggaaag gatgatagta tagttacttt caaatttgca atgtatgtct 10260 atttacgtgc actttgggta ttacaggaac cgcttactga ttttatcaga acaagattag 10320 aggacatacg tgagactctt gtaaagaaga aaatgagtga acatatggtt ggacatccgt 10380 gggagttgat ttataaatat ctggcatttc ttttttatcg tgatggaaat tgtgaagctg 10440 ctgaaaaata tattcataaa agtgaagagt gcttggaaac acaaggactg actatagatg 10500 cgattattca taatggtaag tatgaatatg cagaattgtc aggtgacgag gagatgatgg 10560 caagagagaa agcgtacttt gatgaaaaag ggatagatag aaaaaatgtt tgtactttta 10620 tgtatcattg atgtttaata agatttgacc gaggagtgac aggtaatcgc cggtatatct 10680 ggtattacct gtcatttttt gatgaaataa gctacttttt gcctaaaaaa cgaaactgtt 10740 ggtgttttat gatgattgtg tcaacaaaag agagcaaaag aagaggagaa aagtaatgtc 10800 aatgatttca tgtccgaatt gtggtggaga gatatctgaa aggtcaaaga aatgtgttca 10860 ttgtggatat gtgttagtcg aagaagctaa agtagtgtgc acagaatgtg gaactgaggt 10920 agagagtggc gctgctgtat gtccgaagtg cggctgtcct gtaaatgata gtgagacgcc 10980 tcagaaagtt gaagtgacta gggtaaatgt atcttccgta atcagcaaaa aagtcgttgt 11040 aagcatactg atcgcagtga ttacaattgc aggttttttc tatggagtga agtattcgca 11100 ggaaaagaaa gcaattgaag agtcagtaaa gcagaaggaa gactatcaaa gtacgctaga 11160 gcttgcttcg ctaatgatgc ttcaaggagc ttcggatgca gaaacttgtg ggaatttggt 11220 taggaaagtg tggagcaact gcatttataa ggagagggat gaagaaaccg acaagtatac 11280 gtgtgatagc aggggtgcag gatggtttta tgatgatttt aatgatgcat taatggctct 11340 ttacagtgac agcagttttg gcaagaagat aaatgaaatc aaaaacggtc aggaaaccgt 11400 tgcggcgatg atgaaagatc tgaaaaatcc gccggatgag atggcagatg cctatgagga 11460 tattcaaaat ttttatgtgt cctatctaac gctgacagaa atggttgtga atccaactgg 11520 aagtttgagt tctttttcat ctgatttttc cgatgcggat acggaggtgt ccaatgccta 11580 tagccggatg aagttgtatt tagattaaac tattgaggaa aaaatggagg tgctttaatg 11640 cgggggagaa actgtggagg gtcatcaggc gacggactgc tggtacttct cgtactgctt 11700 gtcctttttt ataaaatcat gccattcata ggtttatgga ttttaatttt tggtgatgct 11760 gaacgtaaag atctgggtat gggtatgatt attgtcggga tagttctata tgtattatta 11820 gaggtttttt aatgtgagtt tctgtggtaa actataaaag tacaagcttt tgcgccgcac 11880 cgcataaata gcggatttat gaccattatt tggtgaaaaa aatggtgtac acctgtgttt 11940 ttttgttttg cgccgcaaaa tgcgccacgg aaccgcatgc agagcaccct gcaagagaca 12000 gggttatgaa aacagcccga catagagggc aatagacacg gggagaagtc atttaataag 12060 gccactgtta aaagttatga aaacagcccg acatagaggg caatagacat aaagaccaaa 12120 aacaggtcat ctgcatactg tgttatgaaa acagcccgat atagagggtg tgagagatat 12180 agttctcgtc acagtgcaga aaatgaccta ttatgtgccg aaaaacaaaa tgaaaaaaga 12240 atggaaaggc gtatttaatg aaatgctgat ctgttgattt gaattaacaa aaaaaggtcg 12300 ccccacggat gacaaaaaca tccgggggcg accctttt 12338 <210> 65 <211> 6098 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 65 tactgtgtgc ataagtcttc cttagatcca taggtacagc agttttattt attagcctta 60 gaaaatggaa aatagagctt ataaatgata tgatatttat gaataaaatg attgcattct 120 cgtgcaaact ttaaatatat tgattatatc ctttacattg gttgttttaa ttactattat 180 taagtaggaa tacgatatac ctctaaatga aagaggacta aaacccgcca aaagtatcag 240 aaaatgttat tgcagtaaga gactacctct atatgaaaga ggactaaaac ttttaacagt 300 ggccttatta aatgacttct gtaagagact acctctatat gaaagaggac taaaacgtct 360 aatgtggata agtataaaaa cgcttatcca tcatttaggt gttttatttt tttgtgatta 420 tatgtacaat agaagagaga aaaaaatcat tgaggtgaaa actatgagaa ttactaaagt 480 agaggttgat agaaaaaaag tactaatttc tagggataaa aacgggggca agttagttta 540 tgaaaatgaa atgcaagata atacagaaca aatcatgcat cacaaaaaaa gttcttttta 600 caaaagtgtg gtaaacaaaa ctatttgtcg tcctgaacaa aaacaaatga aaaaattagt 660 tcatggatta ttacaagaaa atagtcaaga aaaaataaaa gtttcagatg tcactaaact 720 taatatctca aatttcttaa atcatcgttt caaaaaaagt ttatattatt ttcctgaaaa 780 tagtcctgac aaaagcgaag aatacagaat agaaataaat ctctcccaat tgttagaaga 840 tagcttaaaa aaacagcaag ggacatttat atgttgggaa tcttttagca aagacatgga 900 attatacatt aattgggcgg aaaattatat ttcatcaaaa acgaagctaa taaaaaaatc 960 cattcgaaac aatagaattc aatctactga atcaagaagt ggacaactaa tggatagata 1020 tatgaaagac attttaaata aaaacaaacc tttcgatatc caatcagtta gcgaaaagta 1080 ccaacttgaa aaattgacta gtgctttaaa agctactttt aaagaagcga agaaaaacga 1140 caaagagatt aactataagc ttaagtccac tctccaaaac catgaaagac aaataataga 1200 agaattgaag gaaaattccg aactgaacca atttaatata gaaataagaa aacatcttga 1260 aacttatttt cctattaaga aaacaaacag aaaagttgga gatataagga atttagaaat 1320 aggagaaatc caaaaaatag taaatcatcg gttgaaaaat aaaatagttc aacgcattct 1380 ccaagaaggg aaattagctt cttatgagat tgaatcaaca gttaactcta attccttaca 1440 aaaaattaaa attgaagaag catttgcctt aaagtttatc aatgcttgtt tatttgcttc 1500 taacaattta aggaatatgg tatatcctgt ttgcaaaaag gatatattaa tgataggtga 1560 atttaaaaat agttttaaag aaataaaaca caaaaaattc attcgtcaat ggtcgcaatt 1620 cttctctcaa gaaataactg ttgatgacat tgaattagct tcatgggggc tgagaggagc 1680 cattgcacca ataagaaatg aaataattca tttaaagaag catagctgga aaaaattttt 1740 taataaccct actttcaaag tgaaaaaaag taaaataata aatgggaaaa cgaaagatgt 1800 tacatctgaa ttcctttata aagaaacttt atttaaggat tatttctata gtgagttaga 1860 ttctgttcca gaattgatta ttaataaaat ggaaagtagc aaaattttag attattattc 1920 cagtgaccag cttaaccaag tttttacaat tccgaatttc gaattatctt tactgacttc 1980 ggccgttccc tttgcaccta gctttaaacg agtttatttg aaaggctttg attatcagaa 2040 tcaagatgaa gcacaaccgg attataatct taaattaaat atctataacg aaaaagcctt 2100 taattcggag gcatttcagg cgcaatattc attatttaaa atggtttatt atcaagtctt 2160 tttaccgcaa ttcactacaa ataacgattt atttaagtca agtgtggatt ttattttaac 2220 attaaacaaa gaacggaaag gttacgccaa agcatttcaa gatattcgaa agatgaataa 2280 agatgaaaag ccctcagaat atatgagtta cattcagagt caattaatgc tctatcaaaa 2340 aaagcaagaa gaaaaagaga aaattaatca ttttgaaaaa tttataaatc aagtgtttat 2400 taaaggtttc aattctttta tagaaaagaa tagattaacc tatatttgcc atccaaccaa 2460 aaacacagtg ccagaaaatg ataatataga aatacctttc cacacggata tggatgattc 2520 caatattgca ttttggctta tgtgtaaatt attagatgct aaacaactta gcgaattacg 2580 taatgaaatg ataaaattca gttgttcctt acaatcaact gaagaaataa gcacatttac 2640 caaggcgcga gaagtgattg gtttagctct tttaaatggc gaaaaaggat gtaatgattg 2700 gaaagaactt tttgatgata aagaagcttg gaaaaagaac atgtccttat atgtttccga 2760 ggaattgctt caatcattgc cgtacacaca agaagatggt caaacacctg taattaatcg 2820 aagtatcgat ttagtaaaaa aatacggtac agaaacaata ctagagaaat tattttcctc 2880 ctcagatgat tataaagttt cagctaaaga tatcgcaaaa ttacatgaat atgatgtaac 2940 ggagaaaata gcacagcaag agagtctaca taagcaatgg atagaaaagc ccggtttagc 3000 ccgtgactca gcatggacaa aaaaatacca aaatgtgatt aatgatatta gtaattacca 3060 atgggctaag acaaaggtcg aattaacaca agtaaggcat cttcatcaat taactattga 3120 tttgctttca aggttagcag gatatatgtc tatcgctgac cgtgatttcc agttttctag 3180 taattatatt ttagaaagag agaactctga gtatagagtt acaagttgga tattattaag 3240 tgaaaataaa aataaaaata aatataacga ctacgaattg tataatctaa aaaatgcctc 3300 tataaaagta tcatcaaaaa atgatcccca gttaaaagtt gatcttaagc aattacgatt 3360 aaccttagag tacttagaac tttttgataa ccgattgaaa gaaaaacgaa ataacatttc 3420 acattttaat taccttaacg gacagttagg gaactctatt ttagaattat ttgacgatgc 3480 tcgagatgta ctttcctatg atcgtaaact aaagaatgcg gtgtctaaat ctttgaaaga 3540 aattttaagc tctcatggaa tggaagtgac atttaaacca ctatatcaaa ccaatcatca 3600 tttaaaaatt gataaactcc aacctaaaaa aatacaccac ttaggtgaaa aaagtactgt 3660 ttcttcaaat caagtttcta atgaatactg tcaactagta agaacgctat taacgatgaa 3720 gtaattcttt taaagcacat taattacctc taaatgaaaa gaggactaaa actgaaagag 3780 gactaaaaca ccagatgtgg ataactatat tagtggctat taaaaattcg tcgatattag 3840 agaggaaact ttagatgaag atgaaatgga aattaaaaga aaatgacgtt cgcaaagggg 3900 tggtggtcat tgagtaaaat tgacatcgga gaagtaaccc actttttaca aggtctaaag 3960 aaaagtaacg aaaacgcccg aaaaatgata gaagacattc aatcggctgt caaagcctac 4020 gctgatgata caactttaaa aggaaaagca gtggattctt cacaaagata ctttgatgaa 4080 acgtatactg ttatttgtaa aagtatcata gaagcattag atgaaagcga agagagatta 4140 caacaatata ttcatgattt tggagatcaa gtggattctt cacctaacgc acgaattgat 4200 gcggaattac tacaagaagc aatgagtagg ttagctgaca taaagcggaa gcaagaagca 4260 cttatgcaat ccttatcttc ttctacagca acgctttacg aaggcaagca acaagcgtta 4320 cacactcaat tcacggatgc gctggagcaa gaaaaaatat tggaacgcta tattactttt 4380 gaacaaactc acgggaattt ttttgactca tttggagaac ttgtctatcg aacgggacaa 4440 gcagtgcgtg aattagctaa taacgtcaca ttcgagagcc aaacaggaag ctatcatttt 4500 gataaaatag atgcttctag attccaaact ttgcaagaaa tgttgccaaa ggcaaagaaa 4560 aaagcattta attttaatga ctaccaaata acatggaatg gcaccacgca ccttttatgg 4620 aaaaatggta aagtggatgc agaagcaacc aaagcttata acgaggcgaa actgaatgga 4680 aagctaccaa aggaaggtaa tgtagcaaca caagatgcag aactattaaa aggcattttg 4740 gcttcactga aaaacaagaa agatcctatc actggagcag atataagcag tgtgcatgta 4800 ttatctatcc ttagcgggct cgcattctcc tatacagctg ggaattataa gggaagaaaa 4860 cttactgttc caaaaagttt cttagacaaa ttaaagaaaa accgaaaatc taaagtacct 4920 aaactatcta gtttatcaga aaaacaacaa ctaaaactcg caaataaata caagaaaaaa 4980 tcacctattc caattccaga tgatgctaaa atcaaagctc agacgaaaaa ggctggttat 5040 gaacaaatat cttataaatg gaaagagaat gggataacct ttgaagttag atggcatact 5100 aggacaccag gtgcaccaaa ggaacaagga aatacgtttg ttatagaaag aaaaattcag 5160 ggtacagcag aagggaaaac aaaagttcaa caaatattgg ttggagataa taagtgggtg 5220 agtaaaagtg agtggcaaaa ggctataact gataagaaaa atggtgtaag tacctcggag 5280 caaaataaaa tgttgtctga tggacattgg aaagaataga aaggagcaaa atgatggaag 5340 attattataa aggttttgag ggatatccag agatagattt ttatacgtat atagatgata 5400 tgaaattggg tatagcaatg tgggaaggat actttgacaa cattatgaaa gaaattaatc 5460 caagtaacgg aagatggact tcattagcgt attattatca tttagatgag gggtggtatg 5520 atgaaagtcc ttgggaaata ccaagtaata cagaagcatt agaattattg gaaacaatcc 5580 atatatctaa tctagatact atcacacaag agatattact taaattaata aatttattaa 5640 agaagaatat aaatagacaa gtttatattg aatactcata aaaaagatga ttatgatata 5700 ttatagaaca aacgaacaag ccccaaatac gaggtttgtt cgtttgtttt caatataatt 5760 atttgccacc aagtgagata ttacggtttt aaatagctta tttgacgata ccaaaccctg 5820 ataagagaaa gaagaaagag aaagctggtg tagttgtttt aagtgaacta gataaaaaat 5880 taatagcaaa acttgaaaaa gatggtgtga aaatatcaaa agaagatgtt ataggaataa 5940 aataattgcc agatgatgag aaatcgtttg gctggaaaaa ggaaatccat ccgctggatt 6000 tgagcatatt cttattgaac atggtgaaca atttgctaaa tagggaattt caaaagctga 6060 gttacctgat tttttgatga ctgctttaga aaaggaaa 6098 <210> 66 <211> 6222 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 66 attctttaaa aatatctaat aatttattta ctatatactc taatacatct tttaacctat 60 ctaaaacatc atcacctaca acatcccaaa aatcatctaa aaagttaaaa aaatccatct 120 ttatcaactc ctatatctat tttttattgt gtaattcctg agttacaaaa ccattataac 180 acgtattaca cacgtagtca atacttcaaa aaaatttttt gtatattttt ttgaataagt 240 aaataaaaag agctgtgtag ctctttatta aaatcaatat ttttattttg ttaacaaact 300 tagacaacat taaatttaga aacctatata tatttcagta cttttcattt ttaggtagtc 360 taaatcagaa atggttttgt ctaaatgatg tatgtaagtt ttagtcccct tcgtttttag 420 ggtagtctaa atcagaagtc atttaataag gccactgtta aaagttttag tccccttcgt 480 ttttagggta gtctaaatcc catccaaatt atgggataat atgttacttt ttattttaat 540 atttgattat ttattgtttt tttactgatt tagattaccc ctttaattta ttttaccata 600 tttttctcat aatgcaaact aatattccaa aatttttgtt tcttttctta tgatcttttc 660 tccgatagtt atttctccag ataagatttt catttttttg aattgatctt ctgttagaat 720 taatgttctt actgatgaat tttctggaac tatcattgac aactgatttt cataggaaat 780 tattttttct tttgtgctag aacttacaat gtatactgat ttttgtacct gataatatcc 840 ttttcttata atttcttttc taaattttgc atattctttt ttttcttttc ctgtttgcat 900 tggaaaatca tacattagaa tccctacata attagtactc ataatcctct atccttaact 960 caggaatttc tacttctgac atttctcctg taaaataatt tctaatatta tctaaaaaat 1020 aatcaatcac ttgagccaat tcatattttt tatttttcca ataaactttt tgtgttaata 1080 ccaataacaa tttttgtctt aatgatttat tcaaacttac ttcttcctgt tgattaaaat 1140 atacgatata atctaccatt ggacgaaata tttcaataat atcatctgca aaattataat 1200 tattaaattg tgaactgtga tgtattccca aacttggatg aaatccttta gccacaattt 1260 ttgaagagat taagcttctc aaaaccatat acccataatt taatgccgaa tttgtcccgt 1320 cttcaccaaa tctcttaaat tttttcccaa aaagttcacc aaaatacatt cttgcagcaa 1380 ttgcttcctg atgttccgct tcttttcctt ttaatctaat attattttca tatgcttcca 1440 acttatatga tacttcctga gattttttca aaaactgcaa taaatttctt tgattttcta 1500 tttttctcat tacaattttt ctccagattt cttctttttt atcgtcaatc cagctcactt 1560 gctcattaat tcttgttgtt acttgaaaat gattatacag tcctaatgaa tgtaaaactg 1620 gctgatgttt ttcattacaa attatcagtg gaatattatg ttctgataat cttaactgta 1680 atattccgct aattttacat ctgcaatttt caactacaat tgccatgata tcatttaaag 1740 atactttatc agccttattt tcatcatctt catttatcat cacaagctgg ttatttaaaa 1800 ctgataattc attgactctt gttacatgga taatattaga catttttatt actcctttac 1860 tctaaagctt tatattcaaa cataactttc acaagttcac acaattcttc tgaatttcta 1920 tcagtcatta attttttctt ttttaaattt ttcaaatgta caattttttc cgattctaaa 1980 gtctgaattt ctattttctt atctgctcct attttaaatg ttgctacaaa accatattcc 2040 tttaatatat ccactattga tttcataatt gcatttttaa gttttctatc ataagaaagt 2100 aattttctta aattttccag cacttctaaa agtgaaattt cagcatgcgg aatatagtta 2160 aaatgtgcaa tatagtttcg tatatacaaa tcttttttct cttgttttaa tttttttact 2220 tttttatcag aatagatgct tcttttttct acattatctt tgtataattc tttataaaaa 2280 tttatatatt tttcaacaat ttgcccactt ttatatttta catttttact gttatcaaaa 2340 ttaaatattt cttcaatata atgattttca ggaaattcac ctttcaatct aaatcttaag 2400 tccctttccc agatcgaagt atatcccaca agtctgtgga gtatttttaa taacaagcct 2460 tgcaacaagt ttaattcatt aaattccact ttatttttca aatgagtata tttttgtata 2520 tttccaattg ctttttcata ttctttataa tcttcatcat taaatttttc atctttttta 2580 ggtcttgcat attttctatg taaattttgc tgcattgtat aatttttttc tatttcattt 2640 tttttattgc tgtattcttt caattctttt aaacttattt tatacttcgc tttatcagct 2700 attttttcaa gtaaatttaa catcccatat ttttttatat tataaaaagc tctatgcttt 2760 ataatatttt ctccatcaaa atatatttta tttgtgtcaa atttcttcaa ttctttccta 2820 tcttttattt tattttcatt aaaatctaaa aattttccaa tttcattcgc ttctaattca 2880 aaatcttctg ttactctatt attatctaaa tttaaaagat ttataagttc aagttcatct 2940 gaaaaagttt cttctttatt tgcactctga tatttttcaa gacttccctt caaattagtc 3000 aattctttat gattaagcaa ttttaaaatt aaataaaaca tattcaaatt ttcagtgtat 3060 tttaatatct ttcctaattt tatctctctt acaaattcat ttatttcatg tggaatttct 3120 ttattcctat tatgtttttc ataatttttt aaaattttat catatttttc tttattatct 3180 ttttttattt ttattttaga aaatatatca ttattatcat tgttattatt actttctata 3240 tattttaaat tatttttatt caaataatct ataaaacctt ttaaaaatat ttgttgtata 3300 aaatcaatgt atgtattttt ttcttcttta tcttgattat taatcatctc cctactttgt 3360 ataatagcaa gatattctac tggtacagtt ttttctatat tttcaaattt ttgatattta 3420 taatgtcctg ttttttgatt tctttgttta tttattttta ttacttcatt agttatttta 3480 aaaaaaactt tactattttt aacaaattta ttaagaaatt caccataata aatatttttc 3540 aaaagatata tttgagcatc tttttcttct ttatccttag gaacactcca aaaaaatttt 3600 aaagtatttc ttaaatcttc tattttatta tataatttcg taaaagaagg aacaaaagga 3660 atattcttat ttacaaaatt aaattttgta ttttttaaat atttaattat cacatccttt 3720 tcataataat taaatacatt tgcactattt aactgcttaa atatcttcaa tttcaatttt 3780 ttctcattta tttcattttg aaacattttt tttgaaattt cagaaggagc tatattttta 3840 aatgcaaata tatctttccc ttctaattcc aaattaaaat gcacaatccc atgtctaata 3900 ctgctaatag cttcatcaat atttgcaaaa aaatcttcta tctcattttt attatccata 3960 ttaaaatcat aactatagaa catttttaaa ttttctttta cttcattttg cttgttttca 4020 ttatatattt tatcaacttc tccagaaaca tatttttctt cgcccttatt attttttaca 4080 gtttttcctc tcattctacc tgtaatatca ttctcatttt cagtttcaag aatatttctc 4140 aatgaaaaat atgcaaccga agaaactcca attatatttc gtaaaaatgc ttcattttgt 4200 ctattcctag caataaaatc acttgttgca atctctccaa cttgtaaata ataattgtat 4260 ttcccacaat ttcttacata agtatccaat ttatttagta atttgttttc aattaatttt 4320 tttaaatttt gatattcaaa tattctctta attttatcgt tacttatgtt actcagtctt 4380 ttatacacat aatttttcaa aagctgactc atttcaattt ccacaaaatg acaaaaagca 4440 tattttatat ttttatcatt aagttcttct ttatccaaat aatatttata aaacacttgt 4500 gattttttta attcactcat atccggaatt ttttcaatta attcttttat attatttaca 4560 ttttgtattt cttcgtaaat aattttagca aaattttctt tatcattttt tcttccaatt 4620 attttgtgat agtattctct tattttatat ttttcatgtt tttttgaatt ttctattaaa 4680 aaaaataact tctcaatatc ttctttttta tacaatttat caaatgcttc ctgtacatta 4740 tttatataat cattacgctt tgctgattct ctataataat cataaataat atttcttttg 4800 ctcttccctc caactttttc aacattattt tcattaattt tctgataatt agccttattt 4860 tcttcaaatg aatattttaa agaatttatc ttattcaatt ttgcctcaac atcttttcta 4920 aatatttcta attcttcaga gttcacatct tcatttaaca atattttctt taaaactgaa 4980 aaactatttt tattttttaa atcatattct gaaatatctt cttcagaata atttttatcc 5040 tgtactgcat ttttctcttt cctattcttt aaatacagaa cactatcttt tagatgcaat 5100 actttatttg aaaaaaactt ttttaaattt tctcttctta ttctattttc ttcttcactt 5160 gcattatcag gattttttat atatatatcc agtcttatac ttaaaagctc tgacaatctc 5220 tcactagtcc tattttcttc gctcgtactt tttactaatt ttccctcttc aatatatttt 5280 ttatgcgaaa ttccatcaac ttttgtaact ttcatatata aaaacctcct aatatctata 5340 ttttttactc aatacctaat tcttttttca atgctttttg taaaatttgt gaaaaattca 5400 gatttttttc ctgtgccaat atatctaacc aaacaggaat tgttaaagtt ttctttttaa 5460 gtgcatttgt aacttttgcc acttcataca ctggatcaac agataaaata tacaaatact 5520 gattttcttt cagtttcaca tcctccactt ttgaaggctc aggaaatttt tttcttacat 5580 ccaaaaaatc agccaaatgc agacccaatg tctctctcaa attggaaaca gcctcctcca 5640 tgctatctcc aaatgtagca taataattta tctctccatc ttcaaactta tcaaaatcaa 5700 caatacaacc ataataagtc ccatcttcct tagttaccac tgctggataa aatacatcca 5760 ttttaattat ctccaatcta taccacgtgt taaatacgtg tttaaaaata tttataaaat 5820 tttttagcat ctctgctaaa ataaaacaat tatttcaaat ttttctattc cttaatcact 5880 cattgttagt gattcttttt ttacttggac aatttttcat ttaatttctt caattttttt 5940 aaaatcacat ttttttaata ttccttattt aattgcaaat tttcattact tttggggtgc 6000 tctaaatccc atccaaatta tgggataata atttttagtg aaagcaagaa gggactagaa 6060 tttaatccca acttgttttt caatacttct taatgttcct acaggtatat cttttgaata 6120 tggtactgtg accacacctt ccacacctgg gatcatccat tgataatgac tacctcttat 6180 acgcacaact tttccgccta attttctaaa tcttttttcg at 6222 <210> 67 <211> 6337 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 67 ctttctatct ttttcaaata aaattaggct ctagttagcc taatcgcata attatttatt 60 atagtataat tcttattttt tttcaaccta aaaatttaaa acatctccaa aaattttcgt 120 ttcagaacaa ccaagcaacc atattcaaaa aacaataaaa aatgagcaag aattgaaatt 180 ttattctcac tcagaagtta tttttattaa atatcacttt tcgatattgg ggtggtctat 240 atcaatttaa aagacagaat agataattct ttagagtttt agtccccttc gatattgggg 300 tggtctatat cagaagtcat ttaataaggc cactgttaaa agttttagtc cccttcgata 360 ttggggtggt ctatatccca tcctaatttc ttgctgatga gatatttatt tctaattttt 420 ctattttgtc tttattttca atactttcaa tcctattttt ctctttatta ataatataga 480 accaccctat actattatac catatttttt gatttttcaa aattccaata ttttgttttg 540 tgaaattttt tctcccattg tcacttctcc tgcaagtacc ttcatttttt gaaactgatc 600 ttctgtcagg ataatggaac ggattgatga attttctgga gcgagcattg ataactgttt 660 ttctgccagt tcgatttttt cttttgtttt cgacctcatt atatataccg atttttgaag 720 ctgataatat cccttttcta tcaatttttt cctaaaagtc ctatattcaa atctctcaac 780 atctgtctgc ataggaaaat catacataag cagaccaaaa tactcaatac tcatagtcca 840 tcacgctcaa tgtcggaatt atcacttctt catcttttac aaaataattt cgtatactat 900 ccaaataata gtctaccgct tggaaaaaat catatttctt attgttaaat aataccttct 960 gctgtgctac aagaagtatt ttttgcctta tttccttact taatttcact tcattcaaaa 1020 tatccttgta catataaaca agataatcca ccataggacg aaaaacctct attatatcat 1080 cagaaaaatt ataggcatta aactgtgact tatgatgtaa tcctaaactt ggatgaaatc 1140 cttttgctac aatctttgat gatattatag ctcttaaaat catatatcca taattaagtg 1200 cagaattcac tccatcttca tcaaatcttt taaaactatt actatacaat tcctgaaaat 1260 atatccttga agctattgct tcctgatgtt ctgcactcgc atcatctttt ttcaagtttt 1320 ccttatatgt tttcagtctt tcaatggaaa tatcactttt ttcaagatac tctaacaatg 1380 ctctttgatt ttcaatctta ttctccacta tcctgctcca caatttttcc tttttctctt 1440 tttcccactc aatctgctca tttattcgta aagtcacttg aaaatgatta aataatccca 1500 gcgaatgaat ttcaggctga tgtttctcgt tgcaaataat aatcggaatg ttattttcca 1560 ccagcctcaa ctgcaaaatc gcactaatct tacaatagca gttttcaata actatcgcag 1620 atatatcatt caaagaaatc ttatttttct catcattatt gtcttcatca accattataa 1680 gctgattatt cgatattgac aaatcatcag cccttgttat gtgaattata ttgggcattt 1740 taatcatact ccttataaat ttcattctta taacgtatca ttcgtatttt ctatttttgt 1800 taaaagttct attatcaagt ttttaatata atcagaatta taactttcta attctaaaac 1860 agaaactttt ttaggtttca ttaatctttc aagtatatca ttattaccga taagtttaaa 1920 ttttttcttt aattcatcat aatctaaatt cacatctttt ttaaatactt caaatacact 1980 tgcataagtt gaattattat aacgtgtact atatgataat aaattagaaa ctctatcaat 2040 ttgttctgca atactgtaat cagcaaacgg atttcttaca atatagaaat gtgaaatata 2100 gtttctaata ctttcatttt ccggcttatt aatttcagaa ttttcagaca aatcaattcc 2160 aaatccataa catattttct caaatttttt ataagattct tcatcaaaaa atttatagta 2220 tgctgttgtt gtataaaagc catcagatcc attacgctta ggataagctc tacttattcc 2280 agtattgtag ccacttaact taataattcc taattctctt agcccattta caatatagtg 2340 catatctctt tcaaatctag ccatttgaat agcaagtttc caatttatat ctatcaaata 2400 actttctatt ttattcaaat aattaaattc taccaaatct ctaatttttt tgtattcaga 2460 aactctatta taatcttttt caaatgattt atagttttta ttttgtatat tttttgcaaa 2520 aaagtcatca ttttctttca atttttttat atacttctct ttgtattctt tagaatatcc 2580 atttagttta tcatttagat ttttcaatat tgcatcaatt tcagatattt tattttttct 2640 aatattttta ccatcaatat taaataaaaa ttttgcatca gccattttaa tatcatttga 2700 aattaatcca taaattttat caaaatttgg atttccaata tttaaaaata aattcttttt 2760 ataaatatat aattcattct tacgttcttt aggataatat atttcttgaa atttattttc 2820 attctctgat tccatatctt ctattaaatt atctatttct tttttgtatt tttttaaaaa 2880 atcagaatta aatattattc tacacaatat tttactcttt atttcctgat ctttatcttt 2940 tatatactga tcaacctttt ttttcaaatc ctttttattt atgtttgata actttctttg 3000 ttcatcttgt aatatattcg attttttatc tatctcaaat ttagtttcat catcaaaaat 3060 tacaattttt tctaattttt tctctaaaac atcacaacca ttaatatcat ctttaaattc 3120 agttaatata ttatttttta tatcctcata ataattatta aaaatttctt ttttagtttg 3180 tattttaaaa tcatcaaagt ctttttctat ctctttcatt ttttgaataa attcttctaa 3240 attaagattc caattttcag ttatacattc atttctcaaa gtatttaatt gcattatttc 3300 atctaaaata tctataatat tttgatattc tgaagtattt aaccaaactg atgttgcaaa 3360 aaatctattt ctaattttat ttataaccgc attactattt aacagtgcaa atattgaaat 3420 tatatattca aaatcatcat ttattactat agttttatca ctagtcttta cagttattct 3480 ttcgtaagtt ttattatcat taatgtcttt tatttgtttc ttaatttctt gaatattcat 3540 tttaaaatct gaaaaatcaa aaagttcctc ataatttttt ctcaaatatc caatataaca 3600 ttctattact tttttctgat attttttaat agctttatta ttaccttttg aagcagaaat 3660 ctgagcattt ttataataat tttctataat attttcatct atttcatcaa tgtttcctaa 3720 agttttcttt aattcttgta aaaatatatt cttactttca ttttcttcta aatcatcttc 3780 taaaattaat ttcttataca attctttatt cacatatatt aaagcattta atactatttt 3840 ttctgtttct atagtatcaa atggttcatt cttaggatta ttcctatata aatttaatat 3900 ttcaggaagt actttagaaa aggatggtaa atatttaata tcattattat tttcttctga 3960 aattttaata tcatttattt tagtaattat atttttttta tctttaaata ctacatctaa 4020 atttaatgct tttgacactt cttcatctga tatttttaaa ttttgaatta tatttatgac 4080 tttattatag tcatcttgcg ttccttgtaa atctctttcc ttgctaatcg catgtaatat 4140 cctgtttctt tcatttgttc ctatctttgt aaatttccta ataaaattat ttgtaatgtt 4200 atttttatta tctataaaat ctaagtctct tattattttt atttttgaat ttaaaatttt 4260 tttatcaagt acgtaatttt tttctcgatc tcctccaaag aaatctatat tttcatcatt 4320 atttatattt tctctagaaa aaatcttatt taattccata ttggtagaag caaaaaaagt 4380 aatcaattct aaatccaatt cctctttagc gtgaagtcta gaaaaatcat cagtatttac 4440 tgttgtcata tctatatcat tatgtcttaa tttccctaaa tacataatat gctctaacgt 4500 atattgctta actcttttta aaattttttc agataatata ctttcattta aaattttttc 4560 tatttctatt ttttccattt tctttaatct gactttttgt tcatttacca atattttttc 4620 aattcttcct ttcaaatatc gatatatgat tttatatagt tctttttctt catcagattt 4680 ctttgaaaat tttttcgaat caaaattaac tttataatgt tttttaaata ttccaaaaat 4740 ttctgtatca caatttcctt tttttagttc tttttctaat ttttttatta attcatctat 4800 tttaaattct gctaaaattt tttctatttt ttcttttata ctattatttt ttatattttc 4860 tacaaaaaat tttacaattt tatctttttt attttctctt tctattttaa atttttcgtg 4920 cttatctaat agtacataag attttatata tgttctattt cttctctttt caagaaattc 4980 attattaact ttttttactt tttcaattct tttagtaata ttccaaaatt ctaactcttt 5040 tataacaaaa tcagctatat cttctactgt taaatctaca tttatattta aaattttttc 5100 aacaagcatt tttttatttt tagatttctt tttatcacca ccaacattaa gataaaattt 5160 tacaaaaccc agaatttcta aattactttt tattttttct cttatttcca taaaattagt 5220 caaaataaca tctattttat catctttcaa taatttttct cttaaatgtt cttcataata 5280 tcgattttca aatacttttt ctgtttcatt ttcaattatt ttttctataa tcttatataa 5340 actcatgtta atatttttaa aaatttcgta aattgatttt tttgtttcta attcatcatt 5400 ttctattatt cttaatatta ttgaacaatc atttagtgtt ttattagtat actcatctct 5460 gatatctatc tctatttctt cttcattctc ttgtctcttt atttctattt ttttatcatc 5520 tttagttatt ccttgcctaa ttgcttcatc tattattttc ttttttgtaa tccccaatgc 5580 tttcaatttc tcagattttc catatgcttc tatatataat acaacttctt ctgtttccaa 5640 aaaatcatca ttattttcta ttcttatgat tccttcttta cctttcaact taaatagaat 5700 atttcctgca tgaaattttc ttgtaaattc tttaagaata ttatcatttt ttttgtaatt 5760 aatatatttt ctaataaatt tattattatc aattttttct ttattattat tttcattaat 5820 atttaaaatg tatttgtttc catcatagtt ccttttaact tttactttcc gttttatttt 5880 aaaatctttt ttatcacgaa cttcatacca tctcttatgt ccaaataaat ttcccattcc 5940 aatctcctcg tttctacttt aatctaataa aatattttta aattaaatca attttacatc 6000 tttctaatca aaaatacaat tttccatttt tagtatacca catcaatatt aaatctcaaa 6060 aaaataagga gccgtcaaac atagctccct acttctattt actcataatc cccatctatc 6120 cttacttttc gtaaaatcaa tccttctttc gcctttagat ccaacttaat tttcccattt 6180 gaacctgttc taaatgttct gccttctgtt accaaatcaa taaatctttc atcctgataa 6240 tttgtttcaa attccacatt ttcccagctg ttaaacgaat tatttattac aacaataatt aaatgatcct cgattactct ttcatacaca attattt 6337

    6300 <210> 68 <211> 1477 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <400> 68

    Met Ser Asn Phe Phe Lys Asn Phe Thr Asn Leu Tyr Glu Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Asp Thr Leu Thr Asn Met 20 25 30

    Lys Asp His Leu Glu Tyr Asp Glu Lys Leu Gln Thr Phe Leu Lys Asp 35 40 45

    Gln Asn Ile Asp Asp Ala Tyr Gln Ala Leu Lys Pro Gln Phe Asp Glu 50 55 60

    Ile His Glu Glu Phe Ile Thr Asp Ser Leu Glu Ser Lys Lys Ala Lys 65 70 75 80

    Glu Ile Asp Phe Ser Glu Tyr Leu Asp Leu Phe Gln Glu Lys Lys Glu 85 90 95

    Leu Asn Asp Ser Glu Lys Lys Leu Arg Asn Lys Ile Gly Glu Thr Phe 100 105 110

    Asn Lys Ala Gly Glu Lys Trp Lys Lys Glu Lys Tyr Pro Gln Tyr Glu 115 120 125

    Trp Lys Lys Gly Ser Lys Ile Ala Asn Gly Ala Asp Ile Leu Ser Cys 130 135 140

    Gln Asp Met Leu Gln Phe Ile Lys Tyr Lys Asn Pro Glu Asp Glu Lys 145 150 155 160

    Ile Lys Asn Tyr Ile Asp Asp Thr Leu Lys Gly Phe Phe Thr Tyr Phe 165 170 175

    Gly Gly Phe Asn Gln Asn Arg Ala Asn Tyr Tyr Glu Thr Lys Lys Glu 180 185 190

    Ala Ser Thr Ala Val Ala Thr Arg Ile Val His Glu Asn Leu Pro Lys 195 200 205

    Phe Cys Asp Asn Val Ile Gln Phe Lys His Ile Ile Lys Arg Lys Lys 210 215 220

    Asp Gly Thr Val Glu Lys Thr Glu Arg Lys Thr Glu Tyr Leu Asn Ala 225 230 235 240

    Tyr Gln Tyr Leu Lys Asn Asn Asn Lys Ile Thr Gln Ile Lys Asp Ala 245 250 255

    Glu Thr Glu Lys Met Ile Glu Ser Thr Pro Ile Ala Glu Lys Ile Phe 260 265 270

    Asp Val Tyr Tyr Phe Ser Ser Cys Leu Ser Gln Lys Gln Ile Glu Glu 275 280 285

    Tyr Asn Arg Ile Ile Gly His Tyr Asn Leu Leu Ile Asn Leu Tyr Asn 290 295 300

    Gln Ala Lys Arg Ser Glu Gly Lys His Leu Ser Ala Asn Glu Lys Lys 305 310 315 320

    Tyr Lys Asp Leu Pro Lys Phe Lys Thr Leu Tyr Lys Gln Ile Gly Cys 325 330 335

    Gly Lys Lys Lys Asp Leu Phe Tyr Thr Ile Lys Cys Asp Thr Glu Glu 340 345 350

    Glu Ala Asn Lys Ser Arg Asn Glu Gly Lys Glu Ser His Ser Val Glu 355 360 365

    Glu Ile Ile Asn Lys Ala Gln Glu Ala Ile Asn Lys Tyr Phe Lys Ser 370 375 380

    Asn Asn Asp Cys Glu Asn Ile Asn Thr Val Pro Asp Phe Ile Asn Tyr 385 390 395 400

    Ile Leu Thr Lys Glu Asn Tyr Glu Gly Val Tyr Trp Ser Lys Ala Ala 405 410 415

    Met Asn Thr Ile Ser Asp Lys Tyr Phe Ala Asn Tyr His Asp Leu Gln 420 425 430

    Asp Arg Leu Lys Glu Ala Lys Val Phe Gln Lys Ala Asp Lys Lys Ser 435 440 445

    Glu Asp Asp Ile Lys Ile Pro Glu Ala Ile Glu Leu Ser Gly Leu Phe 450 455 460

    Gly Val Leu Asp Ser Leu Ala Asp Trp Gln Thr Thr Leu Phe Lys Ser

    465

    470

    475

    480

    Ser Ile Leu Ser Asn Glu Asp Lys Leu Lys Ile Ile Thr Asp Ser Gln 485 490 495

    Thr Pro Ser Glu Ala Leu Leu Lys Met Ile Phe Asn Asp Ile Glu Lys 500 505 510

    Asn Met Glu Ser Phe Leu Lys Glu Thr Asn Asp Ile Ile Thr Leu Lys 515 520 525

    Lys Tyr Lys Gly Asn Lys Glu Gly Thr Glu Lys Ile Lys Gln Trp Phe 530 535 540

    Asp Tyr Thr Leu Ala Ile Asn Arg Met Leu Lys Tyr Phe Leu Val Lys 545 550 555 560

    Glu Asn Lys Ile Lys Gly Asn Ser Leu Asp Thr Asn Ile Ser Glu Ala 565 570 575

    Leu Lys Thr Leu Ile Tyr Ser Asp Asp Ala Glu Trp Phe Lys Trp Tyr 580 585 590

    Asp Ala Leu Arg Asn Tyr Leu Thr Gln Lys Pro Gln Asp Glu Ala Lys 595 600 605

    Glu Asn Lys Leu Lys Leu Asn Phe Asp Asn Pro Ser Leu Ala Gly Gly 610 615 620

    Trp Asp Val Asn Lys Glu Cys Ser Asn Phe Cys Val Ile Leu Lys Asp 625 630 635 640

    Lys Asn Glu Lys Lys Tyr Leu Ala Ile Met Lys Lys Gly Glu Asn Thr 645 650 655

    Leu Phe Gln Lys Glu Trp Thr Glu Gly Arg Gly Lys Asn Leu Thr Lys 660 665 670

    Lys Ser Asn Pro Leu Phe Glu Ile Asn Asn Cys Glu Ile Leu Ser Lys 675 680 685

    Met Glu Tyr Asp Phe Trp Ala Asp Val Ser Lys Met Ile Pro Lys Cys 690 695 700

    Ser Thr Gln Leu Lys Ala Val Val Asn His Phe Lys Gln Ser Asp Asn 705 710 715 720

    Glu Phe Ile Phe Pro Ile Gly Tyr Lys Val Thr Ser Gly Glu Lys Phe 725 730 735

    Arg Glu Glu Cys Lys Ile Ser Lys Gln Asp Phe Glu Leu Asn Asn Lys 740 745 750

    Val Phe Asn Lys Asn Glu Leu Ser Val Thr Ala Met Arg Tyr Asp Leu 755 760 765

    Ser Ser Thr Gln Glu Lys Gln Tyr Ile Lys Ala Phe Gln Lys Glu Tyr 770 775 780

    Trp Glu Leu Leu Phe Lys Gln Glu Lys Arg Asp Thr Lys Leu Thr Asn 785 790 795 800

    Asn Glu Ile Phe Asn Glu Trp Ile Asn Phe Cys Asn Lys Lys Tyr Ser 805 810 815

    Glu Leu Leu Ser Trp Glu Arg Lys Tyr Lys Asp Ala Leu Thr Asn Trp 820 825 830

    Ile Asn Phe Cys Lys Tyr Phe Leu Ser Lys Tyr Pro Lys Thr Thr Leu 835 840 845

    Phe Asn Tyr Ser Phe Lys Glu Ser Glu Asn Tyr Asn Ser Leu Asp Glu 850 855 860

    Phe Tyr Arg Asp Val Asp Ile Cys Ser Tyr Lys Leu Asn Ile Asn Thr 865 870 875 880

    Thr Ile Asn Lys Ser Ile Leu Asp Arg Leu Val Glu Glu Gly Lys Leu 885 890 895

    Tyr Leu Phe Glu Ile Lys Asn Gln Asp Ser Asn Asp Gly Lys Ser Ile 900 905 910

    Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp Asn Ala Ile Phe Glu 915 920 925

    Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr 930 935 940

    Arg Lys Ala Ile Ser Lys Asp Lys Leu Gly Ile Val Lys Gly Lys Lys 945 950 955 960

    Thr Lys Asn Gly Thr Glu Ile Ile Lys Asn Tyr Arg Phe Ser Lys Glu 965 970 975

    Lys Phe Ile Leu His Val Pro Ile Thr Leu Asn Phe Cys Ser Asn Asn 980 985 990

    Glu Tyr Val Asn Asp Ile Val Asn Thr Lys Phe Tyr Asn Phe Ser Asn 995 1000 1005

    Leu His Phe Leu Gly Ile Asp Arg Gly Glu Lys His Leu Ala Tyr 1010 1015 1020

    Tyr Ser Leu Val Asn Lys Asn Gly Glu Ile Val Asp Gln Gly Thr 1025 1030 1035

    Leu Asn Leu Pro Phe Thr Asp Lys Asp Gly Asn Gln Arg Ser Ile 1040 1045 1050

    Lys Lys Glu Lys Tyr Phe Tyr Asn Lys Gln Glu Asp Lys Trp Glu 1055 1060 1065

    Ala Lys Glu Val Asp Cys Trp Asn Tyr Asn Asp Leu Leu Asp Ala 1070 1075 1080

    Met Ala Ser Asn Arg Asp Met Ala Arg Lys Asn Trp Gln Arg Ile 1085 1090 1095

    Gly Thr Ile Lys Glu Ala Lys Asn Gly Tyr Val Ser Leu Val Ile 1100 1105 1110

    Arg Lys Ile Ala Asp Leu Ala Val Asn Asn Glu Arg Pro Ala Phe 1115 1120 1125

    Ile Val Leu Glu Asp Leu Asn Thr Gly Phe Lys Arg Ser Arg Gln 1130 1135 1140

    Lys Ile Asp Lys Ser Val Tyr Gln Lys Phe Glu Leu Ala Leu Ala 1145 1150 1155

    Lys Lys Leu Asn Phe Leu Val Asp Lys Asn Ala Lys Arg Asp Glu 1160 1165 1170

    Ile Gly Ser Pro Thr Lys Ala Leu Gln Leu Thr Pro Pro Val Asn

    1175

    1180

    1185

    Asn Tyr Gly Asp Ile Glu Asn Lys Lys Gln Ala Gly Ile Met Leu 1190 1195 1200

    Tyr Thr Arg Ala Asn Tyr Thr Ser Gln Thr Asp Pro Ala Thr Gly 1205 1210 1215

    Trp Arg Lys Thr Ile Tyr Leu Lys Ala Gly Pro Glu Glu Thr Thr 1220 1225 1230 Tyr Lys Lys Asp Gly Lys Ile Lys Asn Lys Ser Val Lys Asp Gln 1235 1240 1245 Ile Ile Glu Thr Phe Thr Asp Ile Gly Phe Asp Gly Lys Asp Tyr 1250 1255 1260

    Tyr Phe Glu Tyr Asp Lys Gly Glu Phe Val Asp Glu Lys Thr Gly 1265 1270 1275

    Glu Ile Lys Pro Lys Lys Trp Arg Leu Tyr Ser Gly Glu Asn Gly 1280 1285 1290

    Lys Ser Leu Asp Arg Phe Arg Gly Glu Arg Glu Lys Asp Lys Tyr 1295 1300 1305

    Glu Trp Lys Ile Asp Lys Ile Asp Ile Val Lys Ile Leu Asp Asp 1310 1315 1320

    Leu Phe Val Asn Phe Asp Lys Asn Ile Ser Leu Leu Lys Gln Leu 1325 1330 1335

    Lys Glu Gly Val Glu Leu Thr Arg Asn Asn Glu His Gly Thr Gly 1340 1345 1350

    Glu Ser Leu Arg Phe Ala Ile Asn Leu Ile Gln Gln Ile Arg Asn 1355 1360 1365

    Thr Gly Asn Asn Glu Arg Asp Asn Asp Phe Ile Leu Ser Pro Val 1370 1375 1380

    Arg Asp Glu Asn Gly Lys His Phe Asp Ser Arg Glu Tyr Trp Asp 1385 1390 1395

    Lys Glu Thr Lys Gly Glu Lys Ile Ser Met Pro Ser Ser Gly Asp 1400 1405 1410

    Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Ile Ile Met Asn 1415 1420 1425

    Ala His Ile Leu Ala Asn Ser Asp Ser Lys Asp Leu Ser Leu Phe 1430 1435 1440

    Val Ser Asp Glu Glu Trp Asp Leu His Leu Asn Asn Lys Thr Glu 1445 1450 1455

    Trp Lys Lys Gln Leu Asn Ile Phe Ser Ser Arg Lys Ala Met Ala 1460 1465 1470

    Lys Arg Lys Lys 1475 <210> 69 <211> 1403 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Falkowbacteria bacterium sequence <400> 69

    Met Leu Phe Phe Met Ser Thr Asp Ile Thr Asn Lys Pro Arg Glu Lys 1 5 10 15

    Gly Val Phe Asp Asn Phe Thr Asn Leu Tyr Glu Phe Ser Lys Thr Leu 20 25 30

    Thr Phe Gly Leu Ile Pro Leu Lys Trp Asp Asp Asn Lys Lys Met Ile 35 40 45

    Val Glu Asp Glu Asp Phe Ser Val Leu Arg Lys Tyr Gly Val Ile Glu 50 55 60

    Glu Asp Lys Arg Ile Ala Glu Ser Ile Lys Ile Ala Lys Phe Tyr Leu 65 70 75 80

    Asn Ile Leu His Arg Glu Leu Ile Gly Lys Val Leu Gly Ser Leu Lys 85 90 95

    Phe Glu Lys Lys Asn Leu Glu Asn Tyr Asp Arg Leu Leu Gly Glu Ile 100 105 110

    Glu Lys Asn Asn Lys Asn Glu Asn Ile Ser Glu Asp Lys Lys Lys Glu 115 120 125

    Ile Arg Lys Asn Phe Lys Lys Glu Leu Ser Ile Ala Gln Asp Ile Leu 130 135 140

    Leu Lys Lys Val Gly Glu Val Phe Glu Ser Asn Gly Ser Gly Ile Leu 145 150 155 160

    Ser Ser Lys Asn Cys Leu Asp Glu Leu Thr Lys Arg Phe Thr Arg Gln 165 170 175

    Glu Val Asp Lys Leu Arg Arg Glu Asn Lys Asp Ile Gly Val Glu Tyr 180 185 190

    Pro Asp Val Ala Tyr Arg Glu Lys Asp Gly Lys Glu Glu Thr Lys Ser 195 200 205

    Phe Phe Ala Met Asp Val Gly Tyr Leu Asp Asp Phe His Lys Asn Arg 210 215 220

    Lys Gln Leu Tyr Ser Val Lys Gly Lys Lys Asn Ser Leu Gly Arg Arg 225 230 235 240

    Ile Leu Asp Asn Phe Glu Ile Phe Cys Lys Asn Lys Lys Leu Tyr Glu 245 250 255

    Lys Tyr Lys Asn Leu Asp Ile Asp Phe Ser Glu Ile Glu Arg Asn Phe 260 265 270

    Asn Leu Thr Leu Glu Lys Val Phe Asp Phe Asp Asn Tyr Asn Glu Arg 275 280 285

    Leu Thr Gln Glu Gly Leu Asp Glu Tyr Ala Lys Ile Leu Gly Gly Glu 290 295 300

    Ser Asn Lys Gln Glu Arg Thr Ala Asn Ile His Gly Leu Asn Gln Ile 305 310 315 320

    Ile Asn Leu Tyr Ile Gln Lys Lys Gln Ser Glu Gln Lys Ala Glu Gln 325 330 335

    Lys Glu Thr Gly Lys Lys Lys Ile Lys Phe Asn Lys Lys Asp Tyr Pro 340 345 350

    Thr Phe Thr Cys Leu Gln Lys Gln Ile Leu Ser Gln Val Phe Arg Lys 355 360 365

    Glu Ile Ile Ile Glu Ser Asp Arg Asp Leu Ile Arg Glu Leu Lys Phe 370 375 380

    Phe Val Glu Glu Ser Lys Glu Lys Val Asp Lys Ala Arg Gly Ile Ile 385 390 395 400

    Glu Phe Leu Leu Asn His Glu Glu Asn Asp Ile Asp Leu Ala Met Val 405 410 415

    Tyr Leu Pro Lys Ser Lys Ile Asn Ser Phe Val Tyr Lys Val Phe Lys 420 425 430

    Glu Pro Gln Asp Phe Leu Ser Val Phe Gln Asp Gly Ala Ser Asn Leu 435 440 445

    Asp Phe Val Ser Phe Asp Lys Ile Lys Thr His Leu Glu Asn Asn Lys 450 455 460

    Leu Thr Tyr Lys Ile Phe Phe Lys Thr Leu Ile Lys Glu Asn His Asp 465 470 475 480

    Phe Glu Ser Phe Leu Ile Leu Leu Gln Gln Glu Ile Asp Leu Leu Ile 485 490 495

    Asp Gly Gly Glu Thr Val Thr Leu Gly Gly Lys Lys Glu Ser Ile Thr 500 505 510

    Ser Leu Asp Glu Lys Lys Asn Arg Leu Lys Glu Lys Leu Gly Trp Phe 515 520 525

    Glu Gly Lys Val Arg Glu Asn Glu Lys Met Lys Asp Glu Glu Glu Gly 530 535 540

    Glu Phe Cys Ser Thr Val Leu Ala Tyr Ser Gln Ala Val Leu Asn Ile 545 550 555 560

    Thr Lys Arg Ala Glu Ile Phe Trp Leu Asn Glu Lys Gln Asp Ala Lys 565 570 575

    Val Gly Glu Asp Asn Lys Asp Met Ile Phe Tyr Lys Lys Phe Asp Glu 580 585 590

    Phe Ala Asp Asp Gly Phe Ala Pro Phe Phe Tyr Phe Asp Lys Phe Gly 595 600 605

    Asn Tyr Leu Lys Arg Arg Ser Arg Asn Thr Thr Lys Glu Ile Lys Leu 610 615 620

    His Phe Gly Asn Asp Asp Leu Leu Glu Gly Trp Asp Met Asn Lys Glu 625 630 635 640

    Pro Glu Tyr Trp Ser Phe Ile Leu Arg Asp Arg Asn Gln Tyr Tyr Leu 645 650 655

    Gly Ile Gly Lys Lys Asp Gly Glu Ile Phe His Lys Lys Leu Gly Asn 660 665 670

    Ser Val Glu Ala Val Lys Glu Ala Tyr Glu Leu Glu Asn Glu Ala Asp 675 680 685

    Phe Tyr Glu Lys Ile Asp Tyr Lys Gln Leu Asn Ile Asp Arg Phe Glu 690 695 700

    Gly Ile Ala Phe Pro Lys Lys Thr Lys Thr Glu Glu Ala Phe Arg Gln

    705

    710

    715

    720

    Val Cys Lys Lys Arg Ala Asp Glu Phe Leu Gly Gly Asp Thr Tyr Glu 725 730 735

    Phe Lys Ile Leu Leu Ala Ile Lys Lys Glu Tyr Asp Asp Phe Lys Ala 740 745 750

    Arg Arg Gln Lys Glu Lys Asp Trp Asp Ser Lys Phe Ser Lys Glu Lys 755 760 765

    Met Ser Lys Leu Ile Glu Tyr Tyr Ile Thr Cys Leu Gly Lys Arg Asp 770 775 780

    Asp Trp Lys Arg Phe Asn Leu Asn Phe Arg Gln Pro Lys Glu Tyr Glu 785 790 795 800

    Asp Arg Ser Asp Phe Val Arg His Ile Gln Arg Gln Ala Tyr Trp Ile 805 810 815

    Asp Pro Arg Lys Val Ser Lys Asp Tyr Val Asp Lys Lys Val Ala Glu 820 825 830

    Gly Glu Met Phe Leu Phe Lys Val His Asn Lys Asp Phe Tyr Asp Phe 835 840 845

    Glu Arg Lys Ser Glu Asp Lys Lys Asn His Thr Ala Asn Leu Phe Thr 850 855 860

    Gln Tyr Leu Leu Glu Leu Phe Ser Cys Glu Asn Ile Lys Asn Ile Lys 865 870 875 880

    Ser Lys Asp Leu Ile Glu Ser Ile Phe Glu Leu Asp Gly Lys Ala Glu 885 890 895

    Ile Arg Phe Arg Pro Lys Thr Asp Asp Val Lys Leu Lys Ile Tyr Gln 900 905 910

    Lys Lys Gly Lys Asp Val Thr Tyr Ala Asp Lys Arg Asp Gly Asn Lys 915 920 925

    Glu Lys Glu Val Ile Gln His Arg Arg Phe Ala Lys Asp Ala Leu Thr 930 935 940

    Leu His Leu Lys Ile Arg Leu Asn Phe Gly Lys His Val Asn Leu Phe 945 950 955 960

    Asp Phe Asn Lys Leu Val Asn Thr Glu Leu Phe Ala Lys Val Pro Val 965 970 975

    Lys Ile Leu Gly Met Asp Arg Gly Glu Asn Asn Leu Ile Tyr Tyr Cys 980 985 990

    Phe Leu Asp Glu His Gly Glu Ile Glu Asn Gly Lys Cys Gly Ser Leu 995 1000 1005

    Asn Arg Val Gly Glu Gln Ile Ile Thr Leu Glu Asp Asp Lys Lys 1010 1015 1020

    Val Lys Glu Pro Val Asp Tyr Phe Gln Leu Leu Val Asp Arg Glu 1025 1030 1035

    Gly Gln Arg Asp Trp Glu Gln Lys Asn Trp Gln Lys Met Thr Arg 1040 1045 1050

    Ile Lys Asp Leu Lys Lys Ala Tyr Leu Gly Asn Val Val Ser Trp 1055 1060 1065

    Ile Ser Lys Glu Met Leu Ser Gly Ile Lys Glu Gly Val Val Thr 1070 1075 1080

    Ile Gly Val Leu Glu Asp Leu Asn Ser Asn Phe Lys Arg Thr Arg 1085 1090 1095

    Phe Phe Arg Glu Arg Gln Val Tyr Gln Gly Phe Glu Lys Ala Leu 1100 1105 1110

    Val Asn Lys Leu Gly Tyr Leu Val Asp Lys Lys Tyr Asp Asn Tyr 1115 1120 1125

    Arg Asn Val Tyr Gln Phe Ala Pro Ile Val Asp Ser Val Glu Glu 1130 1135 1140

    Met Glu Lys Asn Lys Gln Ile Gly Thr Leu Val Tyr Val Pro Ala 1145 1150 1155

    Ser Tyr Thr Ser Lys Ile Cys Pro His Pro Lys Cys Gly Trp Arg 1160 1165 1170

    Glu Arg Leu Tyr Met Lys Asn Ser Ala Ser Lys Glu Lys Ile Val 1175 1180 1185

    Gly Leu Leu Lys Ser Asp Gly Ile Lys Ile Ser Tyr Asp Gln Lys 1190 1195 1200

    Asn Asp Arg Phe Tyr Phe Glu Tyr Gln Trp Glu Gln Glu His Lys 1205 1210 1215

    Ser Asp Gly Lys Lys Lys Lys Tyr Ser Gly Val Asp Lys Val Phe 1220 1225 1230

    Ser Asn Val Ser Arg Met Arg Trp Asp Val Glu Gln Lys Lys Ser 1235 1240 1245

    Ile Asp Phe Val Asp Gly Thr Asp Gly Ser Ile Thr Asn Lys Leu 1250 1255 1260

    Lys Ser Leu Leu Lys Gly Lys Gly Ile Glu Leu Asp Asn Ile Asn 1265 1270 1275

    Gln Gln Ile Val Asn Gln Gln Lys Glu Leu Gly Val Glu Phe Phe 1280 1285 1290

    Gln Ser Ile Ile Phe Tyr Phe Asn Leu Ile Met Gln Ile Arg Asn 1295 1300 1305

    Tyr Asp Lys Glu Lys Ser Gly Ser Glu Ala Asp Tyr Ile Gln Cys 1310 1315 1320

    Pro Ser Cys Leu Phe Asp Ser Arg Lys Pro Glu Met Asn Gly Lys 1325 1330 1335

    Leu Ser Ala Ile Thr Asn Gly Asp Ala Asn Gly Ala Tyr Asn Ile 1340 1345 1350

    Ala Arg Lys Gly Phe Met Gln Leu Cys Arg Ile Arg Glu Asn Pro 1355 1360 1365

    Gln Glu Pro Met Lys Leu Ile Thr Asn Arg Glu Trp Asp Glu Ala 1370 1375 1380

    Val Arg Glu Trp Asp Ile Tyr Ser Ala Ala Gln Lys Ile Pro Val

    1385 1390 1395

    Leu Ser Glu Glu Asn

    1400 <210> 70 <211> 1373 <212> PRT <213> Moraxella bovoculi <400> 70

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Val 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Asp Arg Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met His Gln Lys 35 40 45

    Val Lys Val Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Glu Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly 100 105 110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Ala Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Thr Thr 195 200 205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Pro Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met 290 295 300

    Ser Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys

    325

    330

    335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Val Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe 545 550 555 560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn 565 570 575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Val Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Ser Ile Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Tyr Leu Glu Val Arg Lys Gln Phe Pro Lys Val Phe Phe 625 630 635 640

    Ser Lys Glu Ala Ile Ala Ile Asn Tyr His Pro Ser Lys Glu Leu Val 645 650 655

    Glu Ile Lys Asp Lys Gly Arg Gln Arg Ser Asp Asp Glu Arg Leu Lys 660 665 670

    Leu Tyr Arg Phe Ile Leu Glu Cys Leu Lys Ile His Pro Lys Tyr Asp 675 680 685

    Lys Lys Phe Glu Gly Ala Ile Gly Asp Ile Gln Leu Phe Lys Lys Asp 690 695 700

    Lys Lys Gly Arg Glu Val Pro Ile Ser Glu Lys Asp Leu Phe Asp Lys 705 710 715 720

    Ile Asn Gly Ile Phe Ser Ser Lys Pro Lys Leu Glu Met Glu Asp Phe 725 730 735

    Phe Ile Gly Glu Phe Lys Arg Tyr Asn Pro Ser Gln Asp Leu Val Asp 740 745 750

    Gln Tyr Asn Ile Tyr Lys Lys Ile Asp Ser Asn Asp Asn Arg Lys Lys 755 760 765

    Glu Asn Phe Tyr Asn Asn His Pro Lys Phe Lys Lys Asp Leu Val Arg 770 775 780

    Tyr Tyr Tyr Glu Ser Met Cys Lys His Glu Glu Trp Glu Glu Ser Phe 785 790 795 800

    Glu Phe Ser Lys Lys Leu Gln Asp Ile Gly Cys Tyr Val Asp Val Asn 805 810 815

    Glu Leu Phe Thr Glu Ile Glu Thr Arg Arg Leu Asn Tyr Lys Ile Ser 820 825 830

    Phe Cys Asn Ile Asn Ala Asp Tyr Ile Asp Glu Leu Val Glu Gln Gly 835 840 845

    Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Lys Ala 850 855 860

    His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala Leu Phe Ser 865 870 875 880

    Glu Asp Asn Leu Ala Asp Pro Ile Tyr Lys Leu Asn Gly Glu Ala Gln 885 890 895

    Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr Thr Ile His 900 905 910

    Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn Pro Lys Lys 915 920 925

    Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr Thr Gln Asp 930 935 940

    Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly Val Gln Gly 945 950 955 960

    Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser Ile Gln Gln 965 970 975

    Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu Arg His Leu 980 985 990

    Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu Glu Gln Cys 995 1000 1005

    Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr Gln Met 1010 1015 1020

    Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu Arg 1025 1030 1035

    Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu

    1040

    1045

    1050

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln 1055 1060 1065

    Leu Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 1070 1075 1080

    Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 1085 1090 1095

    Gln Asn Phe Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val 1100 1105 1110

    Leu Lys Asp Lys Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala 1115 1120 1125

    Leu Gln Leu Thr Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys 1130 1135 1140

    Gln Thr Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys

    1145 1150 1155 Ile Asp Pro Glu Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr 1160 1165 1170 Glu Asn Ile Ala Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys 1175 1180 1185

    Ile Cys Tyr Asn Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp 1190 1195 1200

    Tyr Ala Lys Phe Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp 1205 1210 1215

    Thr Ile Cys Ser His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr 1220 1225 1230

    Ala Asn Gln Asn Lys Gly Ala Ala Lys Gly Ile Asn Val Asn Asp 1235 1240 1245

    Glu Leu Lys Ser Leu Phe Ala Arg His His Ile Asn Glu Lys Gln 1250 1255 1260

    Pro Asn Leu Val Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe 1265 1270 1275

    His Lys Ser Leu Met Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg 1280 1285 1290

    Tyr Ser Asn Ala Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val 1295 1300 1305

    Ala Asn Asp Glu Gly Val Phe Phe Asn Ser Ala Leu Ala Asp Asp 1310 1315 1320

    Thr Gln Pro Gln Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala 1325 1330 1335

    Leu Lys Gly Leu Trp Leu Leu Asn Glu Leu Lys Asn Ser Asp Asp 1340 1345 1350

    Phe Ala Gln Asn Arg 1370

    Leu Asn Lys Val Lys Leu Ala Ile Asp Asn Gln Thr Trp Leu Asn

    1355 1360 1365 <210> 71 <211> 1352 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Parcubacteria group bacterium sequence <400> 71

    Met Glu Asn Ile Phe Asp Gln Phe Ile Gly Lys Tyr Ser Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Glu Asp Phe Leu 20 25 30

    Lys Ile Asn Lys Val Phe Glu Lys Asp Gln Thr Ile Asp Asp Ser Tyr 35 40 45

    Asn Gln Ala Lys Phe Tyr Phe Asp Ser Leu His Gln Lys Phe Ile Asp 50 55 60

    Ala Ala Leu Ala Ser Asp Lys Thr Ser Glu Leu Ser Phe Gln Asn Phe 65 70 75 80

    Ala Asp Val Leu Glu Lys Gln Asn Lys Ile Ile Leu Asp Lys Lys Arg 85 90 95

    Glu Met Gly Ala Leu Arg Lys Arg Asp Lys Asn Ala Val Gly Ile Asp 100 105 110

    Arg Leu Gln Lys Glu Ile Asn Asp Ala Glu Asp Ile Ile Gln Lys Glu 115 120 125

    Lys Glu Lys Ile Tyr Lys Asp Val Arg Thr Leu Phe Asp Asn Glu Ala 130 135 140

    Glu Ser Trp Lys Thr Tyr Tyr Gln Glu Arg Glu Val Asp Gly Lys Lys 145 150 155 160

    Ile Thr Phe Ser Lys Ala Asp Leu Lys Gln Lys Gly Ala Asp Phe Leu 165 170 175

    Thr Ala Ala Gly Ile Leu Lys Val Leu Lys Tyr Glu Phe Pro Glu Glu 180 185 190

    Lys Glu Lys Glu Phe Gln Ala Lys Asn Gln Pro Ser Leu Phe Val Glu 195 200 205

    Glu Lys Glu Asn Pro Gly Gln Lys Arg Tyr Ile Phe Asp Ser Phe Asp 210 215 220

    Lys Phe Ala Gly Tyr Leu Thr Lys Phe Gln Gln Thr Lys Lys Asn Leu 225 230 235 240

    Tyr Ala Ala Asp Gly Thr Ser Thr Ala Val Ala Thr Arg Ile Ala Asp 245 250 255

    Asn Phe Ile Ile Phe His Gln Asn Thr Lys Val Phe Arg Asp Lys Tyr 260 265 270

    Lys Asn Asn His Thr Asp Leu Gly Phe Asp Glu Glu Asn Ile Phe Glu 275 280 285

    Ile Glu Arg Tyr Lys Asn Cys Leu Leu Gln Arg Glu Ile Glu His Ile 290 295 300

    Lys Asn Glu Asn Ser Tyr Asn Lys Ile Ile Gly Arg Ile Asn Lys Lys 305 310 315 320

    Ile Lys Glu Tyr Arg Asp Gln Lys Ala Lys Asp Thr Lys Leu Thr Lys 325 330 335

    Ser Asp Phe Pro Phe Phe Lys Asn Leu Asp Lys Gln Ile Leu Gly Glu 340 345 350

    Val Glu Lys Glu Lys Gln Leu Ile Glu Lys Thr Arg Glu Lys Thr Glu 355 360 365

    Glu Asp Val Leu Ile Glu Arg Phe Lys Glu Phe Ile Glu Asn Asn Glu 370 375 380

    Glu Arg Phe Thr Ala Ala Lys Lys Leu Met Asn Ala Phe Cys Asn Gly 385 390 395 400

    Glu Phe Glu Ser Glu Tyr Glu Gly Ile Tyr Leu Lys Asn Lys Ala Ile 405 410 415

    Asn Thr Ile Ser Arg Arg Trp Phe Val Ser Asp Arg Asp Phe Glu Leu 420 425 430

    Lys Leu Pro Gln Gln Lys Ser Lys Asn Lys Ser Glu Lys Asn Glu Pro 435 440 445

    Lys Val Lys Lys Phe Ile Ser Ile Ala Glu Ile Lys Asn Ala Val Glu 450 455 460

    Glu Leu Asp Gly Asp Ile Phe Lys Ala Val Phe Tyr Asp Lys Lys Ile 465 470 475 480

    Ile Ala Gln Gly Gly Ser Lys Leu Glu Gln Phe Leu Val Ile Trp Lys 485 490 495

    Tyr Glu Phe Glu Tyr Leu Phe Arg Asp Ile Glu Arg Glu Asn Gly Glu 500 505 510

    Lys Leu Leu Gly Tyr Asp Ser Cys Leu Lys Ile Ala Lys Gln Leu Gly 515 520 525

    Ile Phe Pro Gln Glu Lys Glu Ala Arg Glu Lys Ala Thr Ala Val Ile 530 535 540

    Lys Asn Tyr Ala Asp Ala Gly Leu Gly Ile Phe Gln Met Met Lys Tyr 545 550 555 560

    Phe Ser Leu Asp Asp Lys Asp Arg Lys Asn Thr Pro Gly Gln Leu Ser 565 570 575

    Thr Asn Phe Tyr Ala Glu Tyr Asp Gly Tyr Tyr Lys Asp Phe Glu Phe 580 585 590

    Ile Lys Tyr Tyr Asn Glu Phe Arg Asn Phe Ile Thr Lys Lys Pro Phe 595 600 605

    Asp Glu Asp Lys Ile Lys Leu Asn Phe Glu Asn Gly Ala Leu Leu Lys 610 615 620

    Gly Trp Asp Glu Asn Lys Glu Tyr Asp Phe Met Gly Val Ile Leu Lys 625 630 635 640

    Lys Glu Gly Arg Leu Tyr Leu Gly Ile Met His Lys Asn His Arg Lys 645 650 655

    Leu Phe Gln Ser Met Gly Asn Ala Lys Gly Asp Asn Ala Asn Arg Tyr 660 665 670

    Gln Lys Met Ile Tyr Lys Gln Ile Ala Asp Ala Ser Lys Asp Val Pro

    675

    680

    685

    Arg Leu Leu Leu Thr Ser Lys Lys Ala Met Glu Lys Phe Lys Pro Ser 690 695 700

    Gln Glu Ile Leu Arg Ile Lys Lys Glu Lys Thr Phe Lys Arg Glu Ser 705 710 715 720

    Lys Asn Phe Ser Leu Arg Asp Leu His Ala Leu Ile Glu Tyr Tyr Arg 725 730 735

    Asn Cys Ile Pro Gln Tyr Ser Asn Trp Ser Phe Tyr Asp Phe Gln Phe 740 745 750

    Gln Asp Thr Gly Lys Tyr Gln Asn Ile Lys Glu Phe Thr Asp Asp Val 755 760 765

    Gln Lys Tyr Gly Tyr Lys Ile Ser Phe Arg Asp Ile Asp Asp Glu Tyr 770 775 780

    Ile Asn Gln Ala Leu Asn Glu Gly Lys Met Tyr Leu Phe Glu Val Val 785 790 795 800

    Asn Lys Asp Ile Tyr Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr 805 810 815

    Leu Tyr Phe Glu His Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val 820 825 830

    Phe Lys Leu Ser Gly Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val 835 840 845

    Asn Glu Arg Glu Lys Ile Thr Thr Gln Lys Asn Gln Cys Ile Leu Asp 850 855 860

    Lys Gly Asp Arg Ala Tyr Lys Tyr Arg Arg Tyr Thr Glu Lys Lys Ile 865 870 875 880

    Met Phe His Met Ser Leu Val Leu Asn Thr Gly Lys Gly Glu Ile Lys 885 890 895

    Gln Val Gln Phe Asn Lys Ile Ile Asn Gln Arg Ile Ser Ser Ser Asp 900 905 910

    Asn Glu Met Arg Val Asn Val Ile Gly Ile Asp Arg Gly Glu Lys Asn 915 920 925

    Leu Leu Tyr Tyr Ser Val Val Lys Gln Asn Gly Glu Ile Ile Glu Gln 930 935 940

    Ala Ser Leu Asn Glu Ile Asn Gly Val Asn Tyr Arg Asp Lys Leu Ile 945 950 955 960

    Glu Arg Glu Lys Glu Arg Leu Lys Asn Arg Gln Ser Trp Lys Pro Val 965 970 975

    Val Lys Ile Lys Asp Leu Lys Lys Gly Tyr Ile Ser His Val Ile His 980 985 990

    Lys Ile Cys Gln Leu Ile Glu Lys Tyr Ser Ala Ile Val Val Leu Glu 995 1000 1005

    Asp Leu Asn Met Arg Phe Lys Gln Ile Arg Gly Gly Ile Glu Arg 1010 1015 1020

    Ser Val Tyr Gln Gln Phe Glu Lys Ala Leu Ile Asp Lys Leu Gly 1025 1030 1035

    Tyr Leu Val Phe Lys Asp Asn Arg Asp Leu Arg Ala Pro Gly Gly 1040 1045 1050

    Val Leu Asn Gly Tyr Gln Leu Ser Ala Pro Phe Val Ser Phe Glu 1055 1060 1065

    Lys Met Arg Lys Gln Thr Gly Ile Leu Phe Tyr Thr Gln Ala Glu 1070 1075 1080

    Tyr Thr Ser Lys Thr Asp Pro Ile Thr Gly Phe Arg Lys Asn Val 1085 1090 1095

    Tyr Ile Ser Asn Ser Ala Ser Leu Asp Lys Ile Lys Glu Ala Val 1100 1105 1110

    Lys Lys Phe Asp Ala Ile Gly Trp Asp Gly Lys Glu Gln Ser Tyr 1115 1120 1125

    Phe Phe Lys Tyr Asn Pro Tyr Asn Leu Ala Asp Glu Lys Tyr Lys 1130 1135 1140

    Asn Ser Thr Val Ser Lys Glu Trp Ala Ile Phe Ala Ser Ala Pro 1145 1150 1155

    Arg Ile Arg Arg Gln Lys Gly Glu Asp Gly Tyr Trp Lys Tyr Asp 1160 1165 1170

    Arg Val Lys Val Asn Glu Glu Phe Glu Lys Leu Leu Lys Val Trp 1175 1180 1185

    Asn Phe Val Asn Pro Lys Ala Thr Asp Ile Lys Gln Glu Ile Ile 1190 1195 1200

    Lys Lys Glu Lys Ala Gly Asp Leu Gln Gly Glu Lys Glu Leu Asp 1205 1210 1215

    Gly Arg Leu Arg Asn Phe Trp His Ser Phe Ile Tyr Leu Phe Asn 1220 1225 1230

    Leu Val Leu Glu Leu Arg Asn Ser Phe Ser Leu Gln Ile Lys Ile 1235 1240 1245

    Lys Ala Gly Glu Val Ile Ala Val Asp Glu Gly Val Asp Phe Ile 1250 1255 1260

    Ala Ser Pro Val Lys Pro Phe Phe Thr Thr Pro Asn Pro Tyr Ile 1265 1270 1275

    Pro Ser Asn Leu Cys Trp Leu Ala Val Glu Asn Ala Asp Ala Asn 1280 1285 1290

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Val Met Ile Leu Lys Lys 1295 1300 1305

    Ile Arg Glu His Ala Lys Lys Asp Pro Glu Phe Lys Lys Leu Pro 1310 1315 1320

    Asn Leu Phe Ile Ser Asn Ala Glu Trp Asp Glu Ala Ala Arg Asp 1325 1330 1335

    Trp Gly Lys Tyr Ala Gly Thr Thr Ala Leu Asn Leu Asp His

    1340 1345 1350 <210> 72 <211> 1334 <212> PRT <213> Succinivibrio dextrinosolvens <400> 72

    Met Ser Ser Leu Thr Lys Phe Thr Asn Lys Tyr Ser Lys Gln Leu Thr 1 5 10 15

    Ile Lys Asn Glu Leu Ile Pro Val Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Glu Asn Gly Leu Ile Asp Gly Asp Glu Gln Leu Asn Glu Asn Tyr Gln 35 40 45

    Lys Ala Lys Ile Ile Val Asp Asp Phe Leu Arg Asp Phe Ile Asn Lys 50 55 60

    Ala Leu Asn Asn Thr Gln Ile Gly Asn Trp Arg Glu Leu Ala Asp Ala 65 70 75 80

    Leu Asn Lys Glu Asp Glu Asp Asn Ile Glu Lys Leu Gln Asp Lys Ile 85 90 95

    Arg Gly Ile Ile Val Ser Lys Phe Glu Thr Phe Asp Leu Phe Ser Ser 100 105 110

    Tyr Ser Ile Lys Lys Asp Glu Lys Ile Ile Asp Asp Asp Asn Asp Val 115 120 125

    Glu Glu Glu Glu Leu Asp Leu Gly Lys Lys Thr Ser Ser Phe Lys Tyr 130 135 140

    Ile Phe Lys Lys Asn Leu Phe Lys Leu Val Leu Pro Ser Tyr Leu Lys 145 150 155 160

    Thr Thr Asn Gln Asp Lys Leu Lys Ile Ile Ser Ser Phe Asp Asn Phe 165 170 175

    Ser Thr Tyr Phe Arg Gly Phe Phe Glu Asn Arg Lys Asn Ile Phe Thr 180 185 190

    Lys Lys Pro Ile Ser Thr Ser Ile Ala Tyr Arg Ile Val His Asp Asn 195 200 205

    Phe Pro Lys Phe Leu Asp Asn Ile Arg Cys Phe Asn Val Trp Gln Thr 210 215 220

    Glu Cys Pro Gln Leu Ile Val Lys Ala Asp Asn Tyr Leu Lys Ser Lys 225 230 235 240

    Asn Val Ile Ala Lys Asp Lys Ser Leu Ala Asn Tyr Phe Thr Val Gly 245 250 255

    Ala Tyr Asp Tyr Phe Leu Ser Gln Asn Gly Ile Asp Phe Tyr Asn Asn 260 265 270

    Ile Ile Gly Gly Leu Pro Ala Phe Ala Gly His Glu Lys Ile Gln Gly 275 280 285

    Leu Asn Glu Phe Ile Asn Gln Glu Cys Gln Lys Asp Ser Glu Leu Lys 290 295 300

    Ser Lys Leu Lys Asn Arg His Ala Phe Lys Met Ala Val Leu Phe Lys 305 310 315 320

    Gln Ile Leu Ser Asp Arg Glu Lys Ser Phe Val Ile Asp Glu Phe Glu 325 330 335

    Ser Asp Ala Gln Val Ile Asp Ala Val Lys Asn Phe Tyr Ala Glu Gln 340 345 350

    Cys Lys Asp Asn Asn Val Ile Phe Asn Leu Leu Asn Leu Ile Lys Asn

    355

    360

    365

    Ile Ala Phe Leu Ser Asp Asp Glu Leu Asp Gly Ile Phe Ile Glu Gly 370 375 380

    Lys Tyr Leu Ser Ser Val Ser Gln Lys Leu Tyr Ser Asp Trp Ser Lys 385 390 395 400

    Leu Arg Asn Asp Ile Glu Asp Ser Ala Asn Ser Lys Gln Gly Asn Lys 405 410 415

    Glu Leu Ala Lys Lys Ile Lys Thr Asn Lys Gly Asp Val Glu Lys Ala 420 425 430

    Ile Ser Lys Tyr Glu Phe Ser Leu Ser Glu Leu Asn Ser Ile Val His 435 440 445

    Asp Asn Thr Lys Phe Ser Asp Leu Leu Ser Cys Thr Leu His Lys Val 450 455 460

    Ala Ser Glu Lys Leu Val Lys Val Asn Glu Gly Asp Trp Pro Lys His 465 470 475 480

    Leu Lys Asn Asn Glu Glu Lys Gln Lys Ile Lys Glu Pro Leu Asp Ala 485 490 495

    Leu Leu Glu Ile Tyr Asn Thr Leu Leu Ile Phe Asn Cys Lys Ser Phe 500 505 510

    Asn Lys Asn Gly Asn Phe Tyr Val Asp Tyr Asp Arg Cys Ile Asn Glu 515 520 525

    Leu Ser Ser Val Val Tyr Leu Tyr Asn Lys Thr Arg Asn Tyr Cys Thr 530 535 540

    Lys Lys Pro Tyr Asn Thr Asp Lys Phe Lys Leu Asn Phe Asn Ser Pro 545 550 555 560

    Gln Leu Gly Glu Gly Phe Ser Lys Ser Lys Glu Asn Asp Cys Leu Thr 565 570 575

    Leu Leu Phe Lys Lys Asp Asp Asn Tyr Tyr Val Gly Ile Ile Arg Lys 580 585 590

    Gly Ala Lys Ile Asn Phe Asp Asp Thr Gln Ala Ile Ala Asp Asn Thr 595 600 605

    Asp Asn Cys Ile Phe Lys Met Asn Tyr Phe Leu Leu Lys Asp Ala Lys 610 615 620

    Lys Phe Ile Pro Lys Cys Ser Ile Gln Leu Lys Glu Val Lys Ala His 625 630 635 640

    Phe Lys Lys Ser Glu Asp Asp Tyr Ile Leu Ser Asp Lys Glu Lys Phe 645 650 655

    Ala Ser Pro Leu Val Ile Lys Lys Ser Thr Phe Leu Leu Ala Thr Ala 660 665 670

    His Val Lys Gly Lys Lys Gly Asn Ile Lys Lys Phe Gln Lys Glu Tyr 675 680 685

    Ser Lys Glu Asn Pro Thr Glu Tyr Arg Asn Ser Leu Asn Glu Trp Ile 690 695 700

    Ala Phe Cys Lys Glu Phe Leu Lys Thr Tyr Lys Ala Ala Thr Ile Phe 705 710 715 720

    Asp Ile Thr Thr Leu Lys Lys Ala Glu Glu Tyr Ala Asp Ile Val Glu 725 730 735

    Phe Tyr Lys Asp Val Asp Asn Leu Cys Tyr Lys Leu Glu Phe Cys Pro 740 745 750

    Ile Lys Thr Ser Phe Ile Glu Asn Leu Ile Asp Asn Gly Asp Leu Tyr 755 760 765

    Leu Phe Arg Ile Asn Asn Lys Asp Phe Ser Ser Lys Ser Thr Gly Thr 770 775 780

    Lys Asn Leu His Thr Leu Tyr Leu Gln Ala Ile Phe Asp Glu Arg Asn 785 790 795 800

    Leu Asn Asn Pro Thr Ile Met Leu Asn Gly Gly Ala Glu Leu Phe Tyr 805 810 815

    Arg Lys Glu Ser Ile Glu Gln Lys Asn Arg Ile Thr His Lys Ala Gly 820 825 830

    Ser Ile Leu Val Asn Lys Val Cys Lys Asp Gly Thr Ser Leu Asp Asp 835 840 845

    Lys Ile Arg Asn Glu Ile Tyr Gln Tyr Glu Asn Lys Phe Ile Asp Thr 850 855 860

    Leu Ser Asp Glu Ala Lys Lys Val Leu Pro Asn Val Ile Lys Lys Glu 865 870 875 880

    Ala Thr His Asp Ile Thr Lys Asp Lys Arg Phe Thr Ser Asp Lys Phe 885 890 895

    Phe Phe His Cys Pro Leu Thr Ile Asn Tyr Lys Glu Gly Asp Thr Lys 900 905 910

    Gln Phe Asn Asn Glu Val Leu Ser Phe Leu Arg Gly Asn Pro Asp Ile 915 920 925

    Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Ile Tyr Val Thr 930 935 940

    Val Ile Asn Gln Lys Gly Glu Ile Leu Asp Ser Val Ser Phe Asn Thr 945 950 955 960

    Val Thr Asn Lys Ser Ser Lys Ile Glu Gln Thr Val Asp Tyr Glu Glu 965 970 975

    Lys Leu Ala Val Arg Glu Lys Glu Arg Ile Glu Ala Lys Arg Ser Trp 980 985 990

    Asp Ser Ile Ser Lys Ile Ala Thr Leu Lys Glu Gly Tyr Leu Ser Ala 995 1000 1005

    Ile Val His Glu Ile Cys Leu Leu Met Ile Lys His Asn Ala Ile 1010 1015 1020

    Val Val Leu Glu Asn Leu Asn Ala Gly Phe Lys Arg Ile Arg Gly 1025 1030 1035

    Gly Leu Ser Glu Lys Ser Val Tyr Gln Lys Phe Glu Lys Met Leu 1040 1045 1050

    Ile Asn Lys Leu Asn Tyr Phe Val Ser Lys Lys Glu Ser Asp Trp 1055 1060 1065

    Asn Lys Pro Ser Gly Leu Leu Asn Gly Leu Gln Leu Ser Asp Gln

    1070 1075 1080

    Phe Glu Ser Phe Glu Lys Leu Gly Ile Gln Ser Gly Phe Ile Phe 1085 1090 1095

    Tyr Val Pro Ala Ala Tyr Thr Ser Lys Ile Asp Pro Thr Thr Gly 1100 1105 1110

    Phe Ala Asn Val Leu Asn Leu Ser Lys Val Arg Asn Val Asp Ala 1115 1120 1125

    Ile Lys Ser Phe Phe Ser Asn Phe Asn Glu Ile Ser Tyr Ser Lys 1130 1135 1140

    Lys Glu Ala Leu Phe Lys Phe Ser Phe Asp Leu Asp Ser Leu Ser 1145 1150 1155

    Lys Lys Gly Phe Ser Ser Phe Val Lys Phe Ser Lys Ser Lys Trp 1160 1165 1170

    Asn Val Tyr Thr Phe Gly Glu Arg Ile Ile Lys Pro Lys Asn Lys 1175 1180 1185

    Gln Gly Tyr Arg Glu Asp Lys Arg Ile Asn Leu Thr Phe Glu Met

    1190 1195 1200 Lys Lys Leu Leu Asn Glu Tyr Lys Val Ser Phe Asp Leu Glu Asn 1205 1210 1215 Asn Leu Ile Pro Asn Leu Thr Ser Ala Asn Leu Lys Asp Thr Phe 1220 1225 1230 Trp Lys Glu Leu Phe Phe Ile Phe Lys Thr Thr Leu Gln Leu Arg 1235 1240 1245

    Asn Ser Val Thr Asn Gly Lys Glu Asp Val Leu Ile Ser Pro Val 1250 1255 1260

    Lys Asn Ala Lys Gly Glu Phe Phe Val Ser Gly Thr His Asn Lys 1265 1270 1275

    Thr Leu Pro Gln Asp Cys Asp Ala Asn Gly Ala Tyr His Ile Ala 1280 1285 1290

    Leu Lys Gly Leu Met Ile Leu Glu Arg Asn Asn Leu Val Arg Glu 1295 1300 1305

    Glu Lys Asp Thr Lys Lys Ile Met Ala Ile Ser Asn Val Asp Trp 1310 1315 1320

    Phe Glu Tyr Val Gln Lys Arg Arg Gly Val Leu 1325 1330 <210> 73 <211> 1331 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Parcubacteria group bacterium sequence <400> 73

    Met Lys Pro Val Gly Lys Thr Glu Asp Phe Leu Lys Ile Asn Lys Val 1 5 10 15

    Phe Glu Lys Asp Gln Thr Ile Asp Asp Ser Tyr Asn Gln Ala Lys Phe 20 25 30

    Tyr Phe Asp Ser Leu His Gln Lys Phe Ile Asp Ala Ala Leu Ala Ser

    Asp Lys Thr Ser Glu Leu Ser Phe Gln Asn Phe Ala Asp Val Leu Glu 50 55 60

    Lys Gln Asn Lys Ile Ile Leu Asp Lys Lys Arg Glu Met Gly Ala Leu 65 70 75 80

    Arg Lys Arg Asp Lys Asn Ala Val Gly Ile Asp Arg Leu Gln Lys Glu 85 90 95

    Ile Asn Asp Ala Glu Asp Ile Ile Gln Lys Glu Lys Glu Lys Ile Tyr 100 105 110

    Lys Asp Val Arg Thr Leu Phe Asp Asn Glu Ala Glu Ser Trp Lys Thr 115 120 125

    Tyr Tyr Gln Glu Arg Glu Val Asp Gly Lys Lys Ile Thr Phe Ser Lys 130 135 140

    Ala Asp Leu Lys Gln Lys Gly Ala Asp Phe Leu Thr Ala Ala Gly Ile 145 150 155 160

    Leu Lys Val Leu Lys Tyr Glu Phe Pro Glu Glu Lys Glu Lys Glu Phe 165 170 175

    Gln Ala Lys Asn Gln Pro Ser Leu Phe Val Glu Glu Lys Glu Asn Pro 180 185 190

    Gly Gln Lys Arg Tyr Ile Phe Asp Ser Phe Asp Lys Phe Ala Gly Tyr 195 200 205

    Leu Thr Lys Phe Gln Gln Thr Lys Lys Asn Leu Tyr Ala Ala Asp Gly 210 215 220

    Thr Ser Thr Ala Val Ala Thr Arg Ile Ala Asp Asn Phe Ile Ile Phe 225 230 235 240

    His Gln Asn Thr Lys Val Phe Arg Asp Lys Tyr Lys Asn Asn His Thr 245 250 255

    Asp Leu Gly Phe Asp Glu Glu Asn Ile Phe Glu Ile Glu Arg Tyr Lys 260 265 270

    Asn Cys Leu Leu Gln Arg Glu Ile Glu His Ile Lys Asn Glu Asn Ser 275 280 285

    Tyr Asn Lys Ile Ile Gly Arg Ile Asn Lys Lys Ile Lys Glu Tyr Arg 290 295 300

    Asp Gln Lys Ala Lys Asp Thr Lys Leu Thr Lys Ser Asp Phe Pro Phe 305 310 315 320

    Phe Lys Asn Leu Asp Lys Gln Ile Leu Gly Glu Val Glu Lys Glu Lys 325 330 335

    Gln Leu Ile Glu Lys Thr Arg Glu Lys Thr Glu Glu Asp Val Leu Ile 340 345 350

    Glu Arg Phe Lys Glu Phe Ile Glu Asn Asn Glu Glu Arg Phe Thr Ala 355 360 365

    Ala Lys Lys Leu Met Asn Ala Phe Cys Asn Gly Glu Phe Glu Ser Glu 370 375 380

    Tyr Glu Gly Ile Tyr Leu Lys Asn Lys Ala Ile Asn Thr Ile Ser Arg 385 390 395 400

    Arg Trp Phe Val Ser Asp Arg Asp Phe Glu Leu Lys Leu Pro Gln Gln 405 410 415

    Lys Ser Lys Asn Lys Ser Glu Lys Asn Glu Pro Lys Val Lys Lys Phe 420 425 430

    Ile Ser Ile Ala Glu Ile Lys Asn Ala Val Glu Glu Leu Asp Gly Asp 435 440 445

    Ile Phe Lys Ala Val Phe Tyr Asp Lys Lys Ile Ile Ala Gln Gly Gly 450 455 460

    Ser Lys Leu Glu Gln Phe Leu Val Ile Trp Lys Tyr Glu Phe Glu Tyr 465 470 475 480

    Leu Phe Arg Asp Ile Glu Arg Glu Asn Gly Glu Lys Leu Leu Gly Tyr 485 490 495

    Asp Ser Cys Leu Lys Ile Ala Lys Gln Leu Gly Ile Phe Pro Gln Glu 500 505 510

    Lys Glu Ala Arg Glu Lys Ala Thr Ala Val Ile Lys Asn Tyr Ala Asp 515 520 525

    Ala Gly Leu Gly Ile Phe Gln Met Met Lys Tyr Phe Ser Leu Asp Asp 530 535 540

    Lys Asp Arg Lys Asn Thr Pro Gly Gln Leu Ser Thr Asn Phe Tyr Ala 545 550 555 560

    Glu Tyr Asp Gly Tyr Tyr Lys Asp Phe Glu Phe Ile Lys Tyr Tyr Asn 565 570 575

    Glu Phe Arg Asn Phe Ile Thr Lys Lys Pro Phe Asp Glu Asp Lys Ile 580 585 590

    Lys Leu Asn Phe Glu Asn Gly Ala Leu Leu Lys Gly Trp Asp Glu Asn 595 600 605

    Lys Glu Tyr Asp Phe Met Gly Val Ile Leu Lys Lys Glu Gly Arg Leu 610 615 620

    Tyr Leu Gly Ile Met His Lys Asn His Arg Lys Leu Phe Gln Ser Met 625 630 635 640

    Gly Asn Ala Lys Gly Asp Asn Ala Asn Arg Tyr Gln Lys Met Ile Tyr 645 650 655

    Lys Gln Ile Ala Asp Ala Ser Lys Asp Val Pro Arg Leu Leu Leu Thr 660 665 670

    Ser Lys Lys Ala Met Glu Lys Phe Lys Pro Ser Gln Glu Ile Leu Arg 675 680 685

    Ile Lys Lys Glu Lys Thr Phe Lys Arg Glu Ser Lys Asn Phe Ser Leu 690 695 700

    Arg Asp Leu His Ala Leu Ile Glu Tyr Tyr Arg Asn Cys Ile Pro Gln 705 710 715 720

    Tyr Ser Asn Trp Ser Phe Tyr Asp Phe Gln Phe Gln Asp Thr Gly Lys 725 730 735

    Tyr Gln Asn Ile Lys Glu Phe Thr Asp Asp Val Gln Lys Tyr Gly Tyr 740 745 750

    Lys Ile Ser Phe Arg Asp Ile Asp Asp Glu Tyr Ile Asn Gln Ala Leu

    755

    760

    765

    Asn Glu Gly Lys Met Tyr Leu Phe Glu Val Val Asn Lys Asp Ile Tyr 770 775 780

    Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr Leu Tyr Phe Glu His 785 790 795 800

    Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val Phe Lys Leu Ser Gly 805 810 815

    Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val Asn Glu Arg Glu Lys 820 825 830

    Ile Thr Thr Gln Lys Asn Gln Cys Ile Leu Asp Lys Gly Asp Arg Ala 835 840 845

    Tyr Lys Tyr Arg Arg Tyr Thr Glu Lys Lys Ile Met Phe His Met Ser 850 855 860

    Leu Val Leu Asn Thr Gly Lys Gly Glu Ile Lys Gln Val Gln Phe Asn 865 870 875 880

    Lys Ile Ile Asn Gln Arg Ile Ser Ser Ser Asp Asn Glu Met Arg Val 885 890 895

    Asn Val Ile Gly Ile Asp Arg Gly Glu Lys Asn Leu Leu Tyr Tyr Ser 900 905 910

    Val Val Lys Gln Asn Gly Glu Ile Ile Glu Gln Ala Ser Leu Asn Glu 915 920 925

    Ile Asn Gly Val Asn Tyr Arg Asp Lys Leu Ile Glu Arg Glu Lys Glu 930 935 940

    Arg Leu Lys Asn Arg Gln Ser Trp Lys Pro Val Val Lys Ile Lys Asp 945 950 955 960

    Leu Lys Lys Gly Tyr Ile Ser His Val Ile His Lys Ile Cys Gln Leu 965 970 975

    Ile Glu Lys Tyr Ser Ala Ile Val Val Leu Glu Asp Leu Asn Met Arg 980 985 990

    Phe Lys Gln Ile Arg Gly Gly Ile Glu Arg Ser Val Tyr Gln Gln Phe 995 1000 1005

    Glu Lys Ala Leu Ile Asp Lys Leu Gly Tyr Leu Val Phe Lys Asp 1010 1015 1020

    Asn Arg Asp Leu Arg Ala Pro Gly Gly Val Leu Asn Gly Tyr Gln 1025 1030 1035

    Leu Ser Ala Pro Phe Val Ser Phe Glu Lys Met Arg Lys Gln Thr 1040 1045 1050

    Gly Ile Leu Phe Tyr Thr Gln Ala Glu Tyr Thr Ser Lys Thr Asp 1055 1060 1065

    Pro Ile Thr Gly Phe Arg Lys Asn Val Tyr Ile Ser Asn Ser Ala 1070 1075 1080

    Ser Leu Asp Lys Ile Lys Glu Ala Val Lys Lys Phe Asp Ala Ile 1085 1090 1095

    Gly Trp Asp Gly Lys Glu Gln Ser Tyr Phe Phe Lys Tyr Asn Pro 1100 1105 1110

    Tyr Asn Leu Ala Asp Glu Lys Tyr Lys Asn Ser Thr Val Ser Lys 1115 1120 1125

    Glu Trp Ala Ile Phe Ala Ser Ala Pro Arg Ile Arg Arg Gln Lys 1130 1135 1140

    Gly Glu Asp Gly Tyr Trp Lys Tyr Asp Arg Val Lys Val Asn Glu 1145 1150 1155

    Glu Phe Glu Lys Leu Leu Lys Val Trp Asn Phe Val Asn Pro Lys 1160 1165 1170

    Ala Thr Asp Ile Lys Gln Glu Ile Ile Lys Lys Glu Lys Ala Gly 1175 1180 1185

    Asp Leu Gln Gly Glu Lys Glu Leu Asp Gly Arg Leu Arg Asn Phe 1190 1195 1200

    Trp His Ser Phe Ile Tyr Leu Phe Asn Leu Val Leu Glu Leu Arg 1205 1210 1215

    Asn Ser Phe Ser Leu Gln Ile Lys Ile Lys Ala Gly Glu Val Ile 1220 1225 1230

    Ala Val Asp Glu Gly Val Asp Phe Ile Ala Ser Pro Val Lys Pro 1235 1240 1245

    Phe Phe Thr Thr Pro Asn Pro Tyr Ile Pro Ser Asn Leu Cys Trp 1250 1255 1260

    Leu Ala Val Glu Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala 1265 1270 1275

    Arg Lys Gly Val Met Ile Leu Lys Lys Ile Arg Glu His Ala Lys 1280 1285 1290

    Lys Asp Pro Glu Phe Lys Lys Leu Pro Asn Leu Phe Ile Ser Asn 1295 1300 1305

    Ala Glu Trp Asp Glu Ala Ala Arg Asp Trp Gly Lys Tyr Ala Gly 1310 1315 1320

    Thr Thr Ala Leu Asn Leu Asp His 1325 1330 <210> 74 <211> 1323 <212> PRT <213> Prevotella disiens <400> 74

    Met Glu Asn Tyr Gln Glu Phe Thr Asn Leu Phe Gln Leu Asn Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Cys Glu Leu Leu Glu 20 25 30

    Glu Gly Lys Ile Phe Ala Ser Gly Ser Phe Leu Glu Lys Asp Lys Val 35 40 45

    Arg Ala Asp Asn Val Ser Tyr Val Lys Lys Glu Ile Asp Lys Lys His 50 55 60

    Lys Ile Phe Ile Glu Glu Thr Leu Ser Ser Phe Ser Ile Ser Asn Asp 65 70 75 80

    Leu Leu Lys Gln Tyr Phe Asp Cys Tyr Asn Glu Leu Lys Ala Phe Lys 85 90 95

    Lys Asp Cys Lys Ser Asp Glu Glu Glu Val Lys Lys Thr Ala Leu Arg 100 105 110

    Asn Lys Cys Thr Ser Ile Gln Arg Ala Met Arg Glu Ala Ile Ser Gln 115 120 125

    Ala Phe Leu Lys Ser Pro Gln Lys Lys Leu Leu Ala Ile Lys Asn Leu 130 135 140

    Ile Glu Asn Val Phe Lys Ala Asp Glu Asn Val Gln His Phe Ser Glu 145 150 155 160

    Phe Thr Ser Tyr Phe Ser Gly Phe Glu Thr Asn Arg Glu Asn Phe Tyr 165 170 175

    Ser Asp Glu Glu Lys Ser Thr Ser Ile Ala Tyr Arg Leu Val His Asp 180 185 190

    Asn Leu Pro Ile Phe Ile Lys Asn Ile Tyr Ile Phe Glu Lys Leu Lys 195 200 205

    Glu Gln Phe Asp Ala Lys Thr Leu Ser Glu Ile Phe Glu Asn Tyr Lys 210 215 220

    Leu Tyr Val Ala Gly Ser Ser Leu Asp Glu Val Phe Ser Leu Glu Tyr 225 230 235 240

    Phe Asn Asn Thr Leu Thr Gln Lys Gly Ile Asp Asn Tyr Asn Ala Val 245 250 255

    Ile Gly Lys Ile Val Lys Glu Asp Lys Gln Glu Ile Gln Gly Leu Asn 260 265 270

    Glu His Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Arg Arg Leu Pro 275 280 285

    Phe Phe Ile Ser Leu Lys Lys Gln Ile Leu Ser Asp Arg Glu Ala Leu 290 295 300

    Ser Trp Leu Pro Asp Met Phe Lys Asn Asp Ser Glu Val Ile Lys Ala 305 310 315 320

    Leu Lys Gly Phe Tyr Ile Glu Asp Gly Phe Glu Asn Asn Val Leu Thr 325 330 335

    Pro Leu Ala Thr Leu Leu Ser Ser Leu Asp Lys Tyr Asn Leu Asn Gly 340 345 350

    Ile Phe Ile Arg Asn Asn Glu Ala Leu Ser Ser Leu Ser Gln Asn Val 355 360 365

    Tyr Arg Asn Phe Ser Ile Asp Glu Ala Ile Asp Ala Asn Ala Glu Leu 370 375 380

    Gln Thr Phe Asn Asn Tyr Glu Leu Ile Ala Asn Ala Leu Arg Ala Lys 385 390 395 400

    Ile Lys Lys Glu Thr Lys Gln Gly Arg Lys Ser Phe Glu Lys Tyr Glu 405 410 415

    Glu Tyr Ile Asp Lys Lys Val Lys Ala Ile Asp Ser Leu Ser Ile Gln 420 425 430

    Glu Ile Asn Glu Leu Val Glu Asn Tyr Val Ser Glu Phe Asn Ser Asn 435 440 445

    Ser Gly Asn Met Pro Arg Lys Val Glu Asp Tyr Phe Ser Leu Met Arg

    450

    455

    460

    Lys Gly Asp Phe Gly Ser Asn Asp Leu Ile Glu Asn Ile Lys Thr Lys 465 470 475 480

    Leu Ser Ala Ala Glu Lys Leu Leu Gly Thr Lys Tyr Gln Glu Thr Ala 485 490 495

    Lys Asp Ile Phe Lys Lys Asp Glu Asn Ser Lys Leu Ile Lys Glu Leu 500 505 510

    Leu Asp Ala Thr Lys Gln Phe Gln His Phe Ile Lys Pro Leu Leu Gly 515 520 525

    Thr Gly Glu Glu Ala Asp Arg Asp Leu Val Phe Tyr Gly Asp Phe Leu 530 535 540

    Pro Leu Tyr Glu Lys Phe Glu Glu Leu Thr Leu Leu Tyr Asn Lys Val 545 550 555 560

    Arg Asn Arg Leu Thr Gln Lys Pro Tyr Ser Lys Asp Lys Ile Arg Leu 565 570 575

    Cys Phe Asn Lys Pro Lys Leu Met Thr Gly Trp Val Asp Ser Lys Thr 580 585 590

    Glu Lys Ser Asp Asn Gly Thr Gln Tyr Gly Gly Tyr Leu Phe Arg Lys 595 600 605

    Lys Asn Glu Ile Gly Glu Tyr Asp Tyr Phe Leu Gly Ile Ser Ser Lys 610 615 620

    Ala Gln Leu Phe Arg Lys Asn Glu Ala Val Ile Gly Asp Tyr Glu Arg 625 630 635 640

    Leu Asp Tyr Tyr Gln Pro Lys Ala Asn Thr Ile Tyr Gly Ser Ala Tyr 645 650 655

    Glu Gly Glu Asn Ser Tyr Lys Glu Asp Lys Lys Arg Leu Asn Lys Val 660 665 670

    Ile Ile Ala Tyr Ile Glu Gln Ile Lys Gln Thr Asn Ile Lys Lys Ser 675 680 685

    Ile Ile Glu Ser Ile Ser Lys Tyr Pro Asn Ile Ser Asp Asp Asp Lys 690 695 700

    Val Thr Pro Ser Ser Leu Leu Glu Lys Ile Lys Lys Val Ser Ile Asp 705 710 715 720

    Ser Tyr Asn Gly Ile Leu Ser Phe Lys Ser Phe Gln Ser Val Asn Lys 725 730 735

    Glu Val Ile Asp Asn Leu Leu Lys Thr Ile Ser Pro Leu Lys Asn Lys 740 745 750

    Ala Glu Phe Leu Asp Leu Ile Asn Lys Asp Tyr Gln Ile Phe Thr Glu 755 760 765

    Val Gln Ala Val Ile Asp Glu Ile Cys Lys Gln Lys Thr Phe Ile Tyr 770 775 780

    Phe Pro Ile Ser Asn Val Glu Leu Glu Lys Glu Met Gly Asp Lys Asp 785 790 795 800

    Lys Pro Leu Cys Leu Phe Gln Ile Ser Asn Lys Asp Leu Ser Phe Ala 805 810 815

    Lys Thr Phe Ser Ala Asn Leu Arg Lys Lys Arg Gly Ala Glu Asn Leu 820 825 830

    His Thr Met Leu Phe Lys Ala Leu Met Glu Gly Asn Gln Asp Asn Leu 835 840 845

    Asp Leu Gly Ser Gly Ala Ile Phe Tyr Arg Ala Lys Ser Leu Asp Gly 850 855 860

    Asn Lys Pro Thr His Pro Ala Asn Glu Ala Ile Lys Cys Arg Asn Val 865 870 875 880

    Ala Asn Lys Asp Lys Val Ser Leu Phe Thr Tyr Asp Ile Tyr Lys Asn 885 890 895

    Arg Arg Tyr Met Glu Asn Lys Phe Leu Phe His Leu Ser Ile Val Gln 900 905 910

    Asn Tyr Lys Ala Ala Asn Asp Ser Ala Gln Leu Asn Ser Ser Ala Thr 915 920 925

    Glu Tyr Ile Arg Lys Ala Asp Asp Leu His Ile Ile Gly Ile Asp Arg 930 935 940

    Gly Glu Arg Asn Leu Leu Tyr Tyr Ser Val Ile Asp Met Lys Gly Asn 945 950 955 960

    Ile Val Glu Gln Asp Ser Leu Asn Ile Ile Arg Asn Asn Asp Leu Glu 965 970 975

    Thr Asp Tyr His Asp Leu Leu Asp Lys Arg Glu Lys Glu Arg Lys Ala 980 985 990

    Asn Arg Gln Asn Trp Glu Ala Val Glu Gly Ile Lys Asp Leu Lys Lys 995 1000 1005

    Gly Tyr Leu Ser Gln Ala Val His Gln Ile Ala Gln Leu Met Leu 1010 1015 1020

    Lys Tyr Asn Ala Ile Ile Ala Leu Glu Asp Leu Gly Gln Met Phe 1025 1030 1035

    Val Thr Arg Gly Gln Lys Ile Glu Lys Ala Val Tyr Gln Gln Phe 1040 1045 1050

    Glu Lys Ser Leu Val Asp Lys Leu Ser Tyr Leu Val Asp Lys Lys 1055 1060 1065

    Arg Pro Tyr Asn Glu Leu Gly Gly Ile Leu Lys Ala Tyr Gln Leu 1070 1075 1080

    Ala Ser Ser Ile Thr Lys Asn Asn Ser Asp Lys Gln Asn Gly Phe 1085 1090 1095

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val 1100 1105 1110

    Thr Gly Phe Thr Asp Leu Leu Arg Pro Lys Ala Met Thr Ile Lys 1115 1120 1125

    Glu Ala Gln Asp Phe Phe Gly Ala Phe Asp Asn Ile Ser Tyr Asn 1130 1135 1140

    Asp Lys Gly Tyr Phe Glu Phe Glu Thr Asn Tyr Asp Lys Phe Lys 1145 1150 1155

    Ile Arg Met Lys Ser Ala Gln Thr Arg Trp Thr Ile Cys Thr Phe

    1160

    1165

    1170

    Gly Asn Arg Ile Lys Arg Lys Lys Asp Lys Asn Tyr Trp Asn Tyr 1175 1180 1185

    Glu Glu Val Glu Leu Thr Glu Glu Phe Lys Lys Leu Phe Lys Asp 1190 1195 1200

    Ser Asn Ile Asp Tyr Glu Asn Cys Asn Leu Lys Glu Glu Ile Gln 1205 1210 1215

    Asn Lys Asp Asn Arg Lys Phe Phe Asp Asp Leu Ile Lys Leu Leu 1220 1225 1230

    Gln Leu Thr Leu Gln Met Arg Asn Ser Asp Asp Lys Gly Asn Asp 1235 1240 1245

    Tyr Ile Ile Ser Pro Val Ala Asn Ala Glu Gly Gln Phe Phe Asp 1250 1255 1260

    Ser Arg Asn Gly Asp Lys Lys Leu Pro Leu Asp Ala Asp Ala Asn 1265 1270 1275

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Asn Ile Arg Gln 1280 1285 1290

    Ile Lys Gln Thr Lys Asn Asp Lys Lys Leu Asn Leu Ser Ile Ser 1295 1300 1305

    Ser Thr Glu Trp Leu Asp Phe Val Arg Glu Lys Pro Tyr Leu Lys 1310 1315 1320 <210> 75 <211> 1318 <212> PRT <213> Flavobacterium branchiophilum <400> 75

    Met Thr Asn Lys Phe Thr Asn Gln Tyr Ser Leu Ser Lys Thr Leu Arg 1 5 10 15

    Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Phe Ile Gln Glu Lys 20 25 30

    Gly Leu Leu Ser Gln Asp Lys Gln Arg Ala Glu Ser Tyr Gln Glu Met 35 40 45

    Lys Lys Thr Ile Asp Lys Phe His Lys Tyr Phe Ile Asp Leu Ala Leu 50 55 60

    Ser Asn Ala Lys Leu Thr His Leu Glu Thr Tyr Leu Glu Leu Tyr Asn 65 70 75 80

    Lys Ser Ala Glu Thr Lys Lys Glu Gln Lys Phe Lys Asp Asp Leu Lys 85 90 95

    Lys Val Gln Asp Asn Leu Arg Lys Glu Ile Val Lys Ser Phe Ser Asp 100 105 110

    Gly Asp Ala Lys Ser Ile Phe Ala Ile Leu Asp Lys Lys Glu Leu Ile 115 120 125

    Thr Val Glu Leu Glu Lys Trp Phe Glu Asn Asn Glu Gln Lys Asp Ile 130 135 140

    Tyr Phe Asp Glu Lys Phe Lys Thr Phe Thr Thr Tyr Phe Thr Gly Phe 145 150 155 160

    His Gln Asn Arg Lys Asn Met Tyr Ser Val Glu Pro Asn Ser Thr Ala

    165

    170

    175

    Ile Ala Tyr Arg Leu Ile His Glu Asn Leu Pro Lys Phe Leu Glu Asn 180 185 190

    Ala Lys Ala Phe Glu Lys Ile Lys Gln Val Glu Ser Leu Gln Val Asn 195 200 205

    Phe Arg Glu Leu Met Gly Glu Phe Gly Asp Glu Gly Leu Ile Phe Val 210 215 220

    Asn Glu Leu Glu Glu Met Phe Gln Ile Asn Tyr Tyr Asn Asp Val Leu 225 230 235 240

    Ser Gln Asn Gly Ile Thr Ile Tyr Asn Ser Ile Ile Ser Gly Phe Thr 245 250 255

    Lys Asn Asp Ile Lys Tyr Lys Gly Leu Asn Glu Tyr Ile Asn Asn Tyr 260 265 270

    Asn Gln Thr Lys Asp Lys Lys Asp Arg Leu Pro Lys Leu Lys Gln Leu 275 280 285

    Tyr Lys Gln Ile Leu Ser Asp Arg Ile Ser Leu Ser Phe Leu Pro Asp 290 295 300

    Ala Phe Thr Asp Gly Lys Gln Val Leu Lys Ala Ile Phe Asp Phe Tyr 305 310 315 320

    Lys Ile Asn Leu Leu Ser Tyr Thr Ile Glu Gly Gln Glu Glu Ser Gln 325 330 335

    Asn Leu Leu Leu Leu Ile Arg Gln Thr Ile Glu Asn Leu Ser Ser Phe 340 345 350

    Asp Thr Gln Lys Ile Tyr Leu Lys Asn Asp Thr His Leu Thr Thr Ile 355 360 365

    Ser Gln Gln Val Phe Gly Asp Phe Ser Val Phe Ser Thr Ala Leu Asn 370 375 380

    Tyr Trp Tyr Glu Thr Lys Val Asn Pro Lys Phe Glu Thr Glu Tyr Ser 385 390 395 400

    Lys Ala Asn Glu Lys Lys Arg Glu Ile Leu Asp Lys Ala Lys Ala Val 405 410 415

    Phe Thr Lys Gln Asp Tyr Phe Ser Ile Ala Phe Leu Gln Glu Val Leu 420 425 430

    Ser Glu Tyr Ile Leu Thr Leu Asp His Thr Ser Asp Ile Val Lys Lys 435 440 445

    His Ser Ser Asn Cys Ile Ala Asp Tyr Phe Lys Asn His Phe Val Ala 450 455 460

    Lys Lys Glu Asn Glu Thr Asp Lys Thr Phe Asp Phe Ile Ala Asn Ile 465 470 475 480

    Thr Ala Lys Tyr Gln Cys Ile Gln Gly Ile Leu Glu Asn Ala Asp Gln 485 490 495

    Tyr Glu Asp Glu Leu Lys Gln Asp Gln Lys Leu Ile Asp Asn Leu Lys 500 505 510

    Phe Phe Leu Asp Ala Ile Leu Glu Leu Leu His Phe Ile Lys Pro Leu 515 520 525

    His Leu Lys Ser Glu Ser Ile Thr Glu Lys Asp Thr Ala Phe Tyr Asp 530 535 540

    Val Phe Glu Asn Tyr Tyr Glu Ala Leu Ser Leu Leu Thr Pro Leu Tyr 545 550 555 560

    Asn Met Val Arg Asn Tyr Val Thr Gln Lys Pro Tyr Ser Thr Glu Lys 565 570 575

    Ile Lys Leu Asn Phe Glu Asn Ala Gln Leu Leu Asn Gly Trp Asp Ala 580 585 590

    Asn Lys Glu Gly Asp Tyr Leu Thr Thr Ile Leu Lys Lys Asp Gly Asn 595 600 605

    Tyr Phe Leu Ala Ile Met Asp Lys Lys His Asn Lys Ala Phe Gln Lys 610 615 620

    Phe Pro Glu Gly Lys Glu Asn Tyr Glu Lys Met Val Tyr Lys Leu Leu 625 630 635 640

    Pro Gly Val Asn Lys Met Leu Pro Lys Val Phe Phe Ser Asn Lys Asn 645 650 655

    Ile Ala Tyr Phe Asn Pro Ser Lys Glu Leu Leu Glu Asn Tyr Lys Lys 660 665 670

    Glu Thr His Lys Lys Gly Asp Thr Phe Asn Leu Glu His Cys His Thr 675 680 685

    Leu Ile Asp Phe Phe Lys Asp Ser Leu Asn Lys His Glu Asp Trp Lys 690 695 700

    Tyr Phe Asp Phe Gln Phe Ser Glu Thr Lys Ser Tyr Gln Asp Leu Ser 705 710 715 720

    Gly Phe Tyr Arg Glu Val Glu His Gln Gly Tyr Lys Ile Asn Phe Lys 725 730 735

    Asn Ile Asp Ser Glu Tyr Ile Asp Gly Leu Val Asn Glu Gly Lys Leu 740 745 750

    Phe Leu Phe Gln Ile Tyr Ser Lys Asp Phe Ser Pro Phe Ser Lys Gly 755 760 765

    Lys Pro Asn Met His Thr Leu Tyr Trp Lys Ala Leu Phe Glu Glu Gln 770 775 780

    Asn Leu Gln Asn Val Ile Tyr Lys Leu Asn Gly Gln Ala Glu Ile Phe 785 790 795 800

    Phe Arg Lys Ala Ser Ile Lys Pro Lys Asn Ile Ile Leu His Lys Lys 805 810 815

    Lys Ile Lys Ile Ala Lys Lys His Phe Ile Asp Lys Lys Thr Lys Thr 820 825 830

    Ser Glu Ile Val Pro Val Gln Thr Ile Lys Asn Leu Asn Met Tyr Tyr 835 840 845

    Gln Gly Lys Ile Ser Glu Lys Glu Leu Thr Gln Asp Asp Leu Arg Tyr 850 855 860

    Ile Asp Asn Phe Ser Ile Phe Asn Glu Lys Asn Lys Thr Ile Asp Ile 865 870 875 880

    Ile Lys Asp Lys Arg Phe Thr Val Asp Lys Phe Gln Phe His Val Pro

    885

    890

    895

    Ile Thr Met Asn Phe Lys Ala Thr Gly Gly Ser Tyr Ile Asn Gln Thr 900 905 910

    Val Leu Glu Tyr Leu Gln Asn Asn Pro Glu Val Lys Ile Ile Gly Leu 915 920 925

    Asp Arg Gly Glu Arg His Leu Val Tyr Leu Thr Leu Ile Asp Gln Gln 930 935 940

    Gly Asn Ile Leu Lys Gln Glu Ser Leu Asn Thr Ile Thr Asp Ser Lys 945 950 955 960

    Ile Ser Thr Pro Tyr His Lys Leu Leu Asp Asn Lys Glu Asn Glu Arg 965 970 975

    Asp Leu Ala Arg Lys Asn Trp Gly Thr Val Glu Asn Ile Lys Glu Leu 980 985 990

    Lys Glu Gly Tyr Ile Ser Gln Val Val His Lys Ile Ala Thr Leu Met 995 1000 1005

    Leu Glu Glu Asn Ala Ile Val Val Met Glu Asp Leu Asn Phe Gly 1010 1015 1020

    Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr Gln Lys 1025 1030 1035

    Leu Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Leu Lys 1040 1045 1050

    Asp Lys Gln Pro Gln Glu Leu Gly Gly Leu Tyr Asn Ala Leu Gln 1055 1060 1065

    Leu Thr Asn Lys Phe Glu Ser Phe Gln Lys Met Gly Lys Gln Ser 1070 1075 1080

    Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp 1085 1090 1095

    Pro Thr Thr Gly Phe Val Asn Tyr Phe Tyr Thr Lys Tyr Glu Asn 1100 1105 1110

    Val Asp Lys Ala Lys Ala Phe Phe Glu Lys Phe Glu Ala Ile Arg 1115 1120 1125

    Phe Asn Ala Glu Lys Lys Tyr Phe Glu Phe Glu Val Lys Lys Tyr 1130 1135 1140

    Ser Asp Phe Asn Pro Lys Ala Glu Gly Thr Gln Gln Ala Trp Thr 1145 1150 1155

    Ile Cys Thr Tyr Gly Glu Arg Ile Glu Thr Lys Arg Gln Lys Asp 1160 1165 1170

    Gln Asn Asn Lys Phe Val Ser Thr Pro Ile Asn Leu Thr Glu Lys 1175 1180 1185

    Ile Glu Asp Phe Leu Gly Lys Asn Gln Ile Val Tyr Gly Asp Gly 1190 1195 1200

    Asn Cys Ile Lys Ser Gln Ile Ala Ser Lys Asp Asp Lys Ala Phe 1205 1210 1215

    Phe Glu Thr Leu Leu Tyr Trp Phe Lys Met Thr Leu Gln Met Arg 1220 1225 1230

    Asn Ser Glu Thr Arg Thr Asp Ile Asp Tyr Leu Ile Ser Pro Val 1235 1240 1245

    Met Asn Asp Asn Gly Thr Phe Tyr Asn Ser Arg Asp Tyr Glu Lys 1250 1255 1260

    Leu Glu Asn Pro Thr Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala 1265 1270 1275

    Tyr His Ile Ala Lys Lys Gly Leu Met Leu Leu Asn Lys Ile Asp 1280 1285 1290

    Gln Ala Asp Leu Thr Lys Lys Val Asp Leu Ser Ile Ser Asn Arg 1295 1300 1305

    Asp Trp Leu Gln Phe Val Gln Lys Asn Lys 1310 1315 <210> 76 <211> 1310 <212> PRT <213> Helcococcus kunzii <400> 76

    Met Phe Glu Lys Leu Ser Asn Ile Val Ser Ile Ser Lys Thr Ile Arg 1 5 10 15

    Phe Lys Leu Ile Pro Val Gly Lys Thr Leu Glu Asn Ile Glu Lys Leu 20 25 30

    Gly Lys Leu Glu Lys Asp Phe Glu Arg Ser Asp Phe Tyr Pro Ile Leu 35 40 45

    Lys Asn Ile Ser Asp Asp Tyr Tyr Arg Gln Tyr Ile Lys Glu Lys Leu 50 55 60

    Ser Asp Leu Asn Leu Asp Trp Gln Lys Leu Tyr Asp Ala His Glu Leu 65 70 75 80

    Leu Asp Ser Ser Lys Lys Glu Ser Gln Lys Asn Leu Glu Met Ile Gln 85 90 95

    Ala Gln Tyr Arg Lys Val Leu Phe Asn Ile Leu Ser Gly Glu Leu Asp 100 105 110

    Lys Ser Gly Glu Lys Asn Ser Lys Asp Leu Ile Lys Asn Asn Lys Ala 115 120 125

    Leu Tyr Gly Lys Leu Phe Lys Lys Gln Phe Ile Leu Glu Val Leu Pro 130 135 140

    Asp Phe Val Asn Asn Asn Asp Ser Tyr Ser Glu Glu Asp Leu Glu Gly 145 150 155 160

    Leu Asn Leu Tyr Ser Lys Phe Thr Thr Arg Leu Lys Asn Phe Trp Glu 165 170 175

    Thr Arg Lys Asn Val Phe Thr Asp Lys Asp Ile Val Thr Ala Ile Pro 180 185 190

    Phe Arg Ala Val Asn Glu Asn Phe Gly Phe Tyr Tyr Asp Asn Ile Lys 195 200 205

    Ile Phe Asn Lys Asn Ile Glu Tyr Leu Glu Asn Lys Ile Pro Asn Leu 210 215 220

    Glu Asn Glu Leu Lys Glu Ala Asp Ile Leu Asp Asp Asn Arg Ser Val 225 230 235 240

    Lys Asp Tyr Phe Thr Pro Asn Gly Phe Asn Tyr Val Ile Thr Gln Asp 245 250 255

    Gly Ile Asp Val Tyr Gln Ala Ile Arg Gly Gly Phe Thr Lys Glu Asn 260 265 270

    Gly Glu Lys Val Gln Gly Ile Asn Glu Ile Leu Asn Leu Thr Gln Gln 275 280 285

    Gln Leu Arg Arg Lys Pro Glu Thr Lys Asn Val Lys Leu Gly Val Leu 290 295 300

    Thr Lys Leu Arg Lys Gln Ile Leu Glu Tyr Ser Glu Ser Thr Ser Phe 305 310 315 320

    Leu Ile Asp Gln Ile Glu Asp Asp Asn Asp Leu Val Asp Arg Ile Asn 325 330 335

    Lys Phe Asn Val Ser Phe Phe Glu Ser Thr Glu Val Ser Pro Ser Leu 340 345 350

    Phe Glu Gln Ile Glu Arg Leu Tyr Asn Ala Leu Lys Ser Ile Lys Lys 355 360 365

    Glu Glu Val Tyr Ile Asp Ala Arg Asn Thr Gln Lys Phe Ser Gln Met 370 375 380

    Leu Phe Gly Gln Trp Asp Val Ile Arg Arg Gly Tyr Thr Val Lys Ile 385 390 395 400

    Thr Glu Gly Ser Lys Glu Glu Lys Lys Lys Tyr Lys Glu Tyr Leu Glu 405 410 415

    Leu Asp Glu Thr Ser Lys Ala Lys Arg Tyr Leu Asn Ile Arg Glu Ile 420 425 430

    Glu Glu Leu Val Asn Leu Val Glu Gly Phe Glu Glu Val Asp Val Phe 435 440 445

    Ser Val Leu Leu Glu Lys Phe Lys Met Asn Asn Ile Glu Arg Ser Glu 450 455 460

    Phe Glu Ala Pro Ile Tyr Gly Ser Pro Ile Lys Leu Glu Ala Ile Lys 465 470 475 480

    Glu Tyr Leu Glu Lys His Leu Glu Glu Tyr His Lys Trp Lys Leu Leu 485 490 495

    Leu Ile Gly Asn Asp Asp Leu Asp Thr Asp Glu Thr Phe Tyr Pro Leu 500 505 510

    Leu Asn Glu Val Ile Ser Asp Tyr Tyr Ile Ile Pro Leu Tyr Asn Leu 515 520 525

    Thr Arg Asn Tyr Leu Thr Arg Lys His Ser Asp Lys Asp Lys Ile Lys 530 535 540

    Val Asn Phe Asp Phe Pro Thr Leu Ala Asp Gly Trp Ser Glu Ser Lys 545 550 555 560

    Ile Ser Asp Asn Arg Ser Ile Ile Leu Arg Lys Gly Gly Tyr Tyr Tyr 565 570 575

    Leu Gly Ile Leu Ile Asp Asn Lys Leu Leu Ile Asn Lys Lys Asn Lys 580 585 590

    Ser Lys Lys Ile Tyr Glu Ile Leu Ile Tyr Asn Gln Ile Pro Glu Phe

    595

    600

    605

    Ser Lys Ser Ile Pro Asn Tyr Pro Phe Thr Lys Lys Val Lys Glu His 610 615 620

    Phe Lys Asn Asn Val Ser Asp Phe Gln Leu Ile Asp Gly Tyr Val Ser 625 630 635 640

    Pro Leu Ile Ile Thr Lys Glu Ile Tyr Asp Ile Lys Lys Glu Lys Lys 645 650 655

    Tyr Lys Lys Asp Phe Tyr Lys Asp Asn Asn Thr Asn Lys Asn Tyr Leu 660 665 670

    Tyr Thr Ile Tyr Lys Trp Ile Glu Phe Cys Lys Gln Phe Leu Tyr Lys 675 680 685

    Tyr Lys Gly Pro Asn Lys Glu Ser Tyr Lys Glu Met Tyr Asp Phe Ser 690 695 700

    Thr Leu Lys Asp Thr Ser Leu Tyr Val Asn Leu Asn Asp Phe Tyr Ala 705 710 715 720

    Asp Val Asn Ser Cys Ala Tyr Arg Val Leu Phe Asn Lys Ile Asp Glu 725 730 735

    Asn Thr Ile Asp Asn Ala Val Glu Asp Gly Lys Leu Leu Leu Phe Gln 740 745 750

    Ile Tyr Asn Lys Asp Phe Ser Pro Glu Ser Lys Gly Lys Lys Asn Leu 755 760 765

    His Thr Leu Tyr Trp Leu Ser Met Phe Ser Glu Glu Asn Leu Arg Thr 770 775 780

    Arg Lys Leu Lys Leu Asn Gly Gln Ala Glu Ile Phe Tyr Arg Lys Lys 785 790 795 800

    Leu Glu Lys Lys Pro Ile Ile His Lys Glu Gly Ser Ile Leu Leu Asn 805 810 815

    Lys Ile Asp Lys Glu Gly Asn Thr Ile Pro Glu Asn Ile Tyr His Glu 820 825 830

    Cys Tyr Arg Tyr Leu Asn Lys Lys Ile Gly Arg Glu Asp Leu Ser Asp 835 840 845

    Glu Ala Ile Ala Leu Phe Asn Lys Asp Val Leu Lys Tyr Lys Glu Ala 850 855 860

    Arg Phe Asp Ile Ile Lys Asp Arg Arg Tyr Ser Glu Ser Gln Phe Phe 865 870 875 880

    Phe His Val Pro Ile Thr Phe Asn Trp Asp Ile Lys Thr Asn Lys Asn 885 890 895

    Val Asn Gln Ile Val Gln Gly Met Ile Lys Asp Gly Glu Ile Lys His 900 905 910

    Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Tyr Ser Val 915 920 925

    Ile Asp Leu Glu Gly Asn Ile Val Glu Gln Gly Ser Leu Asn Thr Leu 930 935 940

    Glu Gln Asn Arg Phe Asp Asn Ser Thr Val Lys Val Asp Tyr Gln Asn 945 950 955 960

    Lys Leu Arg Thr Arg Glu Glu Asp Arg Asp Arg Ala Arg Lys Asn Trp 965 970 975

    Thr Asn Ile Asn Lys Ile Lys Glu Leu Lys Asp Gly Tyr Leu Ser His 980 985 990

    Val Val His Lys Leu Ser Arg Leu Ile Ile Lys Tyr Glu Ala Ile Val 995 1000 1005

    Ile Met Glu Asn Leu Asn Gln Gly Phe Lys Arg Gly Arg Phe Lys 1010 1015 1020

    Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Leu Ala Leu Met Asn 1025 1030 1035

    Lys Leu Ser Ala Leu Ser Phe Lys Glu Lys Tyr Asp Glu Arg Lys 1040 1045 1050

    Asn Leu Glu Pro Ser Gly Ile Leu Asn Pro Ile Gln Ala Cys Tyr 1055 1060 1065

    Pro Val Asp Ala Tyr Gln Glu Leu Gln Gly Gln Asn Gly Ile Val 1070 1075 1080

    Phe Tyr Leu Pro Ala Ala Tyr Thr Ser Val Ile Asp Pro Val Thr 1085 1090 1095

    Gly Phe Thr Asn Leu Phe Arg Leu Lys Ser Ile Asn Ser Ser Lys 1100 1105 1110

    Tyr Glu Glu Phe Ile Lys Lys Phe Lys Asn Ile Tyr Phe Asp Asn 1115 1120 1125

    Glu Glu Glu Asp Phe Lys Phe Ile Phe Asn Tyr Lys Asp Phe Ala 1130 1135 1140

    Lys Ala Asn Leu Val Ile Leu Asn Asn Ile Lys Ser Lys Asp Trp 1145 1150 1155

    Lys Ile Ser Thr Arg Gly Glu Arg Ile Ser Tyr Asn Ser Lys Lys 1160 1165 1170

    Lys Glu Tyr Phe Tyr Val Gln Pro Thr Glu Phe Leu Ile Asn Lys 1175 1180 1185

    Leu Lys Glu Leu Asn Ile Asp Tyr Glu Asn Ile Asp Ile Ile Pro 1190 1195 1200

    Leu Ile Asp Asn Leu Glu Glu Lys Ala Lys Arg Lys Ile Leu Lys 1205 1210 1215

    Ala Leu Phe Asp Thr Phe Lys Tyr Ser Val Gln Leu Arg Asn Tyr

    1220 1225 1230 Asp Phe Glu Asn Asp Tyr Ile Ile Ser Pro Thr Ala Asp Asp Asn 1235 1240 1245 Gly Asn Tyr Tyr Asn Ser Asn Glu Ile Asp Ile Asp Lys Thr Asn 1250 1255 1260

    Leu Pro Asn Asn Gly Asp Ala Asn Gly Ala Phe Asn Ile Ala Arg 1265 1270 1275

    Lys Gly Leu Leu Leu Lys Asp Arg Ile Val Asn Ser Asn Glu Ser 1280 1285 1290

    Lys Val Asp Leu Lys Ile Lys Asn Glu Asp Trp Ile Asn Phe Ile

    1295

    1300

    1305

    Ile Ser 1310 <210> 77 <211> 1307 <212> PRT <213> Acidaminococcus sp.

    <400> 77

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu

    305

    310

    315

    320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln 865 870 875 880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu 930 935 940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly

    1025

    1030

    1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly 1115 1120 1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn 1130 1135 1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu 1205 1210 1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn 1295 1300 1305 <210> 78 <211> 1307 <212> PRT <213> Francisella tularensis <400> 78

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Lys Tyr 100 105 110

    Ile Asn Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Val Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Asp Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ser 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Glu Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Arg Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Ser Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Ser Ala Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Ile Met Asp Lys Lys His Asn Lys Ile 625 630 635 640

    Phe Ser Asp Lys Ala Ile Glu Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Gln Ile Ala Asp Ala Ser Lys Asp Ile Gln Asn Leu 660 665 670

    Met Ile Ile Asp Gly Lys Thr Val Cys Lys Lys Gly Arg Lys Asp Arg 675 680 685

    Asn Gly Val Asn Arg Gln Leu Leu Ser Leu Lys Arg Lys His Leu Pro 690 695 700

    Glu Asn Ile Tyr Arg Ile Lys Glu Thr Lys Ser Tyr Leu Lys Asn Glu 705 710 715 720

    Ala Arg Phe Ser Arg Lys Asp Leu Tyr Asp Phe Ile Asp Tyr Tyr Lys 725 730 735

    Asp Arg Leu Asp Tyr Tyr Asp Phe Glu Phe Glu Leu Lys Pro Ser Asn 740 745 750

    Glu Tyr Ser Asp Phe Asn Asp Phe Thr Asn His Ile Gly Ser Gln Gly

    755

    760

    765

    Tyr Lys Leu Thr Phe Glu Asn Ile Ser Gln Asp Tyr Ile Asn Ser Leu 770 775 780

    Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Ser Lys Asp Phe 785 790 795 800

    Ser Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys 805 810 815

    Ala Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn 820 825 830

    Gly Glu Ala Glu Leu Phe Tyr Arg Lys Gln Ser Ile Pro Lys Lys Ile 835 840 845

    Thr His Pro Ala Lys Glu Thr Ile Ala Asn Lys Asn Lys Asp Asn Pro 850 855 860

    Lys Lys Glu Ser Val Phe Glu Tyr Asp Leu Ile Lys Asp Lys Arg Phe 865 870 875 880

    Thr Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys 885 890 895

    Ser Ser Gly Ala Asn Lys Phe Asn Asp Glu Ile Asn Leu Leu Leu Lys 900 905 910

    Glu Lys Ala Asn Asp Val His Ile Leu Ser Ile Asp Arg Gly Glu Arg 915 920 925

    His Leu Ala Tyr Tyr Thr Leu Val Asp Gly Lys Gly Asn Ile Ile Lys 930 935 940

    Gln Asp Asn Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr 945 950 955 960

    His Asp Lys Leu Ala Ala Ile Glu Lys Asp Arg Asp Ser Ala Arg Lys 965 970 975

    Asp Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu 980 985 990

    Ser Gln Val Val His Glu Ile Ala Lys Leu Val Ile Glu Tyr Asn Ala 995 1000 1005

    Ile Val Val Phe Glu Asp Leu Asn Phe Gly Phe Lys Arg Gly Arg 1010 1015 1020

    Phe Lys Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu 1025 1030 1035

    Ile Glu Lys Leu Asn Tyr Leu Val Phe Lys Asp Asn Glu Phe Asp 1040 1045 1050

    Lys Thr Gly Gly Val Leu Arg Ala Tyr Gln Leu Thr Ala Pro Phe 1055 1060 1065

    Glu Thr Phe Lys Lys Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr 1070 1075 1080

    Val Pro Ala Gly Phe Thr Ser Lys Ile Cys Pro Val Thr Gly Phe 1085 1090 1095

    Val Asn Gln Leu Tyr Pro Lys Tyr Glu Ser Val Ser Lys Ser Gln 1100 1105 1110

    Glu Phe Phe Ser Lys Phe Asp Lys Ile Cys Tyr Asn Leu Asp Lys 1115 1120 1125

    Gly Tyr Phe Glu Phe Ser Phe Asp Tyr Lys Asn Phe Gly Asp Lys 1130 1135 1140

    Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser Phe Gly Ser Arg Leu 1145 1150 1155

    Ile Asn Phe Arg Asn Ser Asp Lys Asn His Asn Trp Asp Thr Arg 1160 1165 1170

    Glu Val Tyr Pro Thr Lys Glu Leu Glu Lys Leu Leu Lys Asp Tyr 1175 1180 1185

    Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala Ile Cys 1190 1195 1200

    Gly Glu Ser Asp Lys Lys Phe Phe Ala Lys Leu Thr Ser Val Leu 1205 1210 1215

    Asn Thr Ile Leu Gln Met Arg Asn Ser Lys Thr Gly Thr Glu Leu 1220 1225 1230

    Asp Tyr Leu Ile Ser Pro Val Ala Asp Val Asn Gly Asn Phe Phe 1235 1240 1245

    Asp Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala 1250 1255 1260

    Asn Gly Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Asp 1265 1270 1275

    Arg Ile Lys Asn Asn Gln Glu Gly Lys Lys Leu Asn Leu Val Ile 1280 1285 1290

    Lys Asn Glu Glu Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn 1295 1300 1305 <210> 79 <211> 1305 <212> PRT <213> Eubacterium sp.

    <400> 79

    Met Asn Lys Ala Ala Asp Asn Tyr Thr Gly Gly Asn Tyr Asp Glu Phe 1 5 10 15

    Ile Ala Leu Ser Lys Val Gln Lys Thr Leu Arg Asn Glu Leu Lys Pro 20 25 30

    Thr Pro Phe Thr Ala Glu His Ile Lys Gln Arg Gly Ile Ile Ser Glu 35 40 45

    Asp Glu Tyr Arg Ala Gln Gln Ser Leu Glu Leu Lys Lys Ile Ala Asp 50 55 60

    Glu Tyr Tyr Arg Asn Tyr Ile Thr His Lys Leu Asn Asp Ile Asn Asn 65 70 75 80

    Leu Asp Phe Tyr Asn Leu Phe Asp Ala Ile Glu Glu Lys Tyr Lys Lys 85 90 95

    Asn Asp Lys Asp Asn Arg Asp Lys Leu Asp Leu Val Glu Lys Ser Lys 100 105 110

    Arg Gly Glu Ile Ala Lys Met Leu Ser Ala Asp Asp Asn Phe Lys Ser 115 120 125

    Met Phe Glu Ala Lys Leu Ile Thr Lys Leu Leu Pro Asp Tyr Val Glu 130 135 140

    Arg Asn Tyr Thr Gly Glu Asp Lys Glu Lys Ala Leu Glu Thr Leu Ala 145 150 155 160

    Leu Phe Lys Gly Phe Thr Thr Tyr Phe Lys Gly Tyr Phe Lys Thr Arg 165 170 175

    Lys Asn Met Phe Ser Gly Glu Gly Gly Ala Ser Ser Ile Cys His Arg 180 185 190

    Ile Val Asn Val Asn Ala Ser Ile Phe Tyr Asp Asn Leu Lys Thr Phe 195 200 205

    Met Arg Ile Gln Glu Lys Ala Gly Asp Glu Ile Ala Leu Ile Glu Glu 210 215 220

    Glu Leu Thr Glu Lys Leu Asp Gly Trp Arg Leu Glu His Ile Phe Ser 225 230 235 240

    Arg Asp Tyr Tyr Asn Glu Val Leu Ala Gln Lys Gly Ile Asp Tyr Tyr 245 250 255

    Asn Gln Ile Cys Gly Asp Ile Asn Lys His Met Asn Leu Tyr Cys Gln 260 265 270

    Gln Asn Lys Phe Lys Ala Asn Ile Phe Lys Met Met Lys Ile Gln Lys 275 280 285

    Gln Ile Met Gly Ile Ser Glu Lys Ala Phe Glu Ile Pro Pro Met Tyr 290 295 300

    Gln Asn Asp Glu Glu Val Tyr Ala Ser Phe Asn Glu Phe Ile Ser Arg 305 310 315 320

    Leu Glu Glu Val Lys Leu Thr Asp Arg Leu Ile Asn Ile Leu Gln Asn 325 330 335

    Ile Asn Ile Tyr Asn Thr Ala Lys Ile Tyr Ile Asn Ala Arg Tyr Tyr 340 345 350

    Thr Asn Val Ser Ser Tyr Val Tyr Gly Gly Trp Gly Val Ile Asp Ser 355 360 365

    Ala Ile Glu Arg Tyr Leu Tyr Asn Thr Ile Ala Gly Lys Gly Gln Ser 370 375 380

    Lys Val Lys Lys Ile Glu Asn Ala Lys Lys Asp Asn Lys Phe Met Ser 385 390 395 400

    Val Lys Glu Leu Asp Ser Ile Val Ala Glu Tyr Glu Pro Asp Tyr Phe 405 410 415

    Asn Ala Pro Tyr Ile Asp Asp Asp Asp Asn Ala Val Lys Ala Phe Gly 420 425 430

    Gly Gln Gly Val Leu Gly Tyr Phe Asn Lys Met Ser Glu Leu Leu Ala 435 440 445

    Asp Val Ser Leu Tyr Thr Ile Asp Tyr Asn Ser Asp Asp Ser Leu Ile 450 455 460

    Glu Asn Lys Glu Ser Ala Leu Arg Ile Lys Lys Gln Leu Asp Asp Ile 465 470 475 480

    Met Ser Leu Tyr His Trp Leu Gln Thr Phe Ile Ile Asp Glu Val Val

    485

    490

    495

    Glu Lys Asp Asn Ala Phe Tyr Ala Glu Leu Glu Asp Ile Cys Cys Glu 500 505 510

    Leu Glu Asn Val Val Thr Leu Tyr Asp Arg Ile Arg Asn Tyr Val Thr 515 520 525

    Lys Lys Pro Tyr Ser Thr Gln Lys Phe Lys Leu Asn Phe Ala Ser Pro 530 535 540

    Thr Leu Ala Ala Gly Trp Ser Arg Ser Lys Glu Phe Asp Asn Asn Ala 545 550 555 560

    Ile Ile Leu Leu Arg Asn Asn Lys Tyr Tyr Ile Ala Ile Phe Asn Val 565 570 575

    Asn Asn Lys Pro Asp Lys Gln Ile Ile Lys Gly Ser Glu Glu Gln Arg 580 585 590

    Leu Ser Thr Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu Pro Gly Pro 595 600 605

    Asn Lys Met Leu Pro Lys Val Phe Ile Lys Ser Asp Thr Gly Lys Arg 610 615 620

    Asp Tyr Asn Pro Ser Ser Tyr Ile Leu Glu Gly Tyr Glu Lys Asn Arg 625 630 635 640

    His Ile Lys Ser Ser Gly Asn Phe Asp Ile Asn Tyr Cys His Asp Leu 645 650 655

    Ile Asp Tyr Tyr Lys Ala Cys Ile Asn Lys His Pro Glu Trp Lys Asn 660 665 670

    Tyr Gly Phe Lys Phe Lys Glu Thr Asn Gln Tyr Asn Asp Ile Gly Gln 675 680 685

    Phe Tyr Lys Asp Val Glu Lys Gln Gly Tyr Ser Ile Ser Trp Ala Tyr 690 695 700

    Ile Ser Glu Glu Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys Ile Tyr 705 710 715 720

    Leu Phe Glu Ile Tyr Asn Lys Asp Leu Ser Ala His Ser Thr Gly Arg 725 730 735

    Asp Asn Leu His Thr Met Tyr Leu Lys Asn Ile Phe Ser Glu Asp Asn 740 745 750

    Leu Lys Asn Ile Cys Ile Glu Leu Asn Gly Glu Ala Glu Leu Phe Tyr 755 760 765

    Arg Lys Ser Ser Met Lys Ser Asn Ile Thr His Lys Lys Asp Thr Ile 770 775 780

    Leu Val Asn Lys Thr Tyr Ile Asn Glu Thr Gly Val Arg Val Ser Leu 785 790 795 800

    Ser Asp Glu Asp Tyr Met Lys Val Tyr Asn Tyr Tyr Asn Asn Asn Tyr 805 810 815

    Val Ile Asp Thr Glu Asn Asp Lys Asn Leu Ile Asp Ile Ile Glu Lys 820 825 830

    Ile Gly His Arg Lys Ser Lys Ile Asp Ile Val Lys Asp Lys Arg Tyr 835 840 845

    Thr Glu Asp Lys Tyr Phe Leu Tyr Leu Pro Ile Thr Ile Asn Tyr Gly 850 855 860

    Ile Glu Asp Glu Asn Val Asn Ser Lys Ile Ile Glu Tyr Ile Ala Lys 865 870 875 880

    Gln Asp Asn Met Asn Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu 885 890 895

    Ile Tyr Ile Ser Val Ile Asp Asn Lys Gly Asn Ile Ile Glu Gln Lys 900 905 910

    Ser Phe Asn Leu Val Asn Asn Tyr Asp Tyr Lys Asn Lys Leu Lys Asn 915 920 925

    Met Glu Lys Thr Arg Asp Asn Ala Arg Lys Asn Trp Gln Glu Ile Gly 930 935 940

    Lys Ile Lys Asp Val Lys Ser Gly Tyr Leu Ser Gly Val Ile Ser Lys 945 950 955 960

    Ile Ala Arg Met Val Ile Asp Tyr Asn Ala Ile Ile Val Met Glu Asp 965 970 975

    Leu Asn Lys Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Arg Gln Val 980 985 990

    Tyr Gln Lys Phe Glu Asn Met Leu Ile Ser Lys Leu Asn Tyr Leu Val 995 1000 1005

    Phe Lys Glu Arg Lys Ala Asp Glu Asn Gly Gly Ile Leu Arg Gly 1010 1015 1020

    Tyr Gln Leu Thr Tyr Ile Pro Lys Ser Ile Lys Asn Val Gly Lys 1025 1030 1035

    Gln Cys Gly Cys Ile Phe Tyr Val Pro Ala Ala Tyr Thr Ser Lys 1040 1045 1050

    Ile Asp Pro Ala Thr Gly Phe Ile Asn Ile Phe Asp Phe Lys Lys 1055 1060 1065

    Tyr Ser Gly Ser Gly Ile Asn Ala Lys Val Lys Asp Lys Lys Glu 1070 1075 1080

    Phe Leu Met Ser Met Asn Ser Ile Arg Tyr Ile Asn Glu Cys Ser 1085 1090 1095

    Glu Glu Tyr Glu Lys Ile Gly His Arg Glu Leu Phe Ala Phe Ser 1100 1105 1110

    Phe Asp Tyr Asn Asn Phe Lys Thr Tyr Asn Val Ser Ser Pro Val 1115 1120 1125

    Asn Glu Trp Thr Ala Tyr Thr Tyr Gly Glu Arg Ile Lys Lys Leu 1130 1135 1140

    Tyr Lys Asp Gly Arg Trp Leu Arg Ser Glu Val Leu Asn Leu Thr 1145 1150 1155

    Glu Asn Leu Ile Lys Leu Met Glu Gln Tyr Asn Ile Glu Tyr Lys 1160 1165 1170

    Asp Gly His Asp Ile Arg Glu Asp Ile Ser His Met Asp Glu Thr 1175 1180 1185

    Arg Asn Ala Asp Phe Ile Cys Ser Leu Phe Glu Glu Leu Lys Tyr

    1190

    1195

    1200

    Thr Val Gln Leu Arg Asn Ser Lys Ser Glu Ala Glu Asp Glu Asn 1205 1210 1215

    Tyr Asp Arg Leu Val Ser Pro Ile Leu Asn Ser Ser Asn Gly Phe 1220 1225 1230

    Tyr Asp Ser Ser Asp Tyr Met Glu Asn Glu Asn Asn Thr Thr His 1235 1240 1245

    Thr Met Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Cys Ile Ala 1250 1255 1260

    Leu Lys Gly Leu Tyr Glu Ile Asn Lys Ile Lys Gln Asn Trp Ser 1265 1270 1275

    Asp Asp Lys Lys Phe Lys Glu Asn Glu Leu Tyr Ile Asn Val Thr 1280 1285 1290

    Glu Trp Leu Asp Tyr Ile Gln Asn Arg Arg Phe Glu 1295 1300 1305 <210> 80 <211> 1300 <212> PRT <213> Francisella tularensis <400> 80

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys

    210

    215

    220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Val Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Asp Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Arg Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Asn Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Glu Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Lys Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Phe Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile

    930

    935

    940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu His Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Ile Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Asp Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 81 <211> 1300 <212> PRT <213> Francisella tularensis <400> 81

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asp Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Val Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Asp Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Leu Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Glu Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Arg Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val

    660

    665

    670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Asn Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Glu Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu His Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe

    1190 1195 1200 Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215 Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230 Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Asp Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 82 <211> 1300 <212> PRT <213> Francisella tularensis <400> 82

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr

    385

    390

    395

    400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp

    1100

    1105

    1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 83 <211> 1285 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Roizmanbacteria bacterium sequence <400> 83

    Met Lys Ser Phe Asp Ser Phe Thr Asn Leu Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Lys Phe Glu Met Arg Pro Val Gly Asn Thr Gln Lys Met Leu Asp 20 25 30

    Asn Ala Gly Val Phe Glu Lys Asp Lys Leu Ile Gln Lys Lys Tyr Gly 35 40 45

    Lys Thr Lys Pro Tyr Phe Asp Arg Leu His Arg Glu Phe Ile Glu Glu 50 55 60

    Ala Leu Thr Gly Val Glu Leu Ile Gly Leu Asp Glu Asn Phe Arg Thr 65 70 75 80

    Leu Val Asp Trp Gln Lys Asp Lys Lys Asn Asn Val Ala Met Lys Ala 85 90 95

    Tyr Glu Asn Ser Leu Gln Arg Leu Arg Thr Glu Ile Gly Lys Ile Phe

    100

    105

    110

    Asn Leu Lys Ala Glu Asp Trp Val Lys Asn Lys Tyr Pro Ile Leu Gly 115 120 125

    Leu Lys Asn Lys Asn Thr Asp Ile Leu Phe Glu Glu Ala Val Phe Gly 130 135 140

    Ile Leu Lys Ala Arg Tyr Gly Glu Glu Lys Asp Thr Phe Ile Glu Val 145 150 155 160

    Glu Glu Ile Asp Lys Thr Gly Lys Ser Lys Ile Asn Gln Ile Ser Ile 165 170 175

    Phe Asp Ser Trp Lys Gly Phe Thr Gly Tyr Phe Lys Lys Phe Phe Glu 180 185 190

    Thr Arg Lys Asn Phe Tyr Lys Asn Asp Gly Thr Ser Thr Ala Ile Ala 195 200 205

    Thr Arg Ile Ile Asp Gln Asn Leu Lys Arg Phe Ile Asp Asn Leu Ser 210 215 220

    Ile Val Glu Ser Val Arg Gln Lys Val Asp Leu Ala Glu Thr Glu Lys 225 230 235 240

    Ser Phe Ser Ile Ser Leu Ser Gln Phe Phe Ser Ile Asp Phe Tyr Asn 245 250 255

    Lys Cys Leu Leu Gln Asp Gly Ile Asp Tyr Tyr Asn Lys Ile Ile Gly 260 265 270

    Gly Glu Thr Leu Lys Asn Gly Glu Lys Leu Ile Gly Leu Asn Glu Leu 275 280 285

    Ile Asn Gln Tyr Arg Gln Asn Asn Lys Asp Gln Lys Ile Pro Phe Phe 290 295 300

    Lys Leu Leu Asp Lys Gln Ile Leu Ser Glu Lys Ile Leu Phe Leu Asp 305 310 315 320

    Glu Ile Lys Asn Asp Thr Glu Leu Ile Glu Ala Leu Ser Gln Phe Ala 325 330 335

    Lys Thr Ala Glu Glu Lys Thr Lys Ile Val Lys Lys Leu Phe Ala Asp 340 345 350

    Phe Val Glu Asn Asn Ser Lys Tyr Asp Leu Ala Gln Ile Tyr Ile Ser 355 360 365

    Gln Glu Ala Phe Asn Thr Ile Ser Asn Lys Trp Thr Ser Glu Thr Glu 370 375 380

    Thr Phe Ala Lys Tyr Leu Phe Glu Ala Met Lys Ser Gly Lys Leu Ala 385 390 395 400

    Lys Tyr Glu Lys Lys Asp Asn Ser Tyr Lys Phe Pro Asp Phe Ile Ala 405 410 415

    Leu Ser Gln Met Lys Ser Ala Leu Leu Ser Ile Ser Leu Glu Gly His 420 425 430

    Phe Trp Lys Glu Lys Tyr Tyr Lys Ile Ser Lys Phe Gln Glu Lys Thr 435 440 445

    Asn Trp Glu Gln Phe Leu Ala Ile Phe Leu Tyr Glu Phe Asn Ser Leu 450 455 460

    Phe Ser Asp Lys Ile Asn Thr Lys Asp Gly Glu Thr Lys Gln Val Gly 465 470 475 480

    Tyr Tyr Leu Phe Ala Lys Asp Leu His Asn Leu Ile Leu Ser Glu Gln 485 490 495

    Ile Asp Ile Pro Lys Asp Ser Lys Val Thr Ile Lys Asp Phe Ala Asp 500 505 510

    Ser Val Leu Thr Ile Tyr Gln Met Ala Lys Tyr Phe Ala Val Glu Lys 515 520 525

    Lys Arg Ala Trp Leu Ala Glu Tyr Glu Leu Asp Ser Phe Tyr Thr Gln 530 535 540

    Pro Asp Thr Gly Tyr Leu Gln Phe Tyr Asp Asn Ala Tyr Glu Asp Ile 545 550 555 560

    Val Gln Val Tyr Asn Lys Leu Arg Asn Tyr Leu Thr Lys Lys Pro Tyr 565 570 575

    Ser Glu Glu Lys Trp Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn 580 585 590

    Gly Trp Asp Lys Asn Lys Glu Ser Asp Asn Ser Ala Val Ile Leu Gln 595 600 605

    Lys Gly Gly Lys Tyr Tyr Leu Gly Leu Ile Thr Lys Gly His Asn Lys 610 615 620

    Ile Phe Asp Asp Arg Phe Gln Glu Lys Phe Ile Val Gly Ile Glu Gly 625 630 635 640

    Gly Lys Tyr Glu Lys Ile Val Tyr Lys Phe Phe Pro Asp Gln Ala Lys 645 650 655

    Met Phe Pro Lys Val Cys Phe Ser Ala Lys Gly Leu Glu Phe Phe Arg 660 665 670

    Pro Ser Glu Glu Ile Leu Arg Ile Tyr Asn Asn Ala Glu Phe Lys Lys 675 680 685

    Gly Glu Thr Tyr Ser Ile Asp Ser Met Gln Lys Leu Ile Asp Phe Tyr 690 695 700

    Lys Asp Cys Leu Thr Lys Tyr Glu Gly Trp Ala Cys Tyr Thr Phe Arg 705 710 715 720

    His Leu Lys Pro Thr Glu Glu Tyr Gln Asn Asn Ile Gly Glu Phe Phe 725 730 735

    Arg Asp Val Ala Glu Asp Gly Tyr Arg Ile Asp Phe Gln Gly Ile Ser 740 745 750

    Asp Gln Tyr Ile His Glu Lys Asn Glu Lys Gly Glu Leu His Leu Phe 755 760 765

    Glu Ile His Asn Lys Asp Trp Asn Leu Asp Lys Ala Arg Asp Gly Lys 770 775 780

    Ser Lys Thr Thr Gln Lys Asn Leu His Thr Leu Tyr Phe Glu Ser Leu 785 790 795 800

    Phe Ser Asn Asp Asn Val Val Gln Asn Phe Pro Ile Lys Leu Asn Gly 805 810 815

    Gln Ala Glu Ile Phe Tyr Arg Pro Lys Thr Glu Lys Asp Lys Leu Glu

    820

    825

    830

    Ser Lys Lys Asp Lys Lys Gly Asn Lys Val Ile Asp His Lys Arg Tyr 835 840 845

    Ser Glu Asn Lys Ile Phe Phe His Val Pro Leu Thr Leu Asn Arg Thr 850 855 860

    Lys Asn Asp Ser Tyr Arg Phe Asn Ala Gln Ile Asn Asn Phe Leu Ala 865 870 875 880

    Asn Asn Lys Asp Ile Asn Ile Ile Gly Val Asp Arg Gly Glu Lys His 885 890 895

    Leu Val Tyr Tyr Ser Val Ile Thr Gln Ala Ser Asp Ile Leu Glu Ser 900 905 910

    Gly Ser Leu Asn Glu Leu Asn Gly Val Asn Tyr Ala Glu Lys Leu Gly 915 920 925

    Lys Lys Ala Glu Asn Arg Glu Gln Ala Arg Arg Asp Trp Gln Asp Val 930 935 940

    Gln Gly Ile Lys Asp Leu Lys Lys Gly Tyr Ile Ser Gln Val Val Arg 945 950 955 960

    Lys Leu Ala Asp Leu Ala Ile Lys His Asn Ala Ile Ile Ile Leu Glu 965 970 975

    Asp Leu Asn Met Arg Phe Lys Gln Val Arg Gly Gly Ile Glu Lys Ser 980 985 990

    Ile Tyr Gln Gln Leu Glu Lys Ala Leu Ile Asp Lys Leu Ser Phe Leu 995 1000 1005

    Val Asp Lys Gly Glu Lys Asn Pro Glu Gln Ala Gly His Leu Leu 1010 1015 1020

    Lys Ala Tyr Gln Leu Ser Ala Pro Phe Glu Thr Phe Gln Lys Met 1025 1030 1035

    Gly Lys Gln Thr Gly Ile Ile Phe Tyr Thr Gln Ala Ser Tyr Thr 1040 1045 1050

    Ser Lys Ser Asp Pro Val Thr Gly Trp Arg Pro His Leu Tyr Leu 1055 1060 1065

    Lys Tyr Phe Ser Ala Lys Lys Ala Lys Asp Asp Ile Ala Lys Phe 1070 1075 1080

    Thr Lys Ile Glu Phe Val Asn Asp Arg Phe Glu Leu Thr Tyr Asp 1085 1090 1095

    Ile Lys Asp Phe Gln Gln Ala Lys Glu Tyr Pro Asn Lys Thr Val 1100 1105 1110

    Trp Lys Val Cys Ser Asn Val Glu Arg Phe Arg Trp Asp Lys Asn 1115 1120 1125

    Leu Asn Gln Asn Lys Gly Gly Tyr Thr His Tyr Thr Asn Ile Thr 1130 1135 1140

    Glu Asn Ile Gln Glu Leu Phe Thr Lys Tyr Gly Ile Asp Ile Thr 1145 1150 1155

    Lys Asp Leu Leu Thr Gln Ile Ser Thr Ile Asp Glu Lys Gln Asn 1160 1165 1170

    Thr Ser Phe Phe Arg Asp Phe Ile Phe Tyr Phe Asn Leu Ile Cys 1175 1180 1185

    Gln Ile Arg Asn Thr Asp Asp Ser Glu Ile Ala Lys Lys Asn Gly 1190 1195 1200

    Lys Asp Asp Phe Ile Leu Ser Pro Val Glu Pro Phe Phe Asp Ser 1205 1210 1215

    Arg Lys Asp Asn Gly Asn Lys Leu Pro Glu Asn Gly Asp Asp Asn 1220 1225 1230

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Ile Val Ile Leu Asn Lys 1235 1240 1245

    Ile Ser Gln Tyr Ser Glu Lys Asn Glu Asn Cys Glu Lys Met Lys 1250 1255 1260

    Trp Gly Asp Leu Tyr Val Ser Asn Ile Asp Trp Asp Asn Phe Val 1265 1270 1275

    Thr Gln Ala Asn Ala Arg His 1280 1285 <210> 84 <211> 1282 <212> PRT <213> Eubacterium eligens <400> 84

    Met Asn Gly Asn Arg Ser Ile Val Tyr Arg Glu Phe Val Gly Val Thr 1 5 10 15

    Pro Val Ala Lys Thr Leu Arg Asn Glu Leu Arg Pro Val Gly His Thr 20 25 30

    Gln Glu His Ile Ile Gln Asn Gly Leu Ile Gln Glu Asp Glu Leu Arg 35 40 45

    Gln Glu Lys Ser Thr Glu Leu Lys Asn Ile Met Asp Asp Tyr Tyr Arg 50 55 60

    Glu Tyr Ile Asp Lys Ser Leu Ser Gly Leu Thr Asp Leu Asp Phe Thr 65 70 75 80

    Leu Leu Phe Glu Leu Met Asn Ser Val Gln Ser Ser Leu Ser Lys Asp 85 90 95

    Asn Lys Lys Ala Leu Glu Lys Glu His Asn Lys Met Arg Glu Gln Ile 100 105 110

    Cys Thr His Leu Gln Ser Asp Ser Asp Tyr Lys Asn Met Phe Asn Ala 115 120 125

    Lys Leu Phe Lys Glu Ile Leu Pro Asp Phe Ile Lys Asn Tyr Asn Gln 130 135 140

    Tyr Asp Val Lys Asp Lys Ala Gly Lys Leu Glu Thr Leu Ala Leu Phe 145 150 155 160

    Asn Gly Phe Ser Thr Tyr Phe Thr Asp Phe Phe Glu Lys Arg Lys Asn 165 170 175

    Val Phe Thr Lys Glu Ala Val Ser Thr Ser Ile Ala Tyr Arg Ile Val 180 185 190

    His Glu Asn Ser Leu Ile Phe Leu Ala Asn Met Thr Ser Tyr Lys Lys 195 200 205

    Ile Ser Glu Lys Ala Leu Asp Glu Ile Glu Val Ile Glu Lys Asn Asn 210 215 220

    Gln Asp Lys Met Gly Asp Trp Glu Leu Asn Gln Ile Phe Asn Pro Asp 225 230 235 240

    Phe Tyr Asn Met Val Leu Ile Gln Ser Gly Ile Asp Phe Tyr Asn Glu 245 250 255

    Ile Cys Gly Val Val Asn Ala His Met Asn Leu Tyr Cys Gln Gln Thr 260 265 270

    Lys Asn Asn Tyr Asn Leu Phe Lys Met Arg Lys Leu His Lys Gln Ile 275 280 285

    Leu Ala Tyr Thr Ser Thr Ser Phe Glu Val Pro Lys Met Phe Glu Asp 290 295 300

    Asp Met Ser Val Tyr Asn Ala Val Asn Ala Phe Ile Asp Glu Thr Glu 305 310 315 320

    Lys Gly Asn Ile Ile Gly Lys Leu Lys Asp Ile Val Asn Lys Tyr Asp 325 330 335

    Glu Leu Asp Glu Lys Arg Ile Tyr Ile Ser Lys Asp Phe Tyr Glu Thr 340 345 350

    Leu Ser Cys Phe Met Ser Gly Asn Trp Asn Leu Ile Thr Gly Cys Val 355 360 365

    Glu Asn Phe Tyr Asp Glu Asn Ile His Ala Lys Gly Lys Ser Lys Glu 370 375 380

    Glu Lys Val Lys Lys Ala Val Lys Glu Asp Lys Tyr Lys Ser Ile Asn 385 390 395 400

    Asp Val Asn Asp Leu Val Glu Lys Tyr Ile Asp Glu Lys Glu Arg Asn 405 410 415

    Glu Phe Lys Asn Ser Asn Ala Lys Gln Tyr Ile Arg Glu Ile Ser Asn 420 425 430

    Ile Ile Thr Asp Thr Glu Thr Ala His Leu Glu Tyr Asp Glu His Ile 435 440 445

    Ser Leu Ile Glu Ser Glu Glu Lys Ala Asp Glu Ile Lys Lys Arg Leu 450 455 460

    Asp Met Tyr Met Asn Met Tyr His Trp Val Lys Ala Phe Ile Val Asp 465 470 475 480

    Glu Val Leu Asp Arg Asp Glu Met Phe Tyr Ser Asp Ile Asp Asp Ile 485 490 495

    Tyr Asn Ile Leu Glu Asn Ile Val Pro Leu Tyr Asn Arg Val Arg Asn 500 505 510

    Tyr Val Thr Gln Lys Pro Tyr Thr Ser Lys Lys Ile Lys Leu Asn Phe 515 520 525

    Gln Ser Pro Thr Leu Ala Asn Gly Trp Ser Gln Ser Lys Glu Phe Asp 530 535 540

    Asn Asn Ala Ile Ile Leu Ile Arg Asp Asn Lys Tyr Tyr Leu Ala Ile 545 550 555 560

    Phe Asn Ala Lys Asn Lys Pro Asp Lys Lys Ile Ile Gln Gly Asn Ser

    565

    570

    575

    Asp Lys Lys Asn Asp Asn Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu 580 585 590

    Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Leu Ser Lys Lys Gly 595 600 605

    Ile Glu Thr Phe Lys Pro Ser Asp Tyr Ile Ile Ser Gly Tyr Asn Ala 610 615 620

    His Lys His Ile Lys Thr Ser Glu Asn Phe Asp Ile Ser Phe Cys Arg 625 630 635 640

    Asp Leu Ile Asp Tyr Phe Lys Asn Ser Ile Glu Lys His Ala Glu Trp 645 650 655

    Arg Lys Tyr Glu Phe Lys Phe Ser Ala Thr Asp Ser Tyr Asn Asp Ile 660 665 670

    Ser Glu Phe Tyr Arg Glu Val Glu Met Gln Gly Tyr Arg Ile Asp Trp 675 680 685

    Thr Tyr Ile Ser Glu Ala Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys 690 695 700

    Ile Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Glu Asn Ser Thr 705 710 715 720

    Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asn Ile Val Ile Lys Leu Asn Gly Gln Ala Glu Leu 740 745 750

    Phe Tyr Arg Lys Ala Ser Val Lys Asn Pro Val Lys His Lys Lys Asp 755 760 765

    Ser Val Leu Val Asn Lys Thr Tyr Lys Asn Gln Leu Asp Asn Gly Asp 770 775 780

    Val Val Arg Ile Pro Ile Pro Asp Asp Ile Tyr Asn Glu Ile Tyr Lys 785 790 795 800

    Met Tyr Asn Gly Tyr Ile Lys Glu Ser Asp Leu Ser Glu Ala Ala Lys 805 810 815

    Glu Tyr Leu Asp Lys Val Glu Val Arg Thr Ala Gln Lys Asp Ile Val 820 825 830

    Lys Asp Tyr Arg Tyr Thr Val Asp Lys Tyr Phe Ile His Thr Pro Ile 835 840 845

    Thr Ile Asn Tyr Lys Val Thr Ala Arg Asn Asn Val Asn Asp Met Ala 850 855 860

    Val Lys Tyr Ile Ala Gln Asn Asp Asp Ile His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Ile Tyr Ile Ser Val Ile Asp Ser His Gly 885 890 895

    Asn Ile Val Lys Gln Lys Ser Tyr Asn Ile Leu Asn Asn Tyr Asp Tyr 900 905 910

    Lys Lys Lys Leu Val Glu Lys Glu Lys Thr Arg Glu Tyr Ala Arg Lys 915 920 925

    Asn Trp Lys Ser Ile Gly Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 930 935 940

    Ser Gly Val Val His Glu Ile Ala Met Leu Met Val Glu Tyr Asn Ala 945 950 955 960

    Ile Ile Ala Met Glu Asp Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe 965 970 975

    Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 980 985 990

    Lys Leu Asn Tyr Phe Ala Ser Lys Gly Lys Ser Val Asp Glu Pro Gly 995 1000 1005

    Gly Leu Leu Lys Gly Tyr Gln Leu Thr Tyr Val Pro Asp Asn Ile 1010 1015 1020

    Lys Asn Leu Gly Lys Gln Cys Gly Val Ile Phe Tyr Val Pro Ala 1025 1030 1035

    Ala Phe Thr Ser Lys Ile Asp Pro Ser Thr Gly Phe Ile Ser Ala 1040 1045 1050

    Phe Asn Phe Lys Ser Ile Ser Thr Asn Ala Ser Arg Lys Gln Phe 1055 1060 1065

    Phe Met Gln Phe Asp Glu Ile Arg Tyr Cys Ala Glu Lys Asp Met 1070 1075 1080

    Phe Ser Phe Gly Phe Asp Tyr Asn Asn Phe Asp Thr Tyr Asn Ile 1085 1090 1095

    Thr Met Gly Lys Thr Gln Trp Thr Val Tyr Thr Asn Gly Glu Arg 1100 1105 1110

    Leu Gln Ser Glu Phe Asn Asn Ala Arg Arg Thr Gly Lys Thr Lys 1115 1120 1125

    Ser Ile Asn Leu Thr Glu Thr Ile Lys Leu Leu Leu Glu Asp Asn 1130 1135 1140

    Glu Ile Asn Tyr Ala Asp Gly His Asp Val Arg Ile Asp Met Glu 1145 1150 1155

    Lys Met Tyr Glu Asp Lys Asn Ser Glu Phe Phe Ala Gln Leu Leu 1160 1165 1170

    Ser Leu Tyr Lys Leu Thr Val Gln Met Arg Asn Ser Tyr Thr Glu 1175 1180 1185

    Ala Glu Glu Gln Glu Lys Gly Ile Ser Tyr Asp Lys Ile Ile Ser 1190 1195 1200

    Pro Val Ile Asn Asp Glu Gly Glu Phe Phe Asp Ser Asp Asn Tyr 1205 1210 1215

    Lys Glu Ser Asp Asp Lys Glu Cys Lys Met Pro Lys Asp Ala Asp 1220 1225 1230

    Ala Asn Gly Ala Tyr Cys Ile Ala Leu Lys Gly Leu Tyr Glu Val 1235 1240 1245

    Leu Lys Ile Lys Ser Glu Trp Thr Glu Asp Gly Phe Asp Arg Asn 1250 1255 1260

    Cys Leu Lys Leu Pro His Ala Glu Trp Leu Asp Phe Ile Gln Asn

    1265

    1270

    1275

    Lys Arg Tyr Glu 1280 <210> 85 <211> 1282 <212> PRT <213> Eubacterium eligens <400> 85

    Met Asn Gly Asn Arg Ser Ile Val Tyr Arg Glu Phe Val Gly Val Ile 1 5 10 15

    Pro Val Ala Lys Thr Leu Arg Asn Glu Leu Arg Pro Val Gly His Thr 20 25 30

    Gln Glu His Ile Ile Gln Asn Gly Leu Ile Gln Glu Asp Glu Leu Arg 35 40 45

    Gln Glu Lys Ser Thr Glu Leu Lys Asn Ile Met Asp Asp Tyr Tyr Arg 50 55 60

    Glu Tyr Ile Asp Lys Ser Leu Ser Gly Val Thr Asp Leu Asp Phe Thr 65 70 75 80

    Leu Leu Phe Glu Leu Met Asn Leu Val Gln Ser Ser Pro Ser Lys Asp 85 90 95

    Asn Lys Lys Ala Leu Glu Lys Glu Gln Ser Lys Met Arg Glu Gln Ile 100 105 110

    Cys Thr His Leu Gln Ser Asp Ser Asn Tyr Lys Asn Ile Phe Asn Ala 115 120 125

    Lys Leu Leu Lys Glu Ile Leu Pro Asp Phe Ile Lys Asn Tyr Asn Gln 130 135 140

    Tyr Asp Val Lys Asp Lys Ala Gly Lys Leu Glu Thr Leu Ala Leu Phe 145 150 155 160

    Asn Gly Phe Ser Thr Tyr Phe Thr Asp Phe Phe Glu Lys Arg Lys Asn 165 170 175

    Val Phe Thr Lys Glu Ala Val Ser Thr Ser Ile Ala Tyr Arg Ile Val 180 185 190

    His Glu Asn Ser Leu Ile Phe Leu Ala Asn Met Thr Ser Tyr Lys Lys 195 200 205

    Ile Ser Glu Lys Ala Leu Asp Glu Ile Glu Val Ile Glu Lys Asn Asn 210 215 220

    Gln Asp Lys Met Gly Asp Trp Glu Leu Asn Gln Ile Phe Asn Pro Asp 225 230 235 240

    Phe Tyr Asn Met Val Leu Ile Gln Ser Gly Ile Asp Phe Tyr Asn Glu 245 250 255

    Ile Cys Gly Val Val Asn Ala His Met Asn Leu Tyr Cys Gln Gln Thr 260 265 270

    Lys Asn Asn Tyr Asn Leu Phe Lys Met Arg Lys Leu His Lys Gln Ile 275 280 285

    Leu Ala Tyr Thr Ser Thr Ser Phe Glu Val Pro Lys Met Phe Glu Asp 290 295 300

    Asp Met Ser Val Tyr Asn Ala Val Asn Ala Phe Ile Asp Glu Thr Glu

    305

    310

    315

    320

    Lys Gly Asn Ile Ile Gly Lys Leu Lys Asp Ile Val Asn Lys Tyr Asp 325 330 335

    Glu Leu Asp Glu Lys Arg Ile Tyr Ile Ser Lys Asp Phe Tyr Glu Thr 340 345 350

    Leu Ser Cys Phe Met Ser Gly Asn Trp Asn Leu Ile Thr Gly Cys Val 355 360 365

    Glu Asn Phe Tyr Asp Glu Asn Ile His Ala Lys Gly Lys Ser Lys Glu 370 375 380

    Glu Lys Val Lys Lys Ala Val Lys Glu Asp Lys Tyr Lys Ser Ile Asn 385 390 395 400

    Asp Val Asn Asp Leu Val Glu Lys Tyr Ile Asp Glu Lys Glu Arg Asn 405 410 415

    Glu Phe Lys Asn Ser Asn Ala Lys Gln Tyr Ile Arg Glu Ile Ser Asn 420 425 430

    Ile Ile Thr Asp Thr Glu Thr Ala His Leu Glu Tyr Asp Asp His Ile 435 440 445

    Ser Leu Ile Glu Ser Glu Glu Lys Ala Asp Glu Met Lys Lys Arg Leu 450 455 460

    Asp Met Tyr Met Asn Met Tyr His Trp Ala Lys Ala Phe Ile Val Asp 465 470 475 480

    Glu Val Leu Asp Arg Asp Glu Met Phe Tyr Ser Asp Ile Asp Asp Ile 485 490 495

    Tyr Asn Ile Leu Glu Asn Ile Val Pro Leu Tyr Asn Arg Val Arg Asn 500 505 510

    Tyr Val Thr Gln Lys Pro Tyr Asn Ser Lys Lys Ile Lys Leu Asn Phe 515 520 525

    Gln Ser Pro Thr Leu Ala Asn Gly Trp Ser Gln Ser Lys Glu Phe Asp 530 535 540

    Asn Asn Ala Ile Ile Leu Ile Arg Asp Asn Lys Tyr Tyr Leu Ala Ile 545 550 555 560

    Phe Asn Ala Lys Asn Lys Pro Asp Lys Lys Ile Ile Gln Gly Asn Ser 565 570 575

    Asp Lys Lys Asn Asp Asn Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu 580 585 590

    Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Leu Ser Lys Lys Gly 595 600 605

    Ile Glu Thr Phe Lys Pro Ser Asp Tyr Ile Ile Ser Gly Tyr Asn Ala 610 615 620

    His Lys His Ile Lys Thr Ser Glu Asn Phe Asp Ile Ser Phe Cys Arg 625 630 635 640

    Asp Leu Ile Asp Tyr Phe Lys Asn Ser Ile Glu Lys His Ala Glu Trp 645 650 655

    Arg Lys Tyr Glu Phe Lys Phe Ser Ala Thr Asp Ser Tyr Ser Asp Ile 660 665 670

    Ser Glu Phe Tyr Arg Glu Val Glu Met Gln Gly Tyr Arg Ile Asp Trp 675 680 685

    Thr Tyr Ile Ser Glu Ala Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys 690 695 700

    Ile Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Glu Asn Ser Thr 705 710 715 720

    Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asp Ile Ile Ile Lys Leu Asn Gly Gln Ala Glu Leu 740 745 750

    Phe Tyr Arg Arg Ala Ser Val Lys Asn Pro Val Lys His Lys Lys Asp 755 760 765

    Ser Val Leu Val Asn Lys Thr Tyr Lys Asn Gln Leu Asp Asn Gly Asp 770 775 780

    Val Val Arg Ile Pro Ile Pro Asp Asp Ile Tyr Asn Glu Ile Tyr Lys 785 790 795 800

    Met Tyr Asn Gly Tyr Ile Lys Glu Ser Asp Leu Ser Glu Ala Ala Lys 805 810 815

    Glu Tyr Leu Asp Lys Val Glu Val Arg Thr Ala Gln Lys Asp Ile Val 820 825 830

    Lys Asp Tyr Arg Tyr Thr Val Asp Lys Tyr Phe Ile His Thr Pro Ile 835 840 845

    Thr Ile Asn Tyr Lys Val Thr Ala Arg Asn Asn Val Asn Asp Met Val 850 855 860

    Val Lys Tyr Ile Ala Gln Asn Asp Asp Ile His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Ile Tyr Ile Ser Val Ile Asp Ser His Gly 885 890 895

    Asn Ile Val Lys Gln Lys Ser Tyr Asn Ile Leu Asn Asn Tyr Asp Tyr 900 905 910

    Lys Lys Lys Leu Val Glu Lys Glu Lys Thr Arg Glu Tyr Ala Arg Lys 915 920 925

    Asn Trp Lys Ser Ile Gly Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 930 935 940

    Ser Gly Val Val His Glu Ile Ala Met Leu Ile Val Glu Tyr Asn Ala 945 950 955 960

    Ile Ile Ala Met Glu Asp Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe 965 970 975

    Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 980 985 990

    Lys Leu Asn Tyr Phe Ala Ser Lys Glu Lys Ser Val Asp Glu Pro Gly 995 1000 1005

    Gly Leu Leu Lys Gly Tyr Gln Leu Thr Tyr Val Pro Asp Asn Ile 1010 1015 1020

    Lys Asn Leu Gly Lys Gln Cys Gly Val Ile Phe Tyr Val Pro Ala

    1025

    1030

    1035

    Ala Phe Thr Ser Lys Ile Asp Pro Ser Thr Gly Phe Ile Ser Ala 1040 1045 1050

    Phe Asn Phe Lys Ser Ile Ser Thr Asn Ala Ser Arg Lys Gln Phe 1055 1060 1065

    Phe Met Gln Phe Asp Glu Ile Arg Tyr Cys Ala Glu Lys Asp Met 1070 1075 1080

    Phe Ser Phe Gly Phe Asp Tyr Asn Asn Phe Asp Thr Tyr Asn Ile 1085 1090 1095

    Thr Met Gly Lys Thr Gln Trp Thr Val Tyr Thr Asn Gly Glu Arg 1100 1105 1110

    Leu Gln Ser Glu Phe Asn Asn Ala Arg Arg Thr Gly Lys Thr Lys 1115 1120 1125

    Ser Ile Asn Leu Thr Glu Thr Ile Lys Leu Leu Leu Glu Asp Asn 1130 1135 1140

    Glu Ile Asn Tyr Ala Asp Gly His Asp Ile Arg Ile Asp Met Glu 1145 1150 1155

    Lys Met Asp Glu Asp Lys Lys Ser Glu Phe Phe Ala Gln Leu Leu 1160 1165 1170

    Ser Leu Tyr Lys Leu Thr Val Gln Met Arg Asn Ser Tyr Thr Glu 1175 1180 1185

    Ala Glu Glu Gln Glu Asn Gly Ile Ser Tyr Asp Lys Ile Ile Ser 1190 1195 1200

    Pro Val Ile Asn Asp Glu Gly Glu Phe Phe Asp Ser Asp Asn Tyr 1205 1210 1215

    Lys Glu Ser Asp Asp Lys Glu Cys Lys Met Pro Lys Asp Ala Asp 1220 1225 1230

    Ala Asn Gly Ala Tyr Cys Ile Ala Leu Lys Gly Leu Tyr Glu Val 1235 1240 1245

    Leu Lys Ile Lys Ser Glu Trp Thr Glu Asp Gly Phe Asp Arg Asn

    1250 1255 1260 Cys Leu Lys Leu Pro His Ala Glu Trp Leu Asp Phe Ile Gln Asn 1265 1270 1275

    Lys Arg Tyr Glu 1280 <210> 86 <211> 1273 <212> PRT <213> Flavobacterium sp.

    <400> 86

    Met Lys Asn Phe Ser Asn Leu Tyr Gln Val Ser Lys Thr Val Arg Phe 1 5 10 15

    Glu Leu Lys Pro Ile Gly Asn Thr Leu Glu Asn Ile Lys Asn Lys Ser 20 25 30

    Leu Leu Lys Asn Asp Ser Ile Arg Ala Glu Ser Tyr Gln Lys Met Lys 35 40 45

    Lys Thr Ile Asp Glu Phe His Lys Tyr Phe Ile Asp Leu Ala Leu Asn

    Asn Lys Lys Leu Ser Tyr Leu Asn Glu Tyr Ile Ala Leu Tyr Thr Gln 65 70 75 80

    Ser Ala Glu Ala Lys Lys Glu Asp Lys Phe Lys Ala Asp Phe Lys Lys 85 90 95

    Val Gln Asp Asn Leu Arg Lys Glu Ile Val Ser Ser Phe Thr Glu Gly 100 105 110

    Glu Ala Lys Ala Ile Phe Ser Val Leu Asp Lys Lys Glu Leu Ile Thr 115 120 125

    Ile Glu Leu Glu Lys Trp Lys Asn Glu Asn Asn Leu Ala Val Tyr Leu 130 135 140

    Asp Glu Ser Phe Lys Ser Phe Thr Thr Tyr Phe Thr Gly Phe His Gln 145 150 155 160

    Asn Arg Lys Asn Met Tyr Ser Ala Glu Ala Asn Ser Thr Ala Ile Ala 165 170 175

    Tyr Arg Leu Ile His Glu Asn Leu Pro Lys Phe Ile Glu Asn Ser Lys 180 185 190

    Ala Phe Glu Lys Ser Ser Gln Ile Ala Glu Leu Gln Pro Lys Ile Glu 195 200 205

    Lys Leu Tyr Lys Glu Phe Glu Ala Tyr Leu Asn Val Asn Ser Ile Ser 210 215 220

    Glu Leu Phe Glu Ile Asp Tyr Phe Asn Glu Val Leu Thr Gln Lys Gly 225 230 235 240

    Ile Thr Val Tyr Asn Asn Ile Ile Gly Gly Arg Thr Ala Thr Glu Gly 245 250 255

    Lys Gln Lys Ile Gln Gly Leu Asn Glu Ile Ile Asn Leu Tyr Asn Gln 260 265 270

    Thr Lys Pro Lys Asn Glu Arg Leu Pro Lys Leu Lys Gln Leu Tyr Lys 275 280 285

    Gln Ile Leu Ser Asp Arg Ile Ser Leu Ser Phe Leu Pro Asp Ala Phe 290 295 300

    Thr Glu Gly Lys Gln Val Leu Lys Ala Val Phe Glu Phe Tyr Lys Ile 305 310 315 320

    Asn Leu Leu Ser Tyr Lys Gln Asp Gly Val Glu Glu Ser Gln Asn Leu 325 330 335

    Leu Glu Leu Ile Gln Gln Val Val Lys Asn Leu Gly Asn Gln Asp Val 340 345 350

    Asn Lys Ile Tyr Leu Lys Asn Asp Thr Ser Leu Thr Thr Ile Ala Gln 355 360 365

    Gln Leu Phe Gly Asp Phe Ser Val Phe Ser Ala Ala Leu Gln Tyr Arg 370 375 380

    Tyr Glu Thr Val Val Asn Pro Lys Tyr Thr Ala Glu Tyr Gln Lys Ala 385 390 395 400

    Asn Glu Ala Lys Gln Glu Lys Leu Asp Lys Glu Lys Ile Lys Phe Val 405 410 415

    Lys Gln Asp Tyr Phe Ser Ile Ala Phe Leu Gln Glu Val Val Ala Asp 420 425 430

    Tyr Val Lys Thr Leu Asp Glu Asn Leu Asp Trp Lys Gln Lys Tyr Thr 435 440 445

    Pro Ser Cys Ile Ala Asp Tyr Phe Thr Thr His Phe Ile Ala Lys Lys 450 455 460

    Glu Asn Glu Ala Asp Lys Thr Phe Asn Phe Ile Ala Asn Ile Lys Ala 465 470 475 480

    Lys Tyr Gln Cys Ile Gln Gly Ile Leu Glu Gln Ala Asp Asp Tyr Glu 485 490 495

    Asp Glu Leu Lys Gln Asp Gln Lys Leu Ile Asp Asn Ile Lys Phe Phe 500 505 510

    Leu Asp Ala Ile Leu Glu Val Val His Phe Ile Lys Pro Leu His Leu 515 520 525

    Lys Ser Glu Ser Ile Thr Glu Lys Asp Asn Ala Phe Tyr Asp Val Phe 530 535 540

    Glu Asn Tyr Tyr Glu Ala Leu Asn Val Val Thr Pro Leu Tyr Asn Met 545 550 555 560

    Val Arg Asn Tyr Val Thr Gln Lys Pro Tyr Ser Thr Glu Lys Ile Lys 565 570 575

    Leu Asn Phe Glu Asn Ala Gln Leu Leu Asn Gly Trp Asp Ala Asn Lys 580 585 590

    Glu Lys Asp Tyr Leu Thr Thr Ile Leu Lys Arg Asp Gly Asn Tyr Phe 595 600 605

    Leu Ala Ile Met Asp Lys Lys His Asn Lys Thr Phe Gln Gln Phe Thr 610 615 620

    Glu Asp Asp Glu Asn Tyr Glu Lys Ile Val Tyr Lys Leu Leu Pro Gly 625 630 635 640

    Val Asn Lys Met Leu Pro Lys Val Phe Phe Ser Asn Lys Asn Ile Ala 645 650 655

    Phe Phe Asn Pro Ser Lys Glu Ile Leu Asp Asn Tyr Lys Asn Asn Thr 660 665 670

    His Lys Lys Gly Ala Thr Phe Asn Leu Lys Asp Cys His Ala Leu Ile 675 680 685

    Asp Phe Phe Lys Asp Ser Leu Asn Lys His Glu Asp Trp Lys Tyr Phe 690 695 700

    Asp Phe Gln Phe Ser Glu Thr Lys Thr Tyr Gln Asp Leu Ser Gly Phe 705 710 715 720

    Tyr Lys Glu Val Glu His Gln Gly Tyr Lys Ile Asn Phe Lys Lys Val 725 730 735

    Ser Val Ser Gln Ile Asp Thr Leu Ile Glu Glu Gly Lys Met Tyr Leu 740 745 750

    Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Tyr Ala Lys Gly Lys Pro 755 760 765

    Asn Met His Thr Leu Tyr Trp Lys Ala Leu Phe Glu Thr Gln Asn Leu

    770

    775

    780

    Glu Asn Val Ile Tyr Lys Leu Asn Gly Gln Ala Glu Ile Phe Phe Arg 785 790 795 800

    Lys Ala Ser Ile Lys Lys Lys Asn Ile Ile Thr His Lys Ala His Gln 805 810 815

    Pro Ile Ala Ala Lys Asn Pro Leu Thr Pro Thr Ala Lys Asn Thr Phe 820 825 830

    Ala Tyr Asp Leu Ile Lys Asp Lys Arg Tyr Thr Val Asp Lys Phe Gln 835 840 845

    Phe His Val Pro Ile Thr Met Asn Phe Lys Ala Thr Gly Asn Ser Tyr 850 855 860

    Ile Asn Gln Asp Val Leu Ala Tyr Leu Lys Asp Asn Pro Glu Val Asn 865 870 875 880

    Ile Ile Gly Leu Asp Arg Gly Glu Arg His Leu Val Tyr Leu Thr Leu 885 890 895

    Ile Asp Gln Lys Gly Thr Ile Leu Leu Gln Glu Ser Leu Asn Val Ile 900 905 910

    Gln Asp Glu Lys Thr His Thr Pro Tyr His Thr Leu Leu Asp Asn Lys 915 920 925

    Glu Ile Ala Arg Asp Lys Ala Arg Lys Asn Trp Gly Ser Ile Glu Ser 930 935 940

    Ile Lys Glu Leu Lys Glu Gly Tyr Ile Ser Gln Val Val His Lys Ile 945 950 955 960

    Thr Lys Met Met Ile Glu His Asn Ala Ile Val Val Met Glu Asp Leu 965 970 975

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 980 985 990

    Gln Lys Leu Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Leu 995 1000 1005

    Lys Asp Lys Gln Pro His Glu Leu Gly Gly Leu Tyr Asn Ala Leu 1010 1015 1020

    Gln Leu Thr Asn Lys Phe Glu Ser Phe Gln Lys Met Gly Lys Gln 1025 1030 1035

    Ser Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile 1040 1045 1050

    Asp Pro Thr Thr Gly Phe Val

    1055 1060 1065

    Asn Tyr Phe Tyr Thr Lys Tyr Glu

    Asn Val Glu Lys Ala Lys Thr Phe Phe Ser Lys Phe Asp Ser Ile 1070 1075 1080

    Leu Tyr Asn Lys Thr Lys Gly Tyr Phe Glu Phe Val Val Lys Asn 1085 1090 1095

    Tyr Ser Asp Phe Asn Pro Lys Ala Ala Asp Thr Arg Gln Glu Trp 1100 1105 1110

    Thr Ile Cys Thr His Gly Glu Arg Ile Glu Thr Lys Arg Gln Lys 1115 1120 1125

    Glu Gln Asn Asn Asn Phe Val Ser Thr Thr Ile Gln Leu Thr Glu 1130 1135 1140

    Gln Phe Val Asn Phe Phe Glu Lys Val Gly Leu Asp Leu Ser Lys 1145 1150 1155

    Glu Leu Lys Thr Gln Leu Ile Ala Gln Asn Glu Lys Ser Phe Phe 1160 1165 1170

    Glu Glu Leu Phe His Leu Leu Lys Leu Thr Leu Gln Met Arg Asn 1175 1180 1185

    Ser Glu Ser His Thr Glu Ile Asp Tyr Leu Ile Ser Pro Val Ala 1190 1195 1200

    Asn Glu Lys Gly Ile Phe Tyr Asp Ser Arg Lys Ala Thr Ala Ser 1205 1210 1215

    Leu Pro Ile Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Lys 1220 1225 1230

    Lys Gly Leu Trp Ile Met Glu Gln Ile Asn Lys Thr Asn Ser Glu 1235 1240 1245

    Asp Asp Leu Lys Lys Val Lys Leu Ala Ile Ser Asn Arg Glu Trp 1250 1255 1260

    Leu Gln Tyr Val Gln Gln Val Gln Lys Lys 1265 1270 <210> 87 <211> 1264 <212> PRT <213> Prevotella brevis <400> 87

    Met Lys Gln Phe Thr Asn Leu Tyr Gln Leu Ser Lys Thr Leu Arg Phe 1 5 10 15

    Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu His Ile Asn Ala Asn Gly 20 25 30

    Phe Ile Asp Asn Asp Ala His Arg Ala Glu Ser Tyr Lys Lys Val Lys 35 40 45

    Lys Leu Ile Asp Asp Tyr His Lys Asp Tyr Ile Glu Asn Val Leu Asn 50 55 60

    Asn Phe Lys Leu Asn Gly Glu Tyr Leu Gln Ala Tyr Phe Asp Leu Tyr 65 70 75 80

    Ser Gln Asp Thr Lys Asp Lys Gln Phe Lys Asp Ile Gln Asp Lys Leu 85 90 95

    Arg Lys Ser Ile Ala Ser Ala Leu Lys Gly Asp Asp Arg Tyr Lys Thr 100 105 110

    Ile Asp Lys Lys Glu Leu Ile Arg Gln Asp Met Lys Thr Phe Leu Lys 115 120 125

    Lys Asp Thr Asp Lys Ala Leu Leu Asp Glu Phe Tyr Glu Phe Thr Thr 130 135 140

    Tyr Phe Thr Gly Tyr His Glu Asn Arg Lys Asn Met Tyr Ser Asp Glu 145 150 155 160

    Ala Lys Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Asp Asn Leu Pro 165 170 175

    Lys Phe Ile Asp Asn Ile Ala Val Phe Lys Lys Ile Ala Asn Thr Ser 180 185 190

    Val Ala Asp Asn Phe Ser Thr Ile Tyr Lys Asn Phe Glu Glu Tyr Leu 195 200 205

    Asn Val Asn Ser Ile Asp Glu Ile Phe Ser Leu Asp Tyr Tyr Asn Ile 210 215 220

    Val Leu Thr Gln Thr Gln Ile Glu Val Tyr Asn Ser Ile Ile Gly Gly 225 230 235 240

    Arg Thr Leu Glu Asp Asp Thr Lys Ile Gln Gly Ile Asn Glu Phe Val 245 250 255

    Asn Leu Tyr Asn Gln Gln Leu Ala Asn Lys Lys Asp Arg Leu Pro Lys 260 265 270

    Leu Lys Pro Leu Phe Lys Gln Ile Leu Ser Asp Arg Val Gln Leu Ser 275 280 285

    Trp Leu Gln Glu Glu Phe Asn Thr Gly Ala Asp Val Leu Asn Ala Val 290 295 300

    Lys Glu Tyr Cys Thr Ser Tyr Phe Asp Asn Val Glu Glu Ser Val Lys 305 310 315 320

    Val Leu Leu Thr Gly Ile Ser Asp Tyr Asp Leu Ser Lys Ile Tyr Ile 325 330 335

    Thr Asn Asp Leu Ala Leu Thr Asp Val Ser Gln Arg Met Phe Gly Glu 340 345 350

    Trp Ser Ile Ile Pro Asn Ala Ile Glu Gln Arg Leu Arg Ser Asp Asn 355 360 365

    Pro Lys Lys Thr Asn Glu Lys Glu Glu Lys Tyr Ser Asp Arg Ile Ser 370 375 380

    Lys Leu Lys Lys Leu Pro Lys Ser Tyr Ser Leu Gly Tyr Ile Asn Glu 385 390 395 400

    Cys Ile Ser Glu Leu Asn Gly Ile Asp Ile Ala Asp Tyr Tyr Ala Thr 405 410 415

    Leu Gly Ala Ile Asn Thr Glu Ser Lys Gln Glu Pro Ser Ile Pro Thr 420 425 430

    Ser Ile Gln Val His Tyr Asn Ala Leu Lys Pro Ile Leu Asp Thr Asp 435 440 445

    Tyr Pro Arg Glu Lys Asn Leu Ser Gln Asp Lys Leu Thr Val Met Gln 450 455 460

    Leu Lys Asp Leu Leu Asp Asp Phe Lys Ala Leu Gln His Phe Ile Lys 465 470 475 480

    Pro Leu Leu Gly Asn Gly Asp Glu Ala Glu Lys Asp Glu Lys Phe Tyr 485 490 495

    Gly Glu Leu Met Gln Leu Trp Glu Val Ile Asp Ser Ile Thr Pro Leu 500 505 510

    Tyr Asn Lys Val Arg Asn Tyr Cys Thr Arg Lys Pro Phe Ser Thr Glu 515 520 525

    Lys Ile Lys Val Asn Phe Glu Asn Ala Gln Leu Leu Asp Gly Trp Asp

    530

    535

    540

    Glu Asn Lys Glu Ser Thr Asn Ala Ser Ile Ile Leu Arg Lys Asn Gly 545 550 555 560

    Met Tyr Tyr Leu Gly Ile Met Lys Lys Glu Tyr Arg Asn Ile Leu Thr 565 570 575

    Lys Pro Met Pro Ser Asp Gly Asp Cys Tyr Asp Lys Val Val Tyr Lys 580 585 590

    Phe Phe Lys Asp Ile Thr Thr Met Val Pro Lys Cys Thr Thr Gln Met 595 600 605

    Lys Ser Val Lys Glu His Phe Ser Asn Ser Asn Asp Asp Tyr Thr Leu 610 615 620

    Phe Glu Lys Asp Lys Phe Ile Ala Pro Val Val Ile Thr Lys Glu Ile 625 630 635 640

    Phe Asp Leu Asn Asn Val Leu Tyr Asn Gly Val Lys Lys Phe Gln Ile 645 650 655

    Gly Tyr Leu Asn Asn Thr Gly Asp Ser Phe Gly Tyr Asn His Ala Val 660 665 670

    Glu Ile Trp Lys Ser Phe Cys Leu Lys Phe Leu Lys Ala Tyr Lys Ser 675 680 685

    Thr Ser Ile Tyr Asp Phe Ser Ser Ile Glu Lys Asn Ile Gly Cys Tyr 690 695 700

    Asn Asp Leu Asn Ser Phe Tyr Gly Ala Val Asn Leu Leu Leu Tyr Asn 705 710 715 720

    Leu Thr Tyr Arg Lys Val Ser Val Asp Tyr Ile His Gln Leu Val Asp 725 730 735

    Glu Asp Lys Met Tyr Leu Phe Met Ile Tyr Asn Lys Asp Phe Ser Thr 740 745 750

    Tyr Ser Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Lys Met Leu 755 760 765

    Phe Asp Glu Ser Asn Leu Asn Asp Val Val Tyr Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Thr Tyr Gln His Pro Thr 785 790 795 800

    His Pro Ala Asn Lys Pro Ile Asp Asn Lys Asn Val Asn Asn Pro Lys 805 810 815

    Lys Gln Ser Asn Phe Glu Tyr Asp Leu Ile Lys Asp Lys Arg Tyr Thr 820 825 830

    Val Asp Lys Phe Met Phe His Val Pro Ile Thr Leu Asn Phe Lys Gly 835 840 845

    Met Gly Asn Gly Asp Ile Asn Met Gln Val Arg Glu Tyr Ile Lys Thr 850 855 860

    Thr Asp Asp Leu His Phe Ile Gly Ile Asp Arg Gly Glu Arg His Leu 865 870 875 880

    Leu Tyr Ile Cys Val Ile Asn Gly Lys Gly Glu Ile Val Glu Gln Tyr 885 890 895

    Ser Leu Asn Glu Ile Val Asn Asn Tyr Lys Gly Thr Glu Tyr Lys Thr 900 905 910

    Asp Tyr His Thr Leu Leu Ser Glu Arg Asp Lys Lys Arg Lys Glu Glu 915 920 925

    Arg Ser Ser Trp Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Ser Gly 930 935 940

    Tyr Leu Ser Gln Val Ile His Lys Ile Thr Gln Leu Met Ile Lys Tyr 945 950 955 960

    Asn Ala Ile Val Leu Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly 965 970 975

    Arg Gln Lys Val Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Ala Leu 980 985 990

    Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Asp Ala Asn Glu 995 1000 1005

    Ile Gly Gly Leu Leu His Ala Tyr Gln Leu Thr Asn Asp Pro Lys 1010 1015 1020

    Leu Pro Asn Lys Asn Ser Lys Gln Ser Gly Phe Leu Phe Tyr Val 1025 1030 1035

    Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val Thr Gly Phe Val 1040 1045 1050

    Asn Leu Leu Asp Thr Arg Tyr Glu Asn Val Ala Lys Ala Gln Ala 1055 1060 1065

    Phe Phe Lys Lys Phe Asp Ser Ile Arg Tyr Asn Lys Glu Tyr Asp 1070 1075 1080

    Arg Phe Glu Phe Lys Phe Asp Tyr Ser Asn Phe Thr Ala Lys Ala 1085 1090 1095

    Glu Asp Thr Arg Thr Gln Trp Thr Leu Cys Thr Tyr Gly Thr Arg 1100 1105 1110

    Ile Glu Thr Phe Arg Asn Ala Glu Lys Asn Ser Asn Trp Asp Ser 1115 1120 1125

    Arg Glu Ile Asp Leu Thr Thr Glu Trp Lys Thr Leu Phe Thr Gln 1130 1135 1140

    His Asn Ile Pro Leu Asn Ala Asn Leu Lys Glu Ala Ile Leu Leu 1145 1150 1155

    Gln Ala Asn Lys Asn Phe Tyr Thr Asp Ile Leu His Leu Met Lys 1160 1165 1170

    Leu Thr Leu Gln Met Arg Asn Ser Val Thr Gly Thr Asp Ile Asp 1175 1180 1185

    Tyr Met Val Ser Pro Val Ala Asn Glu Cys Gly Glu Phe Phe Asp 1190 1195 1200

    Ser Arg Lys Val Lys Glu Gly Leu Pro Val Asn Ala Asp Ala Asn 1205 1210 1215

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Leu Ala Gln Gln 1220 1225 1230

    Ile Lys Asn Ala Asn Asp Leu Ser Asp Val Lys Leu Ala Ile Thr

    1235

    1240

    1245

    Asn Lys Glu Trp Leu Gln Phe Ala Gln Lys Lys Gln Tyr Leu Lys 1250 1255 1260

    Asp <210> 88 <211> 1264 <212> PRT <213> Moraxella caprae <400> 88

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Met 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met Tyr Gln Lys 35 40 45

    Val Lys Ala Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Gly Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly 100 105 110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Thr Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Ala Thr 195 200 205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Arg Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met

    290

    295

    300

    Gly Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys 325 330 335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Ala Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe 545 550 555 560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn 565 570 575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Ile Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Asn Val Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met Leu Pro Lys Val Phe 625 630 635 640

    Phe Ala Lys Ser Asn Leu Asp Tyr Tyr Asn Pro Ser Ala Glu Leu Leu 645 650 655

    Asp Lys Tyr Ala Gln Gly Thr His Lys Lys Gly Asn Asn Phe Asn Leu 660 665 670

    Lys Asp Cys His Ala Leu Ile Asp Phe Phe Lys Ala Gly Ile Asn Lys 675 680 685

    His Pro Glu Trp Gln His Phe Gly Phe Lys Phe Ser Pro Thr Ser Ser 690 695 700

    Tyr Gln Asp Leu Ser Asp Phe Tyr Arg Glu Val Glu Pro Gln Gly Tyr 705 710 715 720

    Gln Val Lys Phe Val Asp Ile Asn Ala Asp Tyr Ile Asn Glu Leu Val 725 730 735

    Glu Gln Gly Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 740 745 750

    Pro Lys Ala His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala 755 760 765

    Leu Phe Ser Lys Asp Asn Leu Ala Asn Pro Ile Tyr Lys Leu Asn Gly 770 775 780

    Glu Ala Gln Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr 785 790 795 800

    Thr Ile His Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn 805 810 815

    Pro Lys Lys Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr 820 825 830

    Thr Gln Asp Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly 835 840 845

    Val Gln Gly Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser 850 855 860

    Ile Gln Gln Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu 865 870 875 880

    Arg His Leu Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu 885 890 895

    Glu Gln Arg Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr 900 905 910

    Gln Met Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu 915 920 925

    Arg Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu 930 935 940

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln Leu 945 950 955 960

    Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly 965 970 975

    Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr Gln Asn Phe 980 985 990

    Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val Leu Lys Asp Glu 995 1000 1005

    Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala Leu Gln Leu Thr

    1010

    1015

    1020

    Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys Gln Thr Gly Phe 1025 1030 1035

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Glu 1040 1045 1050

    Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr Glu Asn Ile Ala 1055 1060 1065

    Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys Ile Cys Tyr Asn 1070 1075 1080

    Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp Tyr Ala Lys Phe 1085 1090 1095

    Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp Lys Ile Cys Ser 1100 1105 1110

    His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr Ala Asn Gln Asn 1115 1120 1125

    Lys Gly Ala Thr Lys Gly Ile Asn Val Asn Asp Glu Leu Lys Ser 1130 1135 1140

    Leu Phe Ala Arg His His Ile Asn Asp Lys Gln Pro Asn Leu Val 1145 1150 1155

    Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe His Lys Ser Leu 1160 1165 1170

    Ile Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg Tyr Ser Asn Ala 1175 1180 1185

    Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val Ala Asn Asp Glu 1190 1195 1200

    Gly Met Phe Phe Asn Ser Ala Leu Ala Asp Asp Thr Gln Pro Gln 1205 1210 1215

    Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu 1220 1225 1230

    Trp Val Leu Glu Gln Ile Lys Asn Ser Asp Asp Leu Asn Lys Val 1235 1240 1245

    Lys Leu Ala Ile Asp Asn Gln Thr Trp Leu Asn Phe Ala Gln Asn 1250 1255 1260

    Arg <210> 89 <211> 1263 <212> PRT <213> Leptospira inadai <400> 89

    Met Glu Asp Tyr Ser Gly Phe Val Asn Ile Tyr Ser Ile Gln Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu His Ile Glu 20 25 30

    Lys Lys Gly Phe Leu Lys Lys Asp Lys Ile Arg Ala Glu Asp Tyr Lys 35 40 45

    Ala Val Lys Lys Ile Ile Asp Lys Tyr His Arg Ala Tyr Ile Glu Glu

    Val Phe Asp Ser Val Leu His Gln Lys Lys Lys Lys Asp Lys Thr Arg 65 70 75 80

    Phe Ser Thr Gln Phe Ile Lys Glu Ile Lys Glu Phe Ser Glu Leu Tyr 85 90 95

    Tyr Lys Thr Glu Lys Asn Ile Pro Asp Lys Glu Arg Leu Glu Ala Leu 100 105 110

    Ser Glu Lys Leu Arg Lys Met Leu Val Gly Ala Phe Lys Gly Glu Phe 115 120 125

    Ser Glu Glu Val Ala Glu Lys Tyr Lys Asn Leu Phe Ser Lys Glu Leu 130 135 140

    Ile Arg Asn Glu Ile Glu Lys Phe Cys Glu Thr Asp Glu Glu Arg Lys 145 150 155 160

    Gln Val Ser Asn Phe Lys Ser Phe Thr Thr Tyr Phe Thr Gly Phe His 165 170 175

    Ser Asn Arg Gln Asn Ile Tyr Ser Asp Glu Lys Lys Ser Thr Ala Ile 180 185 190

    Gly Tyr Arg Ile Ile His Gln Asn Leu Pro Lys Phe Leu Asp Asn Leu 195 200 205

    Lys Ile Ile Glu Ser Ile Gln Arg Arg Phe Lys Asp Phe Pro Trp Ser 210 215 220

    Asp Leu Lys Lys Asn Leu Lys Lys Ile Asp Lys Asn Ile Lys Leu Thr 225 230 235 240

    Glu Tyr Phe Ser Ile Asp Gly Phe Val Asn Val Leu Asn Gln Lys Gly 245 250 255

    Ile Asp Ala Tyr Asn Thr Ile Leu Gly Gly Lys Ser Glu Glu Ser Gly 260 265 270

    Glu Lys Ile Gln Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Arg Gln Lys 275 280 285

    Asn Asn Ile Asp Arg Lys Asn Leu Pro Asn Val Lys Ile Leu Phe Lys 290 295 300

    Gln Ile Leu Gly Asp Arg Glu Thr Lys Ser Phe Ile Pro Glu Ala Phe 305 310 315 320

    Pro Asp Asp Gln Ser Val Leu Asn Ser Ile Thr Glu Phe Ala Lys Tyr 325 330 335

    Leu Lys Leu Asp Lys Lys Lys Lys Ser Ile Ile Ala Glu Leu Lys Lys 340 345 350

    Phe Leu Ser Ser Phe Asn Arg Tyr Glu Leu Asp Gly Ile Tyr Leu Ala 355 360 365

    Asn Asp Asn Ser Leu Ala Ser Ile Ser Thr Phe Leu Phe Asp Asp Trp 370 375 380

    Ser Phe Ile Lys Lys Ser Val Ser Phe Lys Tyr Asp Glu Ser Val Gly 385 390 395 400

    Asp Pro Lys Lys Lys Ile Lys Ser Pro Leu Lys Tyr Glu Lys Glu Lys 405 410 415

    Glu Lys Trp Leu Lys Gln Lys Tyr Tyr Thr Ile Ser Phe Leu Asn Asp 420 425 430

    Ala Ile Glu Ser Tyr Ser Lys Ser Gln Asp Glu Lys Arg Val Lys Ile 435 440 445

    Arg Leu Glu Ala Tyr Phe Ala Glu Phe Lys Ser Lys Asp Asp Ala Lys 450 455 460

    Lys Gln Phe Asp Leu Leu Glu Arg Ile Glu Glu Ala Tyr Ala Ile Val 465 470 475 480

    Glu Pro Leu Leu Gly Ala Glu Tyr Pro Arg Asp Arg Asn Leu Lys Ala 485 490 495

    Asp Lys Lys Glu Val Gly Lys Ile Lys Asp Phe Leu Asp Ser Ile Lys 500 505 510

    Ser Leu Gln Phe Phe Leu Lys Pro Leu Leu Ser Ala Glu Ile Phe Asp 515 520 525

    Glu Lys Asp Leu Gly Phe Tyr Asn Gln Leu Glu Gly Tyr Tyr Glu Glu 530 535 540

    Ile Asp Ser Ile Gly His Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr 545 550 555 560

    Gly Lys Ile Tyr Ser Lys Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser 565 570 575

    Thr Leu Leu Lys Gly Trp Asp Glu Asn Arg Glu Val Ala Asn Leu Cys 580 585 590

    Val Ile Phe Arg Glu Asp Gln Lys Tyr Tyr Leu Gly Val Met Asp Lys 595 600 605

    Glu Asn Asn Thr Ile Leu Ser Asp Ile Pro Lys Val Lys Pro Asn Glu 610 615 620

    Leu Phe Tyr Glu Lys Met Val Tyr Lys Leu Ile Pro Thr Pro His Met 625 630 635 640

    Gln Leu Pro Arg Ile Ile Phe Ser Ser Asp Asn Leu Ser Ile Tyr Asn 645 650 655

    Pro Ser Lys Ser Ile Leu Lys Ile Arg Glu Ala Lys Ser Phe Lys Glu 660 665 670

    Gly Lys Asn Phe Lys Leu Lys Asp Cys His Lys Phe Ile Asp Phe Tyr 675 680 685

    Lys Glu Ser Ile Ser Lys Asn Glu Asp Trp Ser Arg Phe Asp Phe Lys 690 695 700

    Phe Ser Lys Thr Ser Ser Tyr Glu Asn Ile Ser Glu Phe Tyr Arg Glu 705 710 715 720

    Val Glu Arg Gln Gly Tyr Asn Leu Asp Phe Lys Lys Val Ser Lys Phe 725 730 735

    Tyr Ile Asp Ser Leu Val Glu Asp Gly Lys Leu Tyr Leu Phe Gln Ile 740 745 750

    Tyr Asn Lys Asp Phe Ser Ile Phe Ser Lys Gly Lys Pro Asn Leu His 755 760 765

    Thr Ile Tyr Phe Arg Ser Leu Phe Ser Lys Glu Asn Leu Lys Asp Val

    770

    775

    780

    Cys Leu Lys Leu Asn Gly Glu Ala Glu Met Phe Phe Arg Lys Lys Ser 785 790 795 800

    Ile Asn Tyr Asp Glu Lys Lys Lys Arg Glu Gly His His Pro Glu Leu 805 810 815

    Phe Glu Lys Leu Lys Tyr Pro Ile Leu Lys Asp Lys Arg Tyr Ser Glu 820 825 830

    Asp Lys Phe Gln Phe His Leu Pro Ile Ser Leu Asn Phe Lys Ser Lys 835 840 845

    Glu Arg Leu Asn Phe Asn Leu Lys Val Asn Glu Phe Leu Lys Arg Asn 850 855 860

    Lys Asp Ile Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu 865 870 875 880

    Tyr Leu Val Met Ile Asn Gln Lys Gly Glu Ile Leu Lys Gln Thr Leu 885 890 895

    Leu Asp Ser Met Gln Ser Gly Lys Gly Arg Pro Glu Ile Asn Tyr Lys 900 905 910

    Glu Lys Leu Gln Glu Lys Glu Ile Glu Arg Asp Lys Ala Arg Lys Ser 915 920 925

    Trp Gly Thr Val Glu Asn Ile Lys Glu Leu Lys Glu Gly Tyr Leu Ser 930 935 940

    Ile Val Ile His Gln Ile Ser Lys Leu Met Val Glu Asn Asn Ala Ile 945 950 955 960

    Val Val Leu Glu Asp Leu Asn Ile Gly Phe Lys Arg Gly Arg Gln Lys 965 970 975

    Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys 980 985 990

    Leu Asn Phe Leu Val Phe Lys Glu Asn Lys Pro Thr Glu Pro Gly Gly 995 1000 1005

    Val Leu Lys Ala Tyr Gln Leu Thr Asp Glu Phe Gln Ser Phe Glu 1010 1015 1020

    Lys Leu Ser Lys Gln Thr Gly Phe Leu Phe Tyr Val Pro Ser Trp 1025 1030 1035

    Asn Thr Ser Lys Ile Asp Pro Arg Thr Gly Phe Ile Asp Phe Leu 1040 1045 1050

    His Pro Ala Tyr Glu Asn Ile Glu Lys Ala Lys Gln Trp Ile Asn 1055 1060 1065

    Lys Phe Asp Ser Ile Arg Phe Asn Ser Lys Met Asp Trp Phe Glu 1070 1075 1080

    Phe Thr Ala Asp Thr Arg Lys Phe Ser Glu Asn Leu Met Leu Gly 1085 1090 1095

    Lys Asn Arg Val Trp Val Ile Cys Thr Thr Asn Val Glu Arg Tyr 1100 1105 1110

    Phe Thr Ser Lys Thr Ala Asn Ser Ser Ile Gln Tyr Asn Ser Ile 1115 1120 1125

    Gln Ile Thr Glu Lys Leu Lys Glu Leu Phe Val Asp Ile Pro Phe 1130 1135 1140

    Ser Asn Gly Gln Asp Leu Lys Pro Glu Ile Leu Arg Lys Asn Asp 1145 1150 1155

    Ala Val Phe Phe Lys Ser Leu Leu Phe Tyr Ile Lys Thr Thr Leu 1160 1165 1170

    Ser Leu Arg Gln Asn Asn Gly Lys Lys Gly Glu Glu Glu Lys Asp 1175 1180 1185

    Phe Ile Leu Ser Pro Val Val Asp Ser Lys Gly Arg Phe Phe Asn 1190 1195 1200

    Ser Leu Glu Ala Ser Asp Asp Glu Pro Lys Asp Ala Asp Ala Asn 1205 1210 1215

    Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Met Asn Leu Leu Val 1220 1225 1230

    Leu Asn Glu Thr Lys Glu Glu Asn Leu Ser Arg Pro Lys Trp Lys 1235 1240 1245

    Ile Lys Asn Lys Asp Trp Leu Glu Phe Val Trp Glu Arg Asn Arg 1250 1255 1260 <210> 90 <211> 1262 <212> PRT <213> Porphyromonas crevioricanis <400> 90

    Met Pro Trp Ile Asp Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser

    1 5 10 15

    Lys Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn 20 25 30

    Ile Glu Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser 35 40 45

    Tyr Arg Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile 50 55 60

    Asp Ser Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile 65 70 75 80

    Lys Ala Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg 85 90 95

    Thr Glu Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg 100 105 110

    Gly Leu Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn 115 120 125

    Thr Val Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile 130 135 140

    Lys Glu Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu 145 150 155 160

    Pro Phe Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser 165 170 175

    Phe Thr Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr 180 185 190

    Ser Thr Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu 195 200 205

    Asn Leu Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys 210 215 220

    Glu Pro Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala 225 230 235 240

    Gly Gly Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu 245 250 255

    Asn Tyr Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn 260 265 270

    Ala Leu Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly 275 280 285

    Leu Asn Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp 290 295 300

    Arg Leu Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg 305 310 315 320

    Glu Gln Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu 325 330 335

    Leu Arg Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu 340 345 350

    Gly Arg Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser 355 360 365

    Arg Ile Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys 370 375 380

    Met Leu Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr 385 390 395 400

    Asp His Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp 405 410 415

    Arg Ile Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu 420 425 430

    Asn Ser Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp 435 440 445

    Thr Tyr Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser 450 455 460

    Asn Leu Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu 465 470 475 480

    Leu Ser Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp 485 490 495

    Asn Val Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln 500 505 510

    Arg Phe Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp 515 520 525

    Glu Arg Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln 530 535 540

    Val Ile Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro

    545

    550

    555

    560

    Tyr Ser Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu 565 570 575

    Ser Gly Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu 580 585 590

    Arg Lys Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys 595 600 605

    Arg Ser Phe Glu Asn Lys Val Leu Pro Glu Tyr Lys Glu Gly Glu Pro 610 615 620

    Tyr Phe Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met 625 630 635 640

    Leu Pro Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Glu Pro 645 650 655

    Ser Pro Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly 660 665 670

    Asp Thr Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys 675 680 685

    His Ser Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe 690 695 700

    Ser Asp Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val 705 710 715 720

    Glu Asp Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr 725 730 735

    Val Tyr Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr 740 745 750

    Asn Lys Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr 755 760 765

    Leu Tyr Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile 770 775 780

    Tyr Lys Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu 785 790 795 800

    Lys Asn Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys 805 810 815

    Ser Arg Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val 820 825 830

    Lys Asp Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile 835 840 845

    Thr Met Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val 850 855 860

    Asn Ala His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly 885 890 895

    Thr Ile Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr 900 905 910

    His Asp Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg 915 920 925

    Asn Trp Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu 930 935 940

    Ser Gln Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala 945 950 955 960

    Val Val Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln 965 970 975

    Lys Val Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp 980 985 990

    Lys Leu Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly 995 1000 1005

    Gly Leu Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe 1010 1015 1020

    Lys Glu Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala 1025 1030 1035

    Trp Asn Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu 1040 1045 1050

    Phe His Ala Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe 1055 1060 1065

    Gln Lys Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe 1070 1075 1080

    Glu Phe Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly 1085 1090 1095

    Ser Arg Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys 1100 1105 1110

    Asn Phe Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu 1115 1120 1125

    Phe Ala Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu 1130 1135 1140

    Ile Asp Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys 1145 1150 1155

    Gln Lys Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr 1160 1165 1170

    Val Gln Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu 1175 1180 1185

    Ile Ser Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg 1190 1195 1200

    Glu Gly Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala 1205 1210 1215

    Tyr Asn Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg 1220 1225 1230

    Gln Thr Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys 1235 1240 1245

    Glu Trp Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp

    1250

    1255

    1260 <210> 91 <211> 1262 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Bacteroidetes oral taxon 274 sequence <400> 91

    Met Arg Lys Phe Asn Glu Phe Val Gly Leu Tyr Pro Ile Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu His Ile Gln 20 25 30

    Arg Asn Lys Leu Leu Glu His Asp Ala Val Arg Ala Asp Asp Tyr Val 35 40 45

    Lys Val Lys Lys Ile Ile Asp Lys Tyr His Lys Cys Leu Ile Asp Glu 50 55 60

    Ala Leu Ser Gly Phe Thr Phe Asp Thr Glu Ala Asp Gly Arg Ser Asn 65 70 75 80

    Asn Ser Leu Ser Glu Tyr Tyr Leu Tyr Tyr Asn Leu Lys Lys Arg Asn 85 90 95

    Glu Gln Glu Gln Lys Thr Phe Lys Thr Ile Gln Asn Asn Leu Arg Lys 100 105 110

    Gln Ile Val Asn Lys Leu Thr Gln Ser Glu Lys Tyr Lys Arg Ile Asp 115 120 125

    Lys Lys Glu Leu Ile Thr Thr Asp Leu Pro Asp Phe Leu Thr Asn Glu 130 135 140

    Ser Glu Lys Glu Leu Val Glu Lys Phe Lys Asn Phe Thr Thr Tyr Phe 145 150 155 160

    Thr Glu Phe His Lys Asn Arg Lys Asn Met Tyr Ser Lys Glu Glu Lys 165 170 175

    Ser Thr Ala Ile Ala Phe Arg Leu Ile Asn Glu Asn Leu Pro Lys Phe 180 185 190

    Val Asp Asn Ile Ala Ala Phe Glu Lys Val Val Ser Ser Pro Leu Ala 195 200 205

    Glu Lys Ile Asn Ala Leu Tyr Glu Asp Phe Lys Glu Tyr Leu Asn Val 210 215 220

    Glu Glu Ile Ser Arg Val Phe Arg Leu Asp Tyr Tyr Asp Glu Leu Leu 225 230 235 240

    Thr Gln Lys Gln Ile Asp Leu Tyr Asn Ala Ile Val Gly Gly Arg Thr 245 250 255

    Glu Glu Asp Asn Lys Ile Gln Ile Lys Gly Leu Asn Gln Tyr Ile Asn 260 265 270

    Glu Tyr Asn Gln Gln Gln Thr Asp Arg Ser Asn Arg Leu Pro Lys Leu 275 280 285

    Lys Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Ser Val Ser Trp 290 295 300

    Leu Pro Pro Lys Phe Asp Ser Asp Lys Asn Leu Leu Ile Lys Ile Lys

    305

    310

    315

    320

    Glu Cys Tyr Asp Ala Leu Ser Glu Lys Glu Lys Val Phe Asp Lys Leu 325 330 335

    Glu Ser Ile Leu Lys Ser Leu Ser Thr Tyr Asp Leu Ser Lys Ile Tyr 340 345 350

    Ile Ser Asn Asp Ser Gln Leu Ser Tyr Ile Ser Gln Lys Met Phe Gly 355 360 365

    Arg Trp Asp Ile Ile Ser Lys Ala Ile Arg Glu Asp Cys Ala Lys Arg 370 375 380

    Asn Pro Gln Lys Ser Arg Glu Ser Leu Glu Lys Phe Ala Glu Arg Ile 385 390 395 400

    Asp Lys Lys Leu Lys Thr Ile Asp Ser Ile Ser Ile Gly Asp Val Asp 405 410 415

    Glu Cys Leu Ala Gln Leu Gly Glu Thr Tyr Val Lys Arg Val Glu Asp 420 425 430

    Tyr Phe Val Ala Met Gly Glu Ser Glu Ile Asp Asp Glu Gln Thr Asp 435 440 445

    Thr Thr Ser Phe Lys Lys Asn Ile Glu Gly Ala Tyr Glu Ser Val Lys 450 455 460

    Glu Leu Leu Asn Asn Ala Asp Asn Ile Thr Asp Asn Asn Leu Met Gln 465 470 475 480

    Asp Lys Gly Asn Val Glu Lys Ile Lys Thr Leu Leu Asp Ala Ile Lys 485 490 495

    Asp Leu Gln Arg Phe Ile Lys Pro Leu Leu Gly Lys Gly Asp Glu Ala 500 505 510

    Asp Lys Asp Gly Val Phe Tyr Gly Glu Phe Thr Ser Leu Trp Thr Lys 515 520 525

    Leu Asp Gln Val Thr Pro Leu Tyr Asn Met Val Arg Asn Tyr Leu Thr 530 535 540

    Ser Lys Pro Tyr Ser Thr Lys Lys Ile Lys Leu Asn Phe Glu Asn Ser 545 550 555 560

    Thr Leu Met Asp Gly Trp Asp Leu Asn Lys Glu Pro Asp Asn Thr Thr 565 570 575

    Val Ile Phe Cys Lys Asp Gly Leu Tyr Tyr Leu Gly Ile Met Gly Lys 580 585 590

    Lys Tyr Asn Arg Val Phe Val Asp Arg Glu Asp Leu Pro His Asp Gly 595 600 605

    Glu Cys Tyr Asp Lys Met Glu Tyr Lys Leu Leu Pro Gly Ala Asn Lys 610 615 620

    Met Leu Pro Lys Val Phe Phe Ser Glu Thr Gly Ile Gln Arg Phe Leu 625 630 635 640

    Pro Ser Glu Glu Leu Leu Gly Lys Tyr Glu Arg Gly Thr His Lys Lys 645 650 655

    Gly Ala Gly Phe Asp Leu Gly Asp Cys Arg Ala Leu Ile Asp Phe Phe 660 665 670

    Lys Lys Ser Ile Glu Arg His Asp Asp Trp Lys Lys Phe Asp Phe Lys 675 680 685

    Phe Ser Asp Thr Ser Thr Tyr Gln Asp Ile Ser Glu Phe Tyr Arg Glu 690 695 700

    Val Glu Gln Gln Gly Tyr Lys Met Ser Phe Arg Lys Val Ser Val Asp 705 710 715 720

    Tyr Ile Lys Ser Leu Val Glu Glu Gly Lys Leu Tyr Leu Phe Gln Ile 725 730 735

    Tyr Asn Lys Asp Phe Ser Ala His Ser Lys Gly Thr Pro Asn Met His 740 745 750

    Thr Leu Tyr Trp Lys Met Leu Phe Asp Glu Glu Asn Leu Lys Asp Val 755 760 765

    Val Tyr Lys Leu Asn Gly Glu Ala Glu Val Phe Phe Arg Lys Ser Ser 770 775 780

    Ile Thr Val Gln Ser Pro Thr His Pro Ala Asn Ser Pro Ile Lys Asn 785 790 795 800

    Lys Asn Lys Asp Asn Gln Lys Lys Glu Ser Lys Phe Glu Tyr Asp Leu 805 810 815

    Ile Lys Asp Arg Arg Tyr Thr Val Asp Lys Phe Leu Phe His Val Pro 820 825 830

    Ile Thr Met Asn Phe Lys Ser Val Gly Gly Ser Asn Ile Asn Gln Leu 835 840 845

    Val Lys Arg His Ile Arg Ser Ala Thr Asp Leu His Ile Ile Gly Ile 850 855 860

    Asp Arg Gly Glu Arg His Leu Leu Tyr Leu Thr Val Ile Asp Ser Arg 865 870 875 880

    Gly Asn Ile Lys Glu Gln Phe Ser Leu Asn Glu Ile Val Asn Glu Tyr 885 890 895

    Asn Gly Asn Thr Tyr Arg Thr Asp Tyr His Glu Leu Leu Asp Thr Arg 900 905 910

    Glu Gly Glu Arg Thr Glu Ala Arg Arg Asn Trp Gln Thr Ile Gln Asn 915 920 925

    Ile Arg Glu Leu Lys Glu Gly Tyr Leu Ser Gln Val Ile His Lys Ile 930 935 940

    Ser Glu Leu Ala Ile Lys Tyr Asn Ala Val Ile Val Leu Glu Asp Leu 945 950 955 960

    Asn Phe Gly Phe Met Arg Ser Arg Gln Lys Val Glu Lys Gln Val Tyr 965 970 975

    Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp 980 985 990

    Lys Lys Lys Pro Val Ala Glu Thr Gly Gly Leu Leu Arg Ala Tyr Gln 995 1000 1005

    Leu Thr Gly Glu Phe Glu Ser Phe Lys Thr Leu Gly Lys Gln Ser 1010 1015 1020

    Gly Ile Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp

    1025 1030 1035

    Pro Val Thr Gly Phe Val Asn Leu Phe Asp Thr His Tyr Glu Asn 1040 1045 1050

    Ile Glu Lys Ala Lys Val Phe Phe Asp Lys Phe Lys Ser Ile Arg 1055 1060 1065

    Tyr Asn Ser Asp Lys Asp Trp Phe Glu Phe Val Val Asp Asp Tyr 1070 1075 1080

    Thr Arg Phe Ser Pro Lys Ala Glu Gly Thr Arg Arg Asp Trp Thr 1085 1090 1095

    Ile Cys Thr Gln Gly Lys Arg Ile Gln Ile Cys Arg Asn His Gln 1100 1105 1110

    Arg Asn Asn Glu Trp Glu Gly Gln Glu Ile Asp Leu Thr Lys Ala 1115 1120 1125

    Phe Lys Glu His Phe Glu Ala Tyr Gly Val Asp Ile Ser Lys Asp 1130 1135 1140

    Leu Arg Glu Gln Ile Asn Thr Gln Asn Lys Lys Glu Phe Phe Glu 1145 1150 1155

    Glu Leu Leu Arg Leu Leu Arg Leu Thr Leu Gln Met Arg Asn Ser 1160 1165 1170

    Met Pro Ser Ser Asp Ile Asp Tyr Leu Ile Ser Pro Val Ala Asn 1175 1180 1185

    Asp Thr Gly Cys Phe Phe Asp Ser Arg Lys Gln Ala Glu Leu Lys 1190 1195 1200

    Glu Asn Ala Val Leu Pro Met Asn Ala Asp Ala Asn Gly Ala Tyr

    1205 1210 1215 Asn Ile Ala Arg Lys Gly Leu Leu Ala Ile Arg Lys Met Lys Gln 1220 1225 1230 Glu Glu Asn Asp Ser Ala Lys Ile Ser Leu Ala Ile Ser Asn Lys 1235 1240 1245 Glu Trp Leu Lys Phe Ala Gln Thr Lys Pro Tyr Leu Glu Asp 1250 1255 1260

    <210> 92 <211> 1260 <212> PRT <213> Porphyromonas crevioricanis <400> 92

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Met Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg

    805

    810

    815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu His Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Val Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 93 <211> 1260 <212> PRT <213> Porphyromonas crevioricanis <400> 93

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys

    580

    585

    590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Val Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg His Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Ala Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp

    1250 1255 1260 <210> 94 <211> 1260 <212> PRT <213> Porphyromonas cansulci <400> 94

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile

    355

    360

    365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Val Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Ala Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe

    1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 95 <211> 1259 <212> PRT <213> Synergistes jonesii <400> 95

    Met Ala Asn Ser Leu Lys Asp Phe Thr Asn Ile Tyr Gln Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Glu Glu His Ile 20 25 30

    Asn Arg Lys Leu Ile Ile Met His Asp Glu Lys Arg Gly Glu Asp Tyr 35 40 45

    Lys Ser Val Thr Lys Leu Ile Asp Asp Tyr His Arg Lys Phe Ile His 50 55 60

    Glu Thr Leu Asp Pro Ala His Phe Asp Trp Asn Pro Leu Ala Glu Ala 65 70 75 80

    Leu Ile Gln Ser Gly Ser Lys Asn Asn Lys Ala Leu Pro Ala Glu Gln 85 90 95

    Lys Glu Met Arg Glu Lys Ile Ile Ser Met Phe Thr Ser Gln Ala Val 100 105 110

    Tyr Lys Lys Leu Phe Lys Lys Glu Leu Phe Ser Glu Leu Leu Pro Glu 115 120 125

    Met Ile Lys Ser Glu Leu Val Ser Asp Leu Glu Lys Gln Ala Gln Leu

    130

    135

    140

    Asp Ala Val Lys Ser Phe Asp Lys Phe Ser Thr Tyr Phe Thr Gly Phe 145 150 155 160

    His Glu Asn Arg Lys Asn Ile Tyr Ser Lys Lys Asp Thr Ser Thr Ser 165 170 175

    Ile Ala Phe Arg Ile Val His Gln Asn Phe Pro Lys Phe Leu Ala Asn 180 185 190

    Val Arg Ala Tyr Thr Leu Ile Lys Glu Arg Ala Pro Glu Val Ile Asp 195 200 205

    Lys Ala Gln Lys Glu Leu Ser Gly Ile Leu Gly Gly Lys Thr Leu Asp 210 215 220

    Asp Ile Phe Ser Ile Glu Ser Phe Asn Asn Val Leu Thr Gln Asp Lys 225 230 235 240

    Ile Asp Tyr Tyr Asn Gln Ile Ile Gly Gly Val Ser Gly Lys Ala Gly 245 250 255

    Asp Lys Lys Leu Arg Gly Val Asn Glu Phe Ser Asn Leu Tyr Arg Gln 260 265 270

    Gln His Pro Glu Val Ala Ser Leu Arg Ile Lys Met Val Pro Leu Tyr 275 280 285

    Lys Gln Ile Leu Ser Asp Arg Thr Thr Leu Ser Phe Val Pro Glu Ala 290 295 300

    Leu Lys Asp Asp Glu Gln Ala Ile Asn Ala Val Asp Gly Leu Arg Ser 305 310 315 320

    Glu Leu Glu Arg Asn Asp Ile Phe Asn Arg Ile Lys Arg Leu Phe Gly 325 330 335

    Lys Asn Asn Leu Tyr Ser Leu Asp Lys Ile Trp Ile Lys Asn Ser Ser 340 345 350

    Ile Ser Ala Phe Ser Asn Glu Leu Phe Lys Asn Trp Ser Phe Ile Glu 355 360 365

    Asp Ala Leu Lys Glu Phe Lys Glu Asn Glu Phe Asn Gly Ala Arg Ser 370 375 380

    Ala Gly Lys Lys Ala Glu Lys Trp Leu Lys Ser Lys Tyr Phe Ser Phe 385 390 395 400

    Ala Asp Ile Asp Ala Ala Val Lys Ser Tyr Ser Glu Gln Val Ser Ala 405 410 415

    Asp Ile Ser Ser Ala Pro Ser Ala Ser Tyr Phe Ala Lys Phe Thr Asn 420 425 430

    Leu Ile Glu Thr Ala Ala Glu Asn Gly Arg Lys Phe Ser Tyr Phe Ala 435 440 445

    Ala Glu Ser Lys Ala Phe Arg Gly Asp Asp Gly Lys Thr Glu Ile Ile 450 455 460

    Lys Ala Tyr Leu Asp Ser Leu Asn Asp Ile Leu His Cys Leu Lys Pro 465 470 475 480

    Phe Glu Thr Glu Asp Ile Ser Asp Ile Asp Thr Glu Phe Tyr Ser Ala 485 490 495

    Phe Ala Glu Ile Tyr Asp Ser Val Lys Asp Val Ile Pro Val Tyr Asn 500 505 510

    Ala Val Arg Asn Tyr Thr Thr Gln Lys Pro Phe Ser Thr Glu Lys Phe 515 520 525

    Lys Leu Asn Phe Glu Asn Pro Ala Leu Ala Lys Gly Trp Asp Lys Asn 530 535 540

    Lys Glu Gln Asn Asn Thr Ala Ile Ile Leu Met Lys Asp Gly Lys Tyr 545 550 555 560

    Tyr Leu Gly Val Ile Asp Lys Asn Asn Lys Leu Arg Ala Asp Asp Leu 565 570 575

    Ala Asp Asp Gly Ser Ala Tyr Gly Tyr Met Lys Met Asn Tyr Lys Phe 580 585 590

    Ile Pro Thr Pro His Met Glu Leu Pro Lys Val Phe Leu Pro Lys Arg 595 600 605

    Ala Pro Lys Arg Tyr Asn Pro Ser Arg Glu Ile Leu Leu Ile Lys Glu 610 615 620

    Asn Lys Thr Phe Ile Lys Asp Lys Asn Phe Asn Arg Thr Asp Cys His 625 630 635 640

    Lys Leu Ile Asp Phe Phe Lys Asp Ser Ile Asn Lys His Lys Asp Trp 645 650 655

    Arg Thr Phe Gly Phe Asp Phe Ser Asp Thr Asp Ser Tyr Glu Asp Ile 660 665 670

    Ser Asp Phe Tyr Met Glu Val Gln Asp Gln Gly Tyr Lys Leu Thr Phe 675 680 685

    Thr Arg Leu Ser Ala Glu Lys Ile Asp Lys Trp Val Glu Glu Gly Arg 690 695 700

    Leu Phe Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Asp Gly Ala Gln 705 710 715 720

    Gly Ser Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asp Val Val Leu Lys Leu Asn Gly Glu Ala Glu Leu 740 745 750

    Phe Phe Arg Arg Lys Ser Ile Asp Lys Pro Ala Val His Ala Lys Gly 755 760 765

    Ser Met Lys Val Asn Arg Arg Asp Ile Asp Gly Asn Pro Ile Asp Glu 770 775 780

    Gly Thr Tyr Val Glu Ile Cys Gly Tyr Ala Asn Gly Lys Arg Asp Met 785 790 795 800

    Ala Ser Leu Asn Ala Gly Ala Arg Gly Leu Ile Glu Ser Gly Leu Val 805 810 815

    Arg Ile Thr Glu Val Lys His Glu Leu Val Lys Asp Lys Arg Tyr Thr 820 825 830

    Ile Asp Lys Tyr Phe Phe His Val Pro Phe Thr Ile Asn Phe Lys Ala 835 840 845

    Gln Gly Gln Gly Asn Ile Asn Ser Asp Val Asn Leu Phe Leu Arg Asn

    850

    855

    860

    Asn Lys Asp Val Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu 865 870 875 880

    Val Tyr Val Ser Leu Ile Asp Arg Asp Gly His Ile Lys Leu Gln Lys 885 890 895

    Asp Phe Asn Ile Ile Gly Gly Met Asp Tyr His Ala Lys Leu Asn Gln 900 905 910

    Lys Glu Lys Glu Arg Asp Thr Ala Arg Lys Ser Trp Lys Thr Ile Gly 915 920 925

    Thr Ile Lys Glu Leu Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu 930 935 940

    Ile Val Arg Leu Ala Val Asp Asn Asn Ala Val Ile Val Met Glu Asp 945 950 955 960

    Leu Asn Ile Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 965 970 975

    Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val 980 985 990

    Phe Lys Asp Ala Gly Tyr Asp Ala Pro Cys Gly Ile Leu Lys Gly Leu 995 1000 1005

    Gln Leu Thr Glu Lys Phe Glu Ser Phe Thr Lys Leu Gly Lys Gln 1010 1015 1020

    Cys Gly Ile Ile Phe Tyr Ile Pro Ala Gly Tyr Thr Ser Lys Ile 1025 1030 1035

    Asp Pro Thr Thr Gly Phe Val Asn Leu Phe Asn Ile Asn Asp Val 1040 1045 1050

    Ser Ser Lys Glu Lys Gln Lys Asp Phe Ile Gly Lys Leu Asp Ser 1055 1060 1065

    Ile Arg Phe Asp Ala Lys Arg Asp Met Phe Thr Phe Glu Phe Asp 1070 1075 1080

    Tyr Asp Lys Phe Arg Thr Tyr Gln Thr Ser Tyr Arg Lys Lys Trp 1085 1090 1095

    Ala Val Trp Thr Asn Gly Lys Arg Ile Val Arg Glu Lys Asp Lys 1100 1105 1110

    Asp Gly Lys Phe Arg Met Asn Asp Arg Leu Leu Thr Glu Asp Met 1115 1120 1125

    Lys Asn Ile Leu Asn Lys Tyr Ala Leu Ala Tyr Lys Ala Gly Glu 1130 1135 1140

    Asp Ile Leu Pro Asp Val Ile Ser Arg Asp Lys Ser Leu Ala Ser 1145 1150 1155

    Glu Ile Phe Tyr Val Phe Lys Asn Thr Leu Gln Met Arg Asn Ser 1160 1165 1170

    Lys Arg Asp Thr Gly Glu Asp Phe Ile Ile Ser Pro Val Leu Asn 1175 1180 1185

    Ala Lys Gly Arg Phe Phe Asp Ser Arg Lys Thr Asp Ala Ala Leu 1190 1195 1200

    Pro Ile Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys 1205 1210 1215 Gly Ser Leu Val Leu Asp Ala Ile Asp Glu Lys Leu Lys Glu Asp 1220 1225 1230 Gly Arg Ile Asp Tyr Lys Asp Met Ala Val Ser Asn Pro Lys Trp 1235 1240 1245

    Phe Glu Phe Met Gln Thr Arg Lys Phe Asp Phe 1250 1255 <210> 96 <211> 1257 <212> PRT <213> Prevotella bryantii <400> 96

    Met Gln Ile Asn Asn Leu Lys Ile Ile Tyr Met Lys Phe Thr Asp Phe 1 5 10 15

    Thr Gly Leu Tyr Ser Leu Ser Lys Thr Leu Arg Phe Glu Leu Lys Pro 20 25 30

    Ile Gly Lys Thr Leu Glu Asn Ile Lys Lys Ala Gly Leu Leu Glu Gln 35 40 45

    Asp Gln His Arg Ala Asp Ser Tyr Lys Lys Val Lys Lys Ile Ile Asp 50 55 60

    Glu Tyr His Lys Ala Phe Ile Glu Lys Ser Leu Ser Asn Phe Glu Leu 65 70 75 80

    Lys Tyr Gln Ser Glu Asp Lys Leu Asp Ser Leu Glu Glu Tyr Leu Met 85 90 95

    Tyr Tyr Ser Met Lys Arg Ile Glu Lys Thr Glu Lys Asp Lys Phe Ala 100 105 110

    Lys Ile Gln Asp Asn Leu Arg Lys Gln Ile Ala Asp His Leu Lys Gly 115 120 125

    Asp Glu Ser Tyr Lys Thr Ile Phe Ser Lys Asp Leu Ile Arg Lys Asn 130 135 140

    Leu Pro Asp Phe Val Lys Ser Asp Glu Glu Arg Thr Leu Ile Lys Glu 145 150 155 160

    Phe Lys Asp Phe Thr Thr Tyr Phe Lys Gly Phe Tyr Glu Asn Arg Glu 165 170 175

    Asn Met Tyr Ser Ala Glu Asp Lys Ser Thr Ala Ile Ser His Arg Ile 180 185 190

    Ile His Glu Asn Leu Pro Lys Phe Val Asp Asn Ile Asn Ala Phe Ser 195 200 205

    Lys Ile Ile Leu Ile Pro Glu Leu Arg Glu Lys Leu Asn Gln Ile Tyr 210 215 220

    Gln Asp Phe Glu Glu Tyr Leu Asn Val Glu Ser Ile Asp Glu Ile Phe 225 230 235 240

    His Leu Asp Tyr Phe Ser Met Val Met Thr Gln Lys Gln Ile Glu Val 245 250 255

    Tyr Asn Ala Ile Ile Gly Gly Lys Ser Thr Asn Asp Lys Lys Ile Gln 260 265 270

    Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Cys 275 280 285

    Lys Leu Pro Lys Leu Lys Leu Leu Phe Lys Gln Ile Leu Ser Asp Arg 290 295 300

    Ile Ala Ile Ser Trp Leu Pro Asp Asn Phe Lys Asp Asp Gln Glu Ala 305 310 315 320

    Leu Asp Ser Ile Asp Thr Cys Tyr Lys Asn Leu Leu Asn Asp Gly Asn 325 330 335

    Val Leu Gly Glu Gly Asn Leu Lys Leu Leu Leu Glu Asn Ile Asp Thr 340 345 350

    Tyr Asn Leu Lys Gly Ile Phe Ile Arg Asn Asp Leu Gln Leu Thr Asp 355 360 365

    Ile Ser Gln Lys Met Tyr Ala Ser Trp Asn Val Ile Gln Asp Ala Val 370 375 380

    Ile Leu Asp Leu Lys Lys Gln Val Ser Arg Lys Lys Lys Glu Ser Ala 385 390 395 400

    Glu Asp Tyr Asn Asp Arg Leu Lys Lys Leu Tyr Thr Ser Gln Glu Ser 405 410 415

    Phe Ser Ile Gln Tyr Leu Asn Asp Cys Leu Arg Ala Tyr Gly Lys Thr 420 425 430

    Glu Asn Ile Gln Asp Tyr Phe Ala Lys Leu Gly Ala Val Asn Asn Glu 435 440 445

    His Glu Gln Thr Ile Asn Leu Phe Ala Gln Val Arg Asn Ala Tyr Thr 450 455 460

    Ser Val Gln Ala Ile Leu Thr Thr Pro Tyr Pro Glu Asn Ala Asn Leu 465 470 475 480

    Ala Gln Asp Lys Glu Thr Val Ala Leu Ile Lys Asn Leu Leu Asp Ser 485 490 495

    Leu Lys Arg Leu Gln Arg Phe Ile Lys Pro Leu Leu Gly Lys Gly Asp 500 505 510

    Glu Ser Asp Lys Asp Glu Arg Phe Tyr Gly Asp Phe Thr Pro Leu Trp 515 520 525

    Glu Thr Leu Asn Gln Ile Thr Pro Leu Tyr Asn Met Val Arg Asn Tyr 530 535 540

    Met Thr Arg Lys Pro Tyr Ser Gln Glu Lys Ile Lys Leu Asn Phe Glu 545 550 555 560

    Asn Ser Thr Leu Leu Gly Gly Trp Asp Leu Asn Lys Glu His Asp Asn 565 570 575

    Thr Ala Ile Ile Leu Arg Lys Asn Gly Leu Tyr Tyr Leu Ala Ile Met 580 585 590

    Lys Lys Ser Ala Asn Lys Ile Phe Asp Lys Asp Lys Leu Asp Asn Ser 595 600 605

    Gly Asp Cys Tyr Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn 610 615 620

    Lys Met Leu Pro Lys Val Phe Phe Ser Lys Ser Arg Ile Asp Glu Phe

    625

    630

    635

    640

    Lys Pro Ser Glu Asn Ile Ile Glu Asn Tyr Lys Lys Gly Thr His Lys 645 650 655

    Lys Gly Ala Asn Phe Asn Leu Ala Asp Cys His Asn Leu Ile Asp Phe 660 665 670

    Phe Lys Ser Ser Ile Ser Lys His Glu Asp Trp Ser Lys Phe Asn Phe 675 680 685

    His Phe Ser Asp Thr Ser Ser Tyr Glu Asp Leu Ser Asp Phe Tyr Arg 690 695 700

    Glu Val Glu Gln Gln Gly Tyr Ser Ile Ser Phe Cys Asp Val Ser Val 705 710 715 720

    Glu Tyr Ile Asn Lys Met Val Glu Lys Gly Asp Leu Tyr Leu Phe Gln 725 730 735

    Ile Tyr Asn Lys Asp Phe Ser Glu Phe Ser Lys Gly Thr Pro Asn Met 740 745 750

    His Thr Leu Tyr Trp Asn Ser Leu Phe Ser Lys Glu Asn Leu Asn Asn 755 760 765

    Ile Ile Tyr Lys Leu Asn Gly Gln Ala Glu Ile Phe Phe Arg Lys Lys 770 775 780

    Ser Leu Asn Tyr Lys Arg Pro Thr His Pro Ala His Gln Ala Ile Lys 785 790 795 800

    Asn Lys Asn Lys Cys Asn Glu Lys Lys Glu Ser Ile Phe Asp Tyr Asp 805 810 815

    Leu Val Lys Asp Lys Arg Tyr Thr Val Asp Lys Phe Gln Phe His Val 820 825 830

    Pro Ile Thr Met Asn Phe Lys Ser Thr Gly Asn Thr Asn Ile Asn Gln 835 840 845

    Gln Val Ile Asp Tyr Leu Arg Thr Glu Asp Asp Thr His Ile Ile Gly 850 855 860

    Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Leu Val Val Ile Asp Ser 865 870 875 880

    His Gly Lys Ile Val Glu Gln Phe Thr Leu Asn Glu Ile Val Asn Glu 885 890 895

    Tyr Gly Gly Asn Ile Tyr Arg Thr Asn Tyr His Asp Leu Leu Asp Thr 900 905 910

    Arg Glu Gln Asn Arg Glu Lys Ala Arg Glu Ser Trp Gln Thr Ile Glu 915 920 925

    Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile Ser Gln Val Ile His Lys 930 935 940

    Ile Thr Asp Leu Met Gln Lys Tyr His Ala Val Val Val Leu Glu Asp 945 950 955 960

    Leu Asn Met Gly Phe Met Arg Gly Arg Gln Lys Val Glu Lys Gln Val 965 970 975

    Tyr Gln Lys Phe Glu Glu Met Leu Ile Asn Lys Leu Asn Tyr Leu Val 980 985 990

    Asn Lys Lys Ala Asp Gln Asn Ser Ala Gly Gly Leu Leu His Ala Tyr 995 1000 1005

    Gln Leu Thr Ser Lys Phe Glu Ser Phe Gln Lys Leu Gly Lys Gln 1010 1015 1020

    Ser Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn Thr Ser Lys Ile 1025 1030 1035

    Asp Pro Val Thr Gly Phe Val Asn Leu Phe Asp Thr Arg Tyr Glu 1040 1045 1050

    Ser Ile Asp Lys Ala Lys Ala Phe Phe Gly Lys Phe Asp Ser Ile 1055 1060 1065

    Arg Tyr Asn Ala Asp Lys Asp Trp Phe Glu Phe Ala Phe Asp Tyr 1070 1075 1080

    Asn Asn Phe Thr Thr Lys Ala Glu Gly Thr Arg Thr Asn Trp Thr 1085 1090 1095

    Ile Cys Thr Tyr Gly Ser Arg Ile Arg Thr Phe Arg Asn Gln Ala 1100 1105 1110

    Lys Asn Ser Gln Trp Asp Asn Glu Glu Ile Asp Leu Thr Lys Ala 1115 1120 1125

    Tyr Lys Ala Phe Phe Ala Lys His Gly Ile Asn Ile Tyr Asp Asn 1130 1135 1140

    Ile Lys Glu Ala Ile Ala Met Glu Thr Glu Lys Ser Phe Phe Glu 1145 1150 1155

    Asp Leu Leu His Leu Leu Lys Leu Thr Leu Gln Met Arg Asn Ser 1160 1165 1170

    Ile Thr Gly Thr Thr Thr Asp Tyr Leu Ile Ser Pro Val His Asp 1175 1180 1185

    Ser Lys Gly Asn Phe Tyr Asp Ser Arg Ile Cys Asp Asn Ser Leu 1190 1195 1200

    Pro Ala Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys 1205 1210 1215

    Gly Leu Met Leu Ile Gln Gln Ile Lys Asp Ser Thr Ser Ser Asn 1220 1225 1230

    Arg Phe Lys Phe Ser Pro Ile Thr Asn Lys Asp Trp Leu Ile Phe 1235 1240 1245

    Ala Gln Glu Lys Pro Tyr Leu Asn Asp 1250 1255 <210> 97 <211> 1253 <212> PRT <213> Prevotella albensis <400> 97

    Met Asn Ile Lys Asn Phe Thr Gly Leu Tyr Pro Leu Ser Lys Thr Leu 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Lys Glu Asn Ile Glu Lys 20 25 30

    Asn Gly Ile Leu Thr Lys Asp Glu Gln Arg Ala Lys Asp Tyr Leu Ile 35 40 45

    Val Lys Gly Phe Ile Asp Glu Tyr His Lys Gln Phe Ile Lys Asp Arg 50 55 60

    Leu Trp Asp Phe Lys Leu Pro Leu Glu Ser Glu Gly Glu Lys Asn Ser 65 70 75 80

    Leu Glu Glu Tyr Gln Glu Leu Tyr Glu Leu Thr Lys Arg Asn Asp Ala 85 90 95

    Gln Glu Ala Asp Phe Thr Glu Ile Lys Asp Asn Leu Arg Ser Ser Ile 100 105 110

    Thr Glu Gln Leu Thr Lys Ser Gly Ser Ala Tyr Asp Arg Ile Phe Lys 115 120 125

    Lys Glu Phe Ile Arg Glu Asp Leu Val Asn Phe Leu Glu Asp Glu Lys 130 135 140

    Asp Lys Asn Ile Val Lys Gln Phe Glu Asp Phe Thr Thr Tyr Phe Thr 145 150 155 160

    Gly Phe Tyr Glu Asn Arg Lys Asn Met Tyr Ser Ser Glu Glu Lys Ser 165 170 175

    Thr Ala Ile Ala Tyr Arg Leu Ile His Gln Asn Leu Pro Lys Phe Met 180 185 190

    Asp Asn Met Arg Ser Phe Ala Lys Ile Ala Asn Ser Ser Val Ser Glu 195 200 205

    His Phe Ser Asp Ile Tyr Glu Ser Trp Lys Glu Tyr Leu Asn Val Asn 210 215 220

    Ser Ile Glu Glu Ile Phe Gln Leu Asp Tyr Phe Ser Glu Thr Leu Thr 225 230 235 240

    Gln Pro His Ile Glu Val Tyr Asn Tyr Ile Ile Gly Lys Lys Val Leu 245 250 255

    Glu Asp Gly Thr Glu Ile Lys Gly Ile Asn Glu Tyr Val Asn Leu Tyr 260 265 270

    Asn Gln Gln Gln Lys Asp Lys Ser Lys Arg Leu Pro Phe Leu Val Pro 275 280 285

    Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Lys Leu Ser Trp Ile Ala 290 295 300

    Glu Glu Phe Asp Ser Asp Lys Lys Met Leu Ser Ala Ile Thr Glu Ser 305 310 315 320

    Tyr Asn His Leu His Asn Val Leu Met Gly Asn Glu Asn Glu Ser Leu 325 330 335

    Arg Asn Leu Leu Leu Asn Ile Lys Asp Tyr Asn Leu Glu Lys Ile Asn 340 345 350

    Ile Thr Asn Asp Leu Ser Leu Thr Glu Ile Ser Gln Asn Leu Phe Gly 355 360 365

    Arg Tyr Asp Val Phe Thr Asn Gly Ile Lys Asn Lys Leu Arg Val Leu 370 375 380

    Thr Pro Arg Lys Lys Lys Glu Thr Asp Glu Asn Phe Glu Asp Arg Ile 385 390 395 400

    Asn Lys Ile Phe Lys Thr Gln Lys Ser Phe Ser Ile Ala Phe Leu Asn

    405

    410

    415

    Lys Leu Pro Gln Pro Glu Met Glu Asp Gly Lys Pro Arg Asn Ile Glu 420 425 430

    Asp Tyr Phe Ile Thr Gln Gly Ala Ile Asn Thr Lys Ser Ile Gln Lys 435 440 445

    Glu Asp Ile Phe Ala Gln Ile Glu Asn Ala Tyr Glu Asp Ala Gln Val 450 455 460

    Phe Leu Gln Ile Lys Asp Thr Asp Asn Lys Leu Ser Gln Asn Lys Thr 465 470 475 480

    Ala Val Glu Lys Ile Lys Thr Leu Leu Asp Ala Leu Lys Glu Leu Gln 485 490 495

    His Phe Ile Lys Pro Leu Leu Gly Ser Gly Glu Glu Asn Glu Lys Asp 500 505 510

    Glu Leu Phe Tyr Gly Ser Phe Leu Ala Ile Trp Asp Glu Leu Asp Thr 515 520 525

    Ile Thr Pro Leu Tyr Asn Lys Val Arg Asn Trp Leu Thr Arg Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Asp Asn Ala Gln Leu Leu 545 550 555 560

    Gly Gly Trp Asp Val Asn Lys Glu His Asp Cys Ala Gly Ile Leu Leu 565 570 575

    Arg Lys Asn Asp Ser Tyr Tyr Leu Gly Ile Ile Asn Lys Lys Thr Asn 580 585 590

    His Ile Phe Asp Thr Asp Ile Thr Pro Ser Asp Gly Glu Cys Tyr Asp 595 600 605

    Lys Ile Asp Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys 610 615 620

    Val Phe Phe Ser Lys Ser Arg Ile Lys Glu Phe Glu Pro Ser Glu Ala 625 630 635 640

    Ile Ile Asn Cys Tyr Lys Lys Gly Thr His Lys Lys Gly Lys Asn Phe 645 650 655

    Asn Leu Thr Asp Cys His Arg Leu Ile Asn Phe Phe Lys Thr Ser Ile 660 665 670

    Glu Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser Asp Thr 675 680 685

    Glu Thr Tyr Glu Asp Ile Ser Gly Phe Tyr Arg Glu Val Glu Gln Gln 690 695 700

    Gly Tyr Arg Leu Thr Ser His Pro Val Ser Ala Ser Tyr Ile His Ser 705 710 715 720

    Leu Val Lys Glu Gly Lys Leu Tyr Leu Phe Gln Ile Trp Asn Lys Asp 725 730 735

    Phe Ser Gln Phe Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp 740 745 750

    Lys Met Leu Phe Asp Lys Arg Asn Leu Ser Asp Val Val Tyr Lys Leu 755 760 765

    Asn Gly Gln Ala Glu Val Phe Tyr Arg Lys Ser Ser Ile Glu His Gln 770 775 780

    Asn Arg Ile Ile His Pro Ala Gln His Pro Ile Thr Asn Lys Asn Glu 785 790 795 800

    Leu Asn Lys Lys His Thr Ser Thr Phe Lys Tyr Asp Ile Ile Lys Asp 805 810 815

    Arg Arg Tyr Thr Val Asp Lys Phe Gln Phe His Val Pro Ile Thr Ile 820 825 830

    Asn Phe Lys Ala Thr Gly Gln Asn Asn Ile Asn Pro Ile Val Gln Glu 835 840 845

    Val Ile Arg Gln Asn Gly Ile Thr His Ile Ile Gly Ile Asp Arg Gly 850 855 860

    Glu Arg His Leu Leu Tyr Leu Ser Leu Ile Asp Leu Lys Gly Asn Ile 865 870 875 880

    Ile Lys Gln Met Thr Leu Asn Glu Ile Ile Asn Glu Tyr Lys Gly Val 885 890 895

    Thr Tyr Lys Thr Asn Tyr His Asn Leu Leu Glu Lys Arg Glu Lys Glu 900 905 910

    Arg Thr Glu Ala Arg His Ser Trp Ser Ser Ile Glu Ser Ile Lys Glu 915 920 925

    Leu Lys Asp Gly Tyr Met Ser Gln Val Ile His Lys Ile Thr Asp Met 930 935 940

    Met Val Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn Gly Gly 945 950 955 960

    Phe Met Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe 965 970 975

    Glu Lys Lys Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Lys Leu 980 985 990

    Asp Ala Asn Glu Val Gly Gly Val Leu Asn Ala Tyr Gln Leu Thr Asn 995 1000 1005

    Lys Phe Glu Ser Phe Lys Lys Ile Gly Lys Gln Ser Gly Phe Leu 1010 1015 1020

    Phe Tyr Ile Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Ile Thr 1025 1030 1035

    Gly Phe Val Asn Leu Phe Asn Thr Arg Tyr Glu Ser Ile Lys Glu 1040 1045 1050

    Thr Lys Val Phe Trp Ser Lys Phe Asp Ile Ile Arg Tyr Asn Lys 1055 1060 1065

    Glu Lys Asn Trp Phe Glu Phe Val Phe Asp Tyr Asn Thr Phe Thr 1070 1075 1080

    Thr Lys Ala Glu Gly Thr Arg Thr Lys Trp Thr Leu Cys Thr His 1085 1090 1095

    Gly Thr Arg Ile Gln Thr Phe Arg Asn Pro Glu Lys Asn Ala Gln 1100 1105 1110

    Trp Asp Asn Lys Glu Ile Asn Leu Thr Glu Ser Phe Lys Ala Leu

    1115 1120 1125

    Phe Glu Lys Tyr Lys Ile Asp Ile Thr Ser Asn Leu Lys Glu Ser 1130 1135 1140

    Ile Met Gln Glu Thr Glu Lys Lys Phe Phe Gln Glu Leu His Asn 1145 1150 1155

    Leu Leu His Leu Thr Leu Gln Met Arg Asn Ser Val Thr Gly Thr 1160 1165 1170

    Asp Ile Asp Tyr Leu Ile Ser Pro Val Ala Asp Glu Asp Gly Asn 1175 1180 1185

    Phe Tyr Asp Ser Arg Ile Asn Gly Lys Asn Phe Pro Glu Asn Ala 1190 1195 1200

    Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Met Leu 1205 1210 1215

    Ile Arg Gln Ile Lys Gln Ala Asp Pro Gln Lys Lys Phe Lys Phe 1220 1225 1230

    Glu Thr Ile Thr Asn Lys Asp Trp Leu Lys Phe Ala Gln Asp Lys 1235 1240 1245

    Pro Tyr Leu Lys Asp 1250 <210> 98 <211> 1250 <212> PRT <213> Smithella sp.

    <400> 98

    Met Gln Thr Leu Phe Glu Asn Phe Thr Asn Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Lys Asp Phe Ile 20 25 30

    Glu Gln Lys Gly Leu Leu Lys Lys Asp Glu Asp Arg Ala Glu Lys Tyr 35 40 45

    Lys Lys Val Lys Asn Ile Ile Asp Glu Tyr His Lys Asp Phe Ile Glu 50 55 60

    Lys Ser Leu Asn Gly Leu Lys Leu Asp Gly Leu Glu Lys Tyr Lys Thr 65 70 75 80

    Leu Tyr Leu Lys Gln Glu Lys Asp Asp Lys Asp Lys Lys Ala Phe Asp 85 90 95

    Lys Glu Lys Glu Asn Leu Arg Lys Gln Ile Ala Asn Ala Phe Arg Asn 100 105 110

    Asn Glu Lys Phe Lys Thr Leu Phe Ala Lys Glu Leu Ile Lys Asn Asp 115 120 125

    Leu Met Ser Phe Ala Cys Glu Glu Asp Lys Lys Asn Val Lys Glu Phe 130 135 140

    Glu Ala Phe Thr Thr Tyr Phe Thr Gly Phe His Gln Asn Arg Ala Asn 145 150 155 160

    Met Tyr Val Ala Asp Glu Lys Arg Thr Ala Ile Ala Ser Arg Leu Ile 165 170 175

    His Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe Glu Lys

    180

    185

    190

    Met Lys Lys Glu Ala Pro Glu Leu Leu Ser Pro Phe Asn Gln Thr Leu 195 200 205

    Lys Asp Met Lys Asp Val Ile Lys Gly Thr Thr Leu Glu Glu Ile Phe 210 215 220

    Ser Leu Asp Tyr Phe Asn Lys Thr Leu Thr Gln Ser Gly Ile Asp Ile 225 230 235 240

    Tyr Asn Ser Val Ile Gly Gly Arg Thr Pro Glu Glu Gly Lys Thr Lys 245 250 255

    Ile Lys Gly Leu Asn Glu Tyr Ile Asn Thr Asp Phe Asn Gln Lys Gln 260 265 270

    Thr Asp Lys Lys Lys Arg Gln Pro Lys Phe Lys Gln Leu Tyr Lys Gln 275 280 285

    Ile Leu Ser Asp Arg Gln Ser Leu Ser Phe Ile Ala Glu Ala Phe Lys 290 295 300

    Asn Asp Thr Glu Ile Leu Glu Ala Ile Glu Lys Phe Tyr Val Asn Glu 305 310 315 320

    Leu Leu His Phe Ser Asn Glu Gly Lys Ser Thr Asn Val Leu Asp Ala 325 330 335

    Ile Lys Asn Ala Val Ser Asn Leu Glu Ser Phe Asn Leu Thr Lys Met 340 345 350

    Tyr Phe Arg Ser Gly Ala Ser Leu Thr Asp Val Ser Arg Lys Val Phe 355 360 365

    Gly Glu Trp Ser Ile Ile Asn Arg Ala Leu Asp Asn Tyr Tyr Ala Thr 370 375 380

    Thr Tyr Pro Ile Lys Pro Arg Glu Lys Ser Glu Lys Tyr Glu Glu Arg 385 390 395 400

    Lys Glu Lys Trp Leu Lys Gln Asp Phe Asn Val Ser Leu Ile Gln Thr 405 410 415

    Ala Ile Asp Glu Tyr Asp Asn Glu Thr Val Lys Gly Lys Asn Ser Gly 420 425 430

    Lys Val Ile Ala Asp Tyr Phe Ala Lys Phe Cys Asp Asp Lys Glu Thr 435 440 445

    Asp Leu Ile Gln Lys Val Asn Glu Gly Tyr Ile Ala Val Lys Asp Leu 450 455 460

    Leu Asn Thr Pro Cys Pro Glu Asn Glu Lys Leu Gly Ser Asn Lys Asp 465 470 475 480

    Gln Val Lys Gln Ile Lys Ala Phe Met Asp Ser Ile Met Asp Ile Met 485 490 495

    His Phe Val Arg Pro Leu Ser Leu Lys Asp Thr Asp Lys Glu Lys Asp 500 505 510

    Glu Thr Phe Tyr Ser Leu Phe Thr Pro Leu Tyr Asp His Leu Thr Gln 515 520 525

    Thr Ile Ala Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu 545 550 555 560

    Gly Gly Trp Asp Leu Asn Lys Glu Thr Asp Asn Thr Ala Ile Ile Leu 565 570 575

    Arg Lys Asp Asn Leu Tyr Tyr Leu Gly Ile Met Asp Lys Arg His Asn 580 585 590

    Arg Ile Phe Arg Asn Val Pro Lys Ala Asp Lys Lys Asp Phe Cys Tyr 595 600 605

    Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro 610 615 620

    Lys Val Phe Phe Ser Gln Ser Arg Ile Gln Glu Phe Thr Pro Ser Ala 625 630 635 640

    Lys Leu Leu Glu Asn Tyr Ala Asn Glu Thr His Lys Lys Gly Asp Asn 645 650 655

    Phe Asn Leu Asn His Cys His Lys Leu Ile Asp Phe Phe Lys Asp Ser 660 665 670

    Ile Asn Lys His Glu Asp Trp Lys Asn Phe Asp Phe Arg Phe Ser Ala 675 680 685

    Thr Ser Thr Tyr Ala Asp Leu Ser Gly Phe Tyr His Glu Val Glu His 690 695 700

    Gln Gly Tyr Lys Ile Ser Phe Gln Ser Val Ala Asp Ser Phe Ile Asp 705 710 715 720

    Asp Leu Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 725 730 735

    Asp Phe Ser Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr 740 745 750

    Trp Lys Met Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys 755 760 765

    Leu Asn Gly Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala Glu 770 775 780

    Lys Asn Thr Thr Ile His Lys Ala Asn Glu Ser Ile Ile Asn Lys Asn 785 790 795 800

    Pro Asp Asn Pro Lys Ala Thr Ser Thr Phe Asn Tyr Asp Ile Val Lys 805 810 815

    Asp Lys Arg Tyr Thr Ile Asp Lys Phe Gln Phe His Ile Pro Ile Thr 820 825 830

    Met Asn Phe Lys Ala Glu Gly Ile Phe Asn Met Asn Gln Arg Val Asn 835 840 845

    Gln Phe Leu Lys Ala Asn Pro Asp Ile Asn Ile Ile Gly Ile Asp Arg 850 855 860

    Gly Glu Arg His Leu Leu Tyr Tyr Ala Leu Ile Asn Gln Lys Gly Lys 865 870 875 880

    Ile Leu Lys Gln Asp Thr Leu Asn Val Ile Ala Asn Glu Lys Gln Lys 885 890 895

    Val Asp Tyr His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr

    900

    905

    910

    Ala Arg Gln Glu Trp Gly Val Ile Glu Thr Ile Lys Glu Leu Lys Glu 915 920 925

    Gly Tyr Leu Ser Gln Val Ile His Lys Leu Thr Asp Leu Met Ile Glu 930 935 940

    Asn Asn Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe Lys Arg 945 950 955 960

    Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met 965 970 975

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Lys Ala Asn 980 985 990

    Glu Leu Gly Gly Leu Leu Asn Ala Phe Gln Leu Ala Asn Lys Phe Glu 995 1000 1005

    Ser Phe Gln Lys Met Gly Lys Gln Asn Gly Phe Ile Phe Tyr Val 1010 1015 1020

    Pro Ala Trp Asn Thr Ser Lys Thr Asp Pro Ala Thr Gly Phe Ile 1025 1030 1035

    Asp Phe Leu Lys Pro Arg Tyr Glu Asn Leu Asn Gln Ala Lys Asp 1040 1045 1050

    Phe Phe Glu Lys Phe Asp Ser Ile Arg Leu Asn Ser Lys Ala Asp 1055 1060 1065

    Tyr Phe Glu Phe Ala Phe Asp Phe Lys Asn Phe Thr Glu Lys Ala 1070 1075 1080

    Asp Gly Gly Arg Thr Lys Trp Thr Val Cys Thr Thr Asn Glu Asp 1085 1090 1095

    Arg Tyr Ala Trp Asn Arg Ala Leu Asn Asn Asn Arg Gly Ser Gln 1100 1105 1110

    Glu Lys Tyr Asp Ile Thr Ala Glu Leu Lys Ser Leu Phe Asp Gly 1115 1120 1125

    Lys Val Asp Tyr Lys Ser Gly Lys Asp Leu Lys Gln Gln Ile Ala 1130 1135 1140

    Ser Gln Glu Ser Ala Asp Phe Phe Lys Ala Leu Met Lys Asn Leu 1145 1150 1155

    Ser Ile Thr Leu Ser Leu Arg His Asn Asn Gly Glu Lys Gly Asp 1160 1165 1170

    Asn Glu Gln Asp Tyr Ile Leu Ser Pro Val Ala Asp Ser Lys Gly 1175 1180 1185

    Arg Phe Phe Asp Ser Arg Lys Ala Asp Asp Asp Met Pro Lys Asn 1190 1195 1200

    Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Trp 1205 1210 1215

    Cys Leu Glu Gln Ile Ser Lys Thr Asp Asp Leu Lys Lys Val Lys 1220 1225 1230

    Leu Ala Ile Ser Asn Lys Glu Trp Leu Glu Phe Val Gln Thr Leu 1235 1240 1245

    Lys Gly 1250 <210> 99 <211> 1250 <212> PRT <213> Smithella sp.

    <400> 99

    Met Gln Thr Leu Phe Glu Asn Phe Thr Asn Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Lys Asp Phe Ile 20 25 30

    Glu Gln Lys Gly Leu Leu Lys Lys Asp Glu Asp Arg Ala Glu Lys Tyr 35 40 45

    Lys Lys Val Lys Asn Ile Ile Asp Glu Tyr His Lys Asp Phe Ile Glu 50 55 60

    Lys Ser Leu Asn Gly Leu Lys Leu Asp Gly Leu Glu Glu Tyr Lys Thr 65 70 75 80

    Leu Tyr Leu Lys Gln Glu Lys Asp Asp Lys Asp Lys Lys Ala Phe Asp 85 90 95

    Lys Glu Lys Glu Asn Leu Arg Lys Gln Ile Ala Asn Ala Phe Arg Asn 100 105 110

    Asn Glu Lys Phe Lys Thr Leu Phe Ala Lys Glu Leu Ile Lys Asn Asp 115 120 125

    Leu Met Ser Phe Ala Cys Glu Glu Asp Lys Lys Asn Val Lys Glu Phe 130 135 140

    Glu Ala Phe Thr Thr Tyr Phe Thr Gly Phe His Gln Asn Arg Ala Asn 145 150 155 160

    Met Tyr Val Ala Asp Glu Lys Arg Thr Ala Ile Ala Ser Arg Leu Ile 165 170 175

    His Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe Glu Lys 180 185 190

    Met Lys Lys Glu Ala Pro Glu Leu Leu Ser Pro Phe Asn Gln Thr Leu 195 200 205

    Lys Asp Met Lys Asp Val Ile Lys Gly Thr Thr Leu Glu Glu Ile Phe 210 215 220

    Ser Leu Asp Tyr Phe Asn Lys Thr Leu Thr Gln Ser Gly Ile Asp Ile 225 230 235 240

    Tyr Asn Ser Val Ile Gly Gly Arg Thr Pro Glu Glu Gly Lys Thr Lys 245 250 255

    Ile Lys Gly Leu Asn Glu Tyr Ile Asn Thr Asp Phe Asn Gln Lys Gln 260 265 270

    Thr Asp Lys Lys Lys Arg Gln Pro Lys Phe Lys Gln Leu Tyr Lys Gln 275 280 285

    Ile Leu Ser Asp Arg Gln Ser Leu Ser Phe Ile Ala Glu Ala Phe Lys 290 295 300

    Asn Asp Thr Glu Ile Leu Glu Ala Ile Glu Lys Phe Tyr Val Asn Glu 305 310 315 320

    Leu Leu His Phe Ser Asn Glu Gly Lys Ser Thr Asn Val Leu Asp Ala 325 330 335

    Ile Lys Asn Ala Val Ser Asn Leu Glu Ser Phe Asn Leu Thr Lys Ile 340 345 350

    Tyr Phe Arg Ser Gly Thr Ser Leu Thr Asp Val Ser Arg Lys Val Phe 355 360 365

    Gly Glu Trp Ser Ile Ile Asn Arg Ala Leu Asp Asn Tyr Tyr Ala Thr 370 375 380

    Thr Tyr Pro Ile Lys Pro Arg Glu Lys Ser Glu Lys Tyr Glu Glu Arg 385 390 395 400

    Lys Glu Lys Trp Leu Lys Gln Asp Phe Asn Val Ser Leu Ile Gln Thr 405 410 415

    Ala Ile Asp Glu Tyr Asp Asn Glu Thr Val Lys Gly Lys Asn Ser Gly 420 425 430

    Lys Val Ile Val Asp Tyr Phe Ala Lys Phe Cys Asp Asp Lys Glu Thr 435 440 445

    Asp Leu Ile Gln Lys Val Asn Glu Gly Tyr Ile Ala Val Lys Asp Leu 450 455 460

    Leu Asn Thr Pro Tyr Pro Glu Asn Glu Lys Leu Gly Ser Asn Lys Asp 465 470 475 480

    Gln Val Lys Gln Ile Lys Ala Phe Met Asp Ser Ile Met Asp Ile Met 485 490 495

    His Phe Val Arg Pro Leu Ser Leu Lys Asp Thr Asp Lys Glu Lys Asp 500 505 510

    Glu Thr Phe Tyr Ser Leu Phe Thr Pro Leu Tyr Asp His Leu Thr Gln 515 520 525

    Thr Ile Ala Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu 545 550 555 560

    Gly Gly Trp Asp Leu Asn Lys Glu Thr Asp Asn Thr Ala Ile Ile Leu 565 570 575

    Arg Lys Glu Asn Leu Tyr Tyr Leu Gly Ile Met Asp Lys Arg His Asn 580 585 590

    Arg Ile Phe Arg Asn Val Pro Lys Ala Asp Lys Lys Asp Ser Cys Tyr 595 600 605

    Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro 610 615 620

    Lys Val Phe Phe Ser Gln Ser Arg Ile Gln Glu Phe Thr Pro Ser Ala 625 630 635 640

    Lys Leu Leu Glu Asn Tyr Glu Asn Glu Thr His Lys Lys Gly Asp Asn 645 650 655

    Phe Asn Leu Asn His Cys His Gln Leu Ile Asp Phe Phe Lys Asp Ser 660 665 670

    Ile Asn Lys His Glu Asp Trp Lys Asn Phe Asp Phe Arg Phe Ser Ala

    675

    680

    685

    Thr Ser Thr Tyr Ala Asp Leu Ser Gly Phe Tyr His Glu Val Glu His 690 695 700

    Gln Gly Tyr Lys Ile Ser Phe Gln Ser Ile Ala Asp Ser Phe Ile Asp 705 710 715 720

    Asp Leu Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 725 730 735

    Asp Phe Ser Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr 740 745 750

    Trp Lys Met Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys 755 760 765

    Leu Asn Gly Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala Glu 770 775 780

    Lys Asn Thr Thr Ile His Lys Ala Asn Glu Ser Ile Ile Asn Lys Asn 785 790 795 800

    Pro Asp Asn Pro Lys Ala Thr Ser Thr Phe Asn Tyr Asp Ile Val Lys 805 810 815

    Asp Lys Arg Tyr Thr Ile Asp Lys Phe Gln Phe His Val Pro Ile Thr 820 825 830

    Met Asn Phe Lys Ala Glu Gly Ile Phe Asn Met Asn Gln Arg Val Asn 835 840 845

    Gln Phe Leu Lys Ala Asn Pro Asp Ile Asn Ile Ile Gly Ile Asp Arg 850 855 860

    Gly Glu Arg His Leu Leu Tyr Tyr Thr Leu Ile Asn Gln Lys Gly Lys 865 870 875 880

    Ile Leu Lys Gln Asp Thr Leu Asn Val Ile Ala Asn Glu Lys Gln Lys 885 890 895

    Val Asp Tyr His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr 900 905 910

    Ala Arg Gln Glu Trp Gly Val Ile Glu Thr Ile Lys Glu Leu Lys Glu 915 920 925

    Gly Tyr Leu Ser Gln Val Ile His Lys Leu Thr Asp Leu Met Ile Glu 930 935 940

    Asn Asn Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe Lys Arg 945 950 955 960

    Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met 965 970 975

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Lys Ala Asn 980 985 990

    Glu Leu Gly Gly Leu Leu Asn Ala Phe Gln Leu Ala Asn Lys Phe Glu 995 1000 1005

    Ser Phe Gln Lys Met Gly Lys Gln Asn Gly Phe Ile Phe Tyr Val 1010 1015 1020

    Pro Ala Trp Asn Thr Ser Lys Thr Asp Pro Ala Thr Gly Phe Ile 1025 1030 1035

    Asp Phe Leu Lys Pro Arg Tyr Glu Asn Leu Lys Gln Ala Lys Asp 1040 1045 1050

    Phe Phe Glu Lys Phe Asp Ser Ile Arg Leu Asn Ser Lys Ala Asp 1055 1060 1065

    Tyr Phe Glu Phe Ala Phe Asp Phe Lys Asn Phe Thr Gly Lys Ala 1070 1075 1080

    Asp Gly Gly Arg Thr Lys Trp Thr Val Cys Thr Thr Asn Glu Asp 1085 1090 1095

    Arg Tyr Ala Trp Asn Arg Ala Leu Asn Asn Asn Arg Gly Ser Gln 1100 1105 1110

    Glu Lys Tyr Asp Ile Thr Ala Glu Leu Lys Ser Leu Phe Asp Gly 1115 1120 1125

    Lys Val Asp Tyr Lys Ser Gly Lys Asp Leu Lys Gln Gln Ile Ala 1130 1135 1140

    Ser Gln Glu Leu Ala Asp Phe Phe Arg Thr Leu Met Lys Tyr Leu 1145 1150 1155

    Ser Val Thr Leu Ser Leu Arg His Asn Asn Gly Glu Lys Gly Glu 1160 1165 1170

    Thr Glu Gln Asp Tyr Ile Leu Ser Pro Val Ala Asp Ser Met Gly 1175 1180 1185

    Lys Phe Phe Asp Ser Arg Lys Ala Gly Asp Asp Met Pro Lys Asn 1190 1195 1200

    Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Trp 1205 1210 1215

    Cys Leu Glu Gln Ile Ser Lys Thr Asp Asp Leu Lys Lys Val Lys 1220 1225 1230

    Leu Ala Ile Ser Asn Lys Glu Trp Leu Glu Phe Met Gln Thr Leu 1235 1240 1245

    Lys Gly 1250 <210> 100 <211> 1247 <212> PRT <213> Prevotella bryantii <400> 100

    Met Lys Phe Thr Asp Phe Thr Gly Leu Tyr Ser Leu Ser Lys Thr Leu 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu Asn Ile Lys Lys 20 25 30

    Ala Gly Leu Leu Glu Gln Asp Gln His Arg Ala Asp Ser Tyr Lys Lys 35 40 45

    Val Lys Lys Ile Ile Asp Glu Tyr His Lys Ala Phe Ile Glu Lys Ser 50 55 60

    Leu Ser Asn Phe Glu Leu Lys Tyr Gln Ser Glu Asp Lys Leu Asp Ser 65 70 75 80

    Leu Glu Glu Tyr Leu Met Tyr Tyr Ser Met Lys Arg Ile Glu Lys Thr 85 90 95

    Glu Lys Asp Lys Phe Ala Lys Ile Gln Asp Asn Leu Arg Lys Gln Ile 100 105 110

    Ala Asp His Leu Lys Gly Asp Glu Ser Tyr Lys Thr Ile Phe Ser Lys 115 120 125

    Asp Leu Ile Arg Lys Asn Leu Pro Asp Phe Val Lys Ser Asp Glu Glu 130 135 140

    Arg Thr Leu Ile Lys Glu Phe Lys Asp Phe Thr Thr Tyr Phe Lys Gly 145 150 155 160

    Phe Tyr Glu Asn Arg Glu Asn Met Tyr Ser Ala Glu Asp Lys Ser Thr 165 170 175

    Ala Ile Ser His Arg Ile Ile His Glu Asn Leu Pro Lys Phe Val Asp 180 185 190

    Asn Ile Asn Ala Phe Ser Lys Ile Ile Leu Ile Pro Glu Leu Arg Glu 195 200 205

    Lys Leu Asn Gln Ile Tyr Gln Asp Phe Glu Glu Tyr Leu Asn Val Glu 210 215 220

    Ser Ile Asp Glu Ile Phe His Leu Asp Tyr Phe Ser Met Val Met Thr 225 230 235 240

    Gln Lys Gln Ile Glu Val Tyr Asn Ala Ile Ile Gly Gly Lys Ser Thr 245 250 255

    Asn Asp Lys Lys Ile Gln Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn 260 265 270

    Gln Lys His Lys Asp Cys Lys Leu Pro Lys Leu Lys Leu Leu Phe Lys 275 280 285

    Gln Ile Leu Ser Asp Arg Ile Ala Ile Ser Trp Leu Pro Asp Asn Phe 290 295 300

    Lys Asp Asp Gln Glu Ala Leu Asp Ser Ile Asp Thr Cys Tyr Lys Asn 305 310 315 320

    Leu Leu Asn Asp Gly Asn Val Leu Gly Glu Gly Asn Leu Lys Leu Leu 325 330 335

    Leu Glu Asn Ile Asp Thr Tyr Asn Leu Lys Gly Ile Phe Ile Arg Asn 340 345 350

    Asp Leu Gln Leu Thr Asp Ile Ser Gln Lys Met Tyr Ala Ser Trp Asn 355 360 365

    Val Ile Gln Asp Ala Val Ile Leu Asp Leu Lys Lys Gln Val Ser Arg 370 375 380

    Lys Lys Lys Glu Ser Ala Glu Asp Tyr Asn Asp Arg Leu Lys Lys Leu 385 390 395 400

    Tyr Thr Ser Gln Glu Ser Phe Ser Ile Gln Tyr Leu Asn Asp Cys Leu 405 410 415

    Arg Ala Tyr Gly Lys Thr Glu Asn Ile Gln Asp Tyr Phe Ala Lys Leu 420 425 430

    Gly Ala Val Asn Asn Glu His Glu Gln Thr Ile Asn Leu Phe Ala Gln 435 440 445

    Val Arg Asn Ala Tyr Thr Ser Val Gln Ala Ile Leu Thr Thr Pro Tyr

    450

    455

    460

    Pro Glu Asn Ala Asn Leu Ala Gln Asp Lys Glu Thr Val Ala Leu Ile 465 470 475 480

    Lys Asn Leu Leu Asp Ser Leu Lys Arg Leu Gln Arg Phe Ile Lys Pro 485 490 495

    Leu Leu Gly Lys Gly Asp Glu Ser Asp Lys Asp Glu Arg Phe Tyr Gly 500 505 510

    Asp Phe Thr Pro Leu Trp Glu Thr Leu Asn Gln Ile Thr Pro Leu Tyr 515 520 525

    Asn Met Val Arg Asn Tyr Met Thr Arg Lys Pro Tyr Ser Gln Glu Lys 530 535 540

    Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu Gly Gly Trp Asp Leu 545 550 555 560

    Asn Lys Glu His Asp Asn Thr Ala Ile Ile Leu Arg Lys Asn Gly Leu 565 570 575

    Tyr Tyr Leu Ala Ile Met Lys Lys Ser Ala Asn Lys Ile Phe Asp Lys 580 585 590

    Asp Lys Leu Asp Asn Ser Gly Asp Cys Tyr Glu Lys Met Val Tyr Lys 595 600 605

    Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Phe Ser Lys 610 615 620

    Ser Arg Ile Asp Glu Phe Lys Pro Ser Glu Asn Ile Ile Glu Asn Tyr 625 630 635 640

    Lys Lys Gly Thr His Lys Lys Gly Ala Asn Phe Asn Leu Ala Asp Cys 645 650 655

    His Asn Leu Ile Asp Phe Phe Lys Ser Ser Ile Ser Lys His Glu Asp 660 665 670

    Trp Ser Lys Phe Asn Phe His Phe Ser Asp Thr Ser Ser Tyr Glu Asp 675 680 685

    Leu Ser Asp Phe Tyr Arg Glu Val Glu Gln Gln Gly Tyr Ser Ile Ser 690 695 700

    Phe Cys Asp Val Ser Val Glu Tyr Ile Asn Lys Met Val Glu Lys Gly 705 710 715 720

    Asp Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Glu Phe Ser 725 730 735

    Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Asn Ser Leu Phe Ser 740 745 750

    Lys Glu Asn Leu Asn Asn Ile Ile Tyr Lys Leu Asn Gly Gln Ala Glu 755 760 765

    Ile Phe Phe Arg Lys Lys Ser Leu Asn Tyr Lys Arg Pro Thr His Pro 770 775 780

    Ala His Gln Ala Ile Lys Asn Lys Asn Lys Cys Asn Glu Lys Lys Glu 785 790 795 800

    Ser Ile Phe Asp Tyr Asp Leu Val Lys Asp Lys Arg Tyr Thr Val Asp 805 810 815

    Lys Phe Gln Phe His Val Pro Ile Thr Met Asn Phe Lys Ser Thr Gly 820 825 830

    Asn Thr Asn Ile Asn Gln Gln Val Ile Asp Tyr Leu Arg Thr Glu Asp 835 840 845

    Asp Thr His Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr 850 855 860

    Leu Val Val Ile Asp Ser His Gly Lys Ile Val Glu Gln Phe Thr Leu 865 870 875 880

    Asn Glu Ile Val Asn Glu Tyr Gly Gly Asn Ile Tyr Arg Thr Asn Tyr 885 890 895

    His Asp Leu Leu Asp Thr Arg Glu Gln Asn Arg Glu Lys Ala Arg Glu 900 905 910

    Ser Trp Gln Thr Ile Glu Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 915 920 925

    Ser Gln Val Ile His Lys Ile Thr Asp Leu Met Gln Lys Tyr His Ala 930 935 940

    Val Val Val Leu Glu Asp Leu Asn Met Gly Phe Met Arg Gly Arg Gln 945 950 955 960

    Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Glu Met Leu Ile Asn 965 970 975

    Lys Leu Asn Tyr Leu Val Asn Lys Lys Ala Asp Gln Asn Ser Ala Gly 980 985 990

    Gly Leu Leu His Ala Tyr Gln Leu Thr Ser Lys Phe Glu Ser Phe Gln 995 1000 1005

    Lys Leu Gly Lys Gln Ser Gly Phe Leu Phe Tyr Ile Pro Ala Trp 1010 1015 1020

    Asn Thr Ser Lys Ile Asp Pro Val Thr Gly Phe Val Asn Leu Phe 1025 1030 1035

    Asp Thr Arg Tyr Glu Ser Ile Asp Lys Ala Lys Ala Phe Phe Gly 1040 1045 1050

    Lys Phe Asp Ser Ile Arg Tyr Asn Ala Asp Lys Asp Trp Phe Glu 1055 1060 1065

    Phe Ala Phe Asp Tyr Asn Asn Phe Thr Thr Lys Ala Glu Gly Thr 1070 1075 1080

    Arg Thr Asn Trp Thr Ile Cys Thr Tyr Gly Ser Arg Ile Arg Thr 1085 1090 1095

    Phe Arg Asn Gln Ala Lys Asn Ser Gln Trp Asp Asn Glu Glu Ile 1100 1105 1110

    Asp Leu Thr Lys Ala Tyr Lys Ala Phe Phe Ala Lys His Gly Ile 1115 1120 1125

    Asn Ile Tyr Asp Asn Ile Lys Glu Ala Ile Ala Met Glu Thr Glu 1130 1135 1140

    Lys Ser Phe Phe Glu Asp Leu Leu His Leu Leu Lys Leu Thr Leu 1145 1150 1155

    Gln Met Arg Asn Ser Ile Thr Gly Thr Thr Thr Asp Tyr Leu Ile

    1160

    1165

    1170

    Ser Pro Val His Asp Ser Lys Gly Asn Phe Tyr Asp Ser Arg Ile 1175 1180 1185

    Cys Asp Asn Ser Leu Pro Ala Asn Ala Asp Ala Asn Gly Ala Tyr 1190 1195 1200

    Asn Ile Ala Arg Lys Gly Leu Met Leu Ile Gln Gln Ile Lys Asp 1205 1210 1215

    Ser Thr Ser Ser Asn Arg Phe Lys Phe Ser Pro Ile Thr Asn Lys 1220 1225 1230

    Asp Trp Leu Ile Phe Ala Gln Glu Lys Pro Tyr Leu Asn Asp 1235 1240 1245 <210> 101 <211> 1247 <212> PRT <213> Unknown <220>

    <223> Description of Unknown: uncultured bacterium sequence <400> 101

    Met Phe Lys Gly Asp Ala Phe Thr Gly Leu Tyr Glu Val Gln Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Val Pro Ile Gly Leu Thr Gln Ser Tyr Leu Glu 20 25 30

    Asn Asp Trp Val Ile Gln Lys Asp Lys Glu Val Glu Glu Asn Tyr Gly 35 40 45

    Lys Ile Lys Ala Tyr Phe Asp Leu Ile His Lys Glu Phe Val Arg Gln 50 55 60

    Ser Leu Glu Asn Ala Trp Leu Cys Gln Leu Asp Asp Phe Tyr Glu Lys 65 70 75 80

    Tyr Ile Glu Leu His Asn Ser Leu Glu Thr Arg Lys Asp Lys Asn Leu 85 90 95

    Ala Lys Gln Phe Glu Lys Val Met Lys Ser Leu Lys Lys Glu Phe Val 100 105 110

    Ser Phe Phe Asp Ala Lys Trp Asn Glu Trp Lys Gln Lys Phe Ser Phe 115 120 125

    Leu Lys Lys Trp Trp Ile Asp Val Leu Asn Glu Lys Glu Val Leu Asp 130 135 140

    Leu Met Ala Glu Phe Tyr Pro Asp Glu Lys Glu Leu Phe Asp Lys Phe 145 150 155 160

    Asp Lys Phe Phe Thr Tyr Phe Ser Asn Phe Lys Glu Ser Arg Lys Asn 165 170 175

    Phe Tyr Ala Asp Asp Gly Arg Ala Trp Ala Ile Ala Thr Arg Ala Ile 180 185 190

    Asp Glu Asn Leu Ile Thr Phe Ile Lys Asn Ile Glu Asp Phe Lys Lys 195 200 205

    Leu Asn Ser Ser Phe Arg Glu Phe Val Asn Asp Asn Phe Ser Glu Glu 210 215 220

    Asp Lys Gln Ile Phe Glu Ile Asp Phe Tyr Asn Asn Cys Leu Leu Gln

    225

    230

    235

    240

    Pro Trp Ile Asp Lys Tyr Asn Lys Ile Val Trp Trp Tyr Ser Leu Glu 245 250 255

    Asn Trp Glu Lys Val Gln Trp Leu Asn Glu Lys Ile Asn Asn Phe Lys 260 265 270

    Gln Asn Gln Asn Lys Ser Asn Ser Lys Asp Leu Lys Phe Pro Arg Met 275 280 285

    Lys Leu Leu Tyr Lys Gln Ile Leu Gly Asp Lys Glu Lys Lys Val Tyr 290 295 300

    Ile Asp Glu Ile Arg Asp Asp Lys Asn Leu Ile Asp Leu Ile Asp Asn 305 310 315 320

    Ser Lys Arg Arg Asn Gln Ile Lys Ile Asp Asn Ala Asn Asp Ile Ile 325 330 335

    Asn Asp Phe Ile Asn Asn Asn Ala Lys Phe Glu Leu Asp Lys Ile Tyr 340 345 350

    Leu Thr Arg Gln Ser Ile Asn Thr Ile Ser Ser Lys Tyr Phe Ser Ser 355 360 365

    Trp Asp Tyr Ile Arg Trp Tyr Phe Trp Thr Gly Glu Leu Gln Glu Phe 370 375 380

    Val Ser Phe Tyr Asp Leu Lys Glu Thr Phe Trp Lys Ile Glu Tyr Glu 385 390 395 400

    Thr Leu Glu Asn Ile Phe Lys Asp Cys Tyr Val Lys Gly Ile Asn Thr 405 410 415

    Glu Ser Gln Asn Asn Ile Val Phe Glu Thr Gln Gly Ile Tyr Glu Asn 420 425 430

    Phe Leu Asn Ile Phe Lys Phe Glu Phe Asn Gln Asn Ile Ser Gln Ile 435 440 445

    Ser Leu Leu Glu Trp Glu Leu Asp Lys Ile Gln Asn Glu Asp Ile Lys 450 455 460

    Lys Asn Glu Lys Gln Val Glu Val Ile Lys Asn Tyr Phe Asp Ser Val 465 470 475 480

    Met Ser Val Tyr Lys Met Thr Lys Tyr Phe Ser Leu Glu Lys Trp Lys 485 490 495

    Lys Arg Val Glu Leu Asp Thr Asp Asn Asn Phe Tyr Asn Asp Phe Asn 500 505 510

    Glu Tyr Leu Glu Gly Phe Glu Ile Trp Lys Asp Tyr Asn Leu Val Arg 515 520 525

    Asn Tyr Ile Thr Lys Lys Gln Val Asn Thr Asp Lys Ile Lys Leu Asn 530 535 540

    Phe Asp Asn Ser Gln Phe Leu Thr Trp Trp Asp Lys Asp Lys Glu Asn 545 550 555 560

    Glu Arg Leu Gly Ile Ile Leu Arg Arg Glu Trp Lys Tyr Tyr Leu Trp 565 570 575

    Ile Leu Lys Lys Trp Asn Thr Leu Asn Phe Gly Asp Tyr Leu Gln Lys 580 585 590

    Glu Trp Glu Ile Phe Tyr Glu Lys Met Asn Tyr Lys Gln Leu Asn Asn 595 600 605

    Val Tyr Arg Gln Leu Pro Arg Leu Leu Phe Pro Leu Thr Lys Lys Leu 610 615 620

    Asn Glu Leu Lys Trp Asp Glu Leu Lys Lys Tyr Leu Ser Lys Tyr Ile 625 630 635 640

    Gln Asn Phe Trp Tyr Asn Glu Glu Ile Ala Gln Ile Lys Ile Glu Phe 645 650 655

    Asp Ile Phe Gln Glu Ser Lys Glu Lys Trp Glu Lys Phe Asp Ile Asp 660 665 670

    Lys Leu Arg Lys Leu Ile Glu Tyr Tyr Lys Lys Trp Val Leu Ala Leu 675 680 685

    Tyr Ser Asp Leu Tyr Asp Leu Glu Phe Ile Lys Tyr Lys Asn Tyr Asp 690 695 700

    Asp Leu Ser Ile Phe Tyr Ser Asp Val Glu Lys Lys Met Tyr Asn Leu 705 710 715 720

    Asn Phe Thr Lys Ile Asp Lys Ser Leu Ile Asp Gly Lys Val Lys Ser 725 730 735

    Trp Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Glu Ser 740 745 750

    Lys Lys Glu Trp Ser Thr Glu Asn Ile His Thr Lys Tyr Phe Lys Leu 755 760 765

    Leu Phe Asn Glu Lys Asn Leu Gln Asn Leu Val Val Lys Leu Ser Trp 770 775 780

    Trp Ala Asp Ile Phe Phe Arg Asp Lys Thr Glu Asn Leu Lys Phe Lys 785 790 795 800

    Lys Asp Lys Asn Gly Gln Glu Ile Leu Asp His Arg Arg Phe Ser Gln 805 810 815

    Asp Lys Ile Met Phe His Ile Ser Ile Thr Leu Asn Ala Asn Cys Trp 820 825 830

    Asp Lys Tyr Trp Phe Asn Gln Tyr Val Asn Glu Tyr Met Asn Lys Glu 835 840 845

    Arg Asp Ile Lys Ile Ile Trp Ile Asp Arg Trp Glu Lys His Leu Ala 850 855 860

    Tyr Tyr Cys Val Ile Asp Lys Ser Trp Lys Ile Phe Asn Asn Glu Ile 865 870 875 880

    Trp Thr Leu Asn Glu Leu Asn Trp Val Asn Tyr Leu Glu Lys Leu Glu 885 890 895

    Lys Ile Glu Ser Ser Arg Lys Asp Ser Arg Ile Ser Trp Trp Glu Ile 900 905 910

    Glu Asn Ile Lys Glu Leu Lys Asn Gly Tyr Ile Ser Gln Val Ile Asn 915 920 925

    Lys Leu Thr Glu Leu Ile Val Lys Tyr Asn Ala Ile Ile Val Phe Glu 930 935 940

    Asp Leu Asn Ile Trp Phe Lys Arg Trp Arg Gln Lys Ile Glu Lys Gln

    945

    950

    955

    960

    Ile Tyr Gln Lys Leu Glu Leu Ala Leu Ala Lys Lys Leu Asn Tyr Leu 965 970 975

    Thr Gln Lys Asp Lys Lys Asp Asp Glu Ile Leu Trp Asn Leu Lys Ala 980 985 990

    Leu Gln Leu Val Pro Lys Val Asn Asp Tyr Gln Asp Ile Trp Asn Tyr 995 1000 1005

    Lys Gln Ser Trp Ile Met Phe Tyr Val Arg Ala Asn Tyr Thr Ser 1010 1015 1020

    Val Thr Cys Pro Asn Cys Trp Leu Arg Lys Asn Leu Tyr Ile Ser 1025 1030 1035

    Asn Ser Ala Thr Lys Glu Asn Gln Lys Lys Ser Leu Asn Ser Ile 1040 1045 1050

    Ala Ile Lys Tyr Asn Asp Trp Lys Phe Ser Phe Ser Tyr Glu Ile 1055 1060 1065

    Asp Asp Lys Ser Trp Lys Gln Lys Gln Ser Leu Asn Lys Lys Lys 1070 1075 1080

    Phe Ile Val Tyr Ser Asp Ile Glu Arg Phe Val Tyr Ser Pro Leu 1085 1090 1095

    Glu Lys Leu Thr Lys Val Ile Asp Val Asn Lys Lys Leu Leu Glu 1100 1105 1110

    Leu Phe Arg Asp Phe Asn Leu Ser Leu Asp Ile Asn Lys Gln Ile 1115 1120 1125

    Gln Glu Lys Asp Leu Asp Ser Val Phe Phe Lys Ser Leu Thr His 1130 1135 1140

    Leu Phe Asn Leu Ile Leu Gln Leu Arg Asn Ser Asp Ser Lys Asp 1145 1150 1155

    Asn Lys Asp Tyr Ile Ser Cys Pro Ser Cys Tyr Tyr His Ser Asn 1160 1165 1170

    Asn Trp Leu Gln Trp Phe Glu Phe Asn Trp Asp Ala Asn Trp Ala 1175 1180 1185

    Tyr Asn Ile Ala Arg Lys Gly Ile Ile Leu Leu Asp Arg Ile Arg 1190 1195 1200

    Lys Asn Gln Glu Lys Pro Asp Leu Tyr Val Ser Asp Ile Asp Trp 1205 1210 1215

    Asp Asn Phe Val Gln Ser Asn Gln Phe Pro Asn Thr Ile Ile Pro 1220 1225 1230

    Ile Gln Asn Ile Glu Lys Gln Val Pro Leu Asn Ile Lys Ile 1235 1240 1245 <210> 102 <211> 1246 <212> PRT <213> Porphyromonas macacae <400> 102

    Met Lys Thr Gln His Phe Phe Glu Asp Phe Thr Ser Leu Tyr Ser Leu 1 5 10 15

    Ser Lys Thr Ile Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu

    Asn Ile Lys Lys Asn Gly Leu Ile Arg Arg Asp Glu Gln Arg Leu Asp 35 40 45

    Asp Tyr Glu Lys Leu Lys Lys Val Ile Asp Glu Tyr His Glu Asp Phe 50 55 60

    Ile Ala Asn Ile Leu Ser Ser Phe Ser Phe Ser Glu Glu Ile Leu Gln 65 70 75 80

    Ser Tyr Ile Gln Asn Leu Ser Glu Ser Glu Ala Arg Ala Lys Ile Glu 85 90 95

    Lys Thr Met Arg Asp Thr Leu Ala Lys Ala Phe Ser Glu Asp Glu Arg 100 105 110

    Tyr Lys Ser Ile Phe Lys Lys Glu Leu Val Lys Lys Asp Ile Pro Val 115 120 125

    Trp Cys Pro Ala Tyr Lys Ser Leu Cys Lys Lys Phe Asp Asn Phe Thr 130 135 140

    Thr Ser Leu Val Pro Phe His Glu Asn Arg Lys Asn Leu Tyr Thr Ser 145 150 155 160

    Asn Glu Ile Thr Ala Ser Ile Pro Tyr Arg Ile Val His Val Asn Leu 165 170 175

    Pro Lys Phe Ile Gln Asn Ile Glu Ala Leu Cys Glu Leu Gln Lys Lys 180 185 190

    Met Gly Ala Asp Leu Tyr Leu Glu Met Met Glu Asn Leu Arg Asn Val 195 200 205

    Trp Pro Ser Phe Val Lys Thr Pro Asp Asp Leu Cys Asn Leu Lys Thr 210 215 220

    Tyr Asn His Leu Met Val Gln Ser Ser Ile Ser Glu Tyr Asn Arg Phe 225 230 235 240

    Val Gly Gly Tyr Ser Thr Glu Asp Gly Thr Lys His Gln Gly Ile Asn 245 250 255

    Glu Trp Ile Asn Ile Tyr Arg Gln Arg Asn Lys Glu Met Arg Leu Pro 260 265 270

    Gly Leu Val Phe Leu His Lys Gln Ile Leu Ala Lys Val Asp Ser Ser 275 280 285

    Ser Phe Ile Ser Asp Thr Leu Glu Asn Asp Asp Gln Val Phe Cys Val 290 295 300

    Leu Arg Gln Phe Arg Lys Leu Phe Trp Asn Thr Val Ser Ser Lys Glu 305 310 315 320

    Asp Asp Ala Ala Ser Leu Lys Asp Leu Phe Cys Gly Leu Ser Gly Tyr 325 330 335

    Asp Pro Glu Ala Ile Tyr Val Ser Asp Ala His Leu Ala Thr Ile Ser 340 345 350

    Lys Asn Ile Phe Asp Arg Trp Asn Tyr Ile Ser Asp Ala Ile Arg Arg 355 360 365

    Lys Thr Glu Val Leu Met Pro Arg Lys Lys Glu Ser Val Glu Arg Tyr 370 375 380

    Ala Glu Lys Ile Ser Lys Gln Ile Lys Lys Arg Gln Ser Tyr Ser Leu 385 390 395 400

    Ala Glu Leu Asp Asp Leu Leu Ala His Tyr Ser Glu Glu Ser Leu Pro 405 410 415

    Ala Gly Phe Ser Leu Leu Ser Tyr Phe Thr Ser Leu Gly Gly Gln Lys 420 425 430

    Tyr Leu Val Ser Asp Gly Glu Val Ile Leu Tyr Glu Glu Gly Ser Asn 435 440 445

    Ile Trp Asp Glu Val Leu Ile Ala Phe Arg Asp Leu Gln Val Ile Leu 450 455 460

    Asp Lys Asp Phe Thr Glu Lys Lys Leu Gly Lys Asp Glu Glu Ala Val 465 470 475 480

    Ser Val Ile Lys Lys Ala Leu Asp Ser Ala Leu Arg Leu Arg Lys Phe 485 490 495

    Phe Asp Leu Leu Ser Gly Thr Gly Ala Glu Ile Arg Arg Asp Ser Ser 500 505 510

    Phe Tyr Ala Leu Tyr Thr Asp Arg Met Asp Lys Leu Lys Gly Leu Leu 515 520 525

    Lys Met Tyr Asp Lys Val Arg Asn Tyr Leu Thr Lys Lys Pro Tyr Ser 530 535 540

    Ile Glu Lys Phe Lys Leu His Phe Asp Asn Pro Ser Leu Leu Ser Gly 545 550 555 560

    Trp Asp Lys Asn Lys Glu Leu Asn Asn Leu Ser Val Ile Phe Arg Gln 565 570 575

    Asn Gly Tyr Tyr Tyr Leu Gly Ile Met Thr Pro Lys Gly Lys Asn Leu 580 585 590

    Phe Lys Thr Leu Pro Lys Leu Gly Ala Glu Glu Met Phe Tyr Glu Lys 595 600 605

    Met Glu Tyr Lys Gln Ile Ala Glu Pro Met Leu Met Leu Pro Lys Val 610 615 620

    Phe Phe Pro Lys Lys Thr Lys Pro Ala Phe Ala Pro Asp Gln Ser Val 625 630 635 640

    Val Asp Ile Tyr Asn Lys Lys Thr Phe Lys Thr Gly Gln Lys Gly Phe 645 650 655

    Asn Lys Lys Asp Leu Tyr Arg Leu Ile Asp Phe Tyr Lys Glu Ala Leu 660 665 670

    Thr Val His Glu Trp Lys Leu Phe Asn Phe Ser Phe Ser Pro Thr Glu 675 680 685

    Gln Tyr Arg Asn Ile Gly Glu Phe Phe Asp Glu Val Arg Glu Gln Ala 690 695 700

    Tyr Lys Val Ser Met Val Asn Val Pro Ala Ser Tyr Ile Asp Glu Ala 705 710 715 720

    Val Glu Asn Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 725 730 735

    Ser Pro Tyr Ser Lys Gly Ile Pro Asn Leu His Thr Leu Tyr Trp Lys

    740

    745

    750

    Ala Leu Phe Ser Glu Gln Asn Gln Ser Arg Val Tyr Lys Leu Cys Gly 755 760 765

    Gly Gly Glu Leu Phe Tyr Arg Lys Ala Ser Leu His Met Gln Asp Thr 770 775 780

    Thr Val His Pro Lys Gly Ile Ser Ile His Lys Lys Asn Leu Asn Lys 785 790 795 800

    Lys Gly Glu Thr Ser Leu Phe Asn Tyr Asp Leu Val Lys Asp Lys Arg 805 810 815

    Phe Thr Glu Asp Lys Phe Phe Phe His Val Pro Ile Ser Ile Asn Tyr 820 825 830

    Lys Asn Lys Lys Ile Thr Asn Val Asn Gln Met Val Arg Asp Tyr Ile 835 840 845

    Ala Gln Asn Asp Asp Leu Gln Ile Ile Gly Ile Asp Arg Gly Glu Arg 850 855 860

    Asn Leu Leu Tyr Ile Ser Arg Ile Asp Thr Arg Gly Asn Leu Leu Glu 865 870 875 880

    Gln Phe Ser Leu Asn Val Ile Glu Ser Asp Lys Gly Asp Leu Arg Thr 885 890 895

    Asp Tyr Gln Lys Ile Leu Gly Asp Arg Glu Gln Glu Arg Leu Arg Arg 900 905 910

    Arg Gln Glu Trp Lys Ser Ile Glu Ser Ile Lys Asp Leu Lys Asp Gly 915 920 925

    Tyr Met Ser Gln Val Val His Lys Ile Cys Asn Met Val Val Glu His 930 935 940

    Lys Ala Ile Val Val Leu Glu Asn Leu Asn Leu Ser Phe Met Lys Gly 945 950 955 960

    Arg Lys Lys Val Glu Lys Ser Val Tyr Glu Lys Phe Glu Arg Met Leu 965 970 975

    Val Asp Lys Leu Asn Tyr Leu Val Val Asp Lys Lys Asn Leu Ser Asn 980 985 990

    Glu Pro Gly Gly Leu Tyr Ala Ala Tyr Gln Leu Thr Asn Pro Leu Phe 995 1000 1005

    Ser Phe Glu Glu Leu His Arg Tyr Pro Gln Ser Gly Ile Leu Phe 1010 1015 1020

    Phe Val Asp Pro Trp Asn Thr Ser Leu Thr Asp Pro Ser Thr Gly 1025 1030 1035

    Phe Val Asn Leu Leu Gly Arg Ile Asn Tyr Thr Asn Val Gly Asp 1040 1045 1050

    Ala Arg Lys Phe Phe Asp Arg Phe Asn Ala Ile Arg Tyr Asp Gly 1055 1060 1065

    Lys Gly Asn Ile Leu Phe Asp Leu Asp Leu Ser Arg Phe Asp Val 1070 1075 1080

    Arg Val Glu Thr Gln Arg Lys Leu Trp Thr Leu Thr Thr Phe Gly 1085 1090 1095

    Ser Arg Ile Ala Lys Ser Lys Lys Ser Gly Lys Trp Met Val Glu 1100 1105 1110

    Arg Ile Glu Asn Leu Ser Leu Cys Phe Leu Glu Leu Phe Glu Gln 1115 1120 1125 Phe Asn Ile Gly Tyr Arg Val Glu Lys Asp Leu Lys Lys Ala Ile 1130 1135 1140 Leu Ser Gln Asp Arg Lys Glu Phe Tyr Val Arg Leu Ile Tyr Leu 1145 1150 1155 Phe Asn Leu Met Met Gln Ile Arg Asn Ser Asp Gly Glu Glu Asp 1160 1165 1170

    Tyr Ile Leu Ser Pro Ala Leu Asn Glu Lys Asn Leu Gln Phe Asp 1175 1180 1185

    Ser Arg Leu Ile Glu Ala Lys Asp Leu Pro Val Asp Ala Asp Ala 1190 1195 1200

    Asn Gly Ala Tyr Asn Val Ala Arg Lys Gly Leu Met Val Val Gln 1205 1210 1215

    Arg Ile Lys Arg Gly Asp His Glu Ser Ile His Arg Ile Gly Arg 1220 1225 1230

    Ala Gln Trp Leu Arg Tyr Val Gln Glu Gly Ile Val Glu 1235 1240 1245 <210> 103 <211> 1241 <212> PRT <213> Butyrivibrio proteoclasticus <400> 103

    Met Leu Leu Tyr Glu Asn Tyr Thr Lys Arg Asn Gln Ile Thr Lys Ser 1 5 10 15

    Leu Arg Leu Glu Leu Arg Pro Gln Gly Lys Thr Leu Arg Asn Ile Lys 20 25 30

    Glu Leu Asn Leu Leu Glu Gln Asp Lys Ala Ile Tyr Ala Leu Leu Glu 35 40 45

    Arg Leu Lys Pro Val Ile Asp Glu Gly Ile Lys Asp Ile Ala Arg Asp 50 55 60

    Thr Leu Lys Asn Cys Glu Leu Ser Phe Glu Lys Leu Tyr Glu His Phe 65 70 75 80

    Leu Ser Gly Asp Lys Lys Ala Tyr Ala Lys Glu Ser Glu Arg Leu Lys 85 90 95

    Lys Glu Ile Val Lys Thr Leu Ile Lys Asn Leu Pro Glu Gly Ile Gly 100 105 110

    Lys Ile Ser Glu Ile Asn Ser Ala Lys Tyr Leu Asn Gly Val Leu Tyr 115 120 125

    Asp Phe Ile Asp Lys Thr His Lys Asp Ser Glu Glu Lys Gln Asn Ile 130 135 140

    Leu Ser Asp Ile Leu Glu Thr Lys Gly Tyr Leu Ala Leu Phe Ser Lys 145 150 155 160

    Phe Leu Thr Ser Arg Ile Thr Thr Leu Glu Gln Ser Met Pro Lys Arg 165 170 175

    Val Ile Glu Asn Phe Glu Ile Tyr Ala Ala Asn Ile Pro Lys Met Gln 180 185 190

    Asp Ala Leu Glu Arg Gly Ala Val Ser Phe Ala Ile Glu Tyr Glu Ser 195 200 205

    Ile Cys Ser Val Asp Tyr Tyr Asn Gln Ile Leu Ser Gln Glu Asp Ile 210 215 220

    Asp Ser Tyr Asn Arg Leu Ile Ser Gly Ile Met Asp Glu Asp Gly Ala 225 230 235 240

    Lys Glu Lys Gly Ile Asn Gln Thr Ile Ser Glu Lys Asn Ile Lys Ile 245 250 255

    Lys Ser Glu His Leu Glu Glu Lys Pro Phe Arg Ile Leu Lys Gln Leu 260 265 270

    His Lys Gln Ile Leu Glu Glu Arg Glu Lys Ala Phe Thr Ile Asp His 275 280 285

    Ile Asp Ser Asp Glu Glu Val Val Gln Val Thr Lys Glu Ala Phe Glu 290 295 300

    Gln Thr Lys Glu Gln Trp Glu Asn Ile Lys Lys Ile Asn Gly Phe Tyr 305 310 315 320

    Ala Lys Asp Pro Gly Asp Ile Thr Leu Phe Ile Val Val Gly Pro Asn 325 330 335

    Gln Thr His Val Leu Ser Gln Leu Ile Tyr Gly Glu His Asp Arg Ile 340 345 350

    Arg Leu Leu Leu Glu Glu Tyr Glu Lys Asn Thr Leu Glu Val Leu Pro 355 360 365

    Arg Arg Thr Lys Ser Glu Lys Ala Arg Tyr Asp Lys Phe Val Asn Ala 370 375 380

    Val Pro Lys Lys Val Ala Lys Glu Ser His Thr Phe Asp Gly Leu Gln 385 390 395 400

    Lys Met Thr Gly Asp Asp Arg Leu Phe Ile Leu Tyr Arg Asp Glu Leu 405 410 415

    Ala Arg Asn Tyr Met Arg Ile Lys Glu Ala Tyr Gly Thr Phe Glu Arg 420 425 430

    Asp Ile Leu Lys Ser Arg Arg Gly Ile Lys Gly Asn Arg Asp Val Gln 435 440 445

    Glu Ser Leu Val Ser Phe Tyr Asp Glu Leu Thr Lys Phe Arg Ser Ala 450 455 460

    Leu Arg Ile Ile Asn Ser Gly Asn Asp Glu Lys Ala Asp Pro Ile Phe 465 470 475 480

    Tyr Asn Thr Phe Asp Gly Ile Phe Glu Lys Ala Asn Arg Thr Tyr Lys 485 490 495

    Ala Glu Asn Leu Cys Arg Asn Tyr Val Thr Lys Ser Pro Ala Asp Asp 500 505 510

    Ala Arg Ile Met Ala Ser Cys Leu Gly Thr Pro Ala Arg Leu Arg Thr 515 520 525

    His Trp Trp Asn Gly Glu Glu Asn Phe Ala Ile Asn Asp Val Ala Met

    530

    535

    540

    Ile Arg Arg Gly Asp Glu Tyr Tyr Tyr Phe Val Leu Thr Pro Asp Val 545 550 555 560

    Lys Pro Val Asp Leu Lys Thr Lys Asp Glu Thr Asp Ala Gln Ile Phe 565 570 575

    Val Gln Arg Lys Gly Ala Lys Ser Phe Leu Gly Leu Pro Lys Ala Leu 580 585 590

    Phe Lys Cys Ile Leu Glu Pro Tyr Phe Glu Ser Pro Glu His Lys Asn 595 600 605

    Asp Lys Asn Cys Val Ile Glu Glu Tyr Val Ser Lys Pro Leu Thr Ile 610 615 620

    Asp Arg Arg Ala Tyr Asp Ile Phe Lys Asn Gly Thr Phe Lys Lys Thr 625 630 635 640

    Asn Ile Gly Ile Asp Gly Leu Thr Glu Glu Lys Phe Lys Asp Asp Cys 645 650 655

    Arg Tyr Leu Ile Asp Val Tyr Lys Glu Phe Ile Ala Val Tyr Thr Arg 660 665 670

    Tyr Ser Cys Phe Asn Met Ser Gly Leu Lys Arg Ala Asp Glu Tyr Asn 675 680 685

    Asp Ile Gly Glu Phe Phe Ser Asp Val Asp Thr Arg Leu Cys Thr Met 690 695 700

    Glu Trp Ile Pro Val Ser Phe Glu Arg Ile Asn Asp Met Val Asp Lys 705 710 715 720

    Lys Glu Gly Leu Leu Phe Leu Val Arg Ser Met Phe Leu Tyr Asn Arg 725 730 735

    Pro Arg Lys Pro Tyr Glu Arg Thr Phe Ile Gln Leu Phe Ser Asp Ser 740 745 750

    Asn Met Glu His Thr Ser Met Leu Leu Asn Ser Arg Ala Met Ile Gln 755 760 765

    Tyr Arg Ala Ala Ser Leu Pro Arg Arg Val Thr His Lys Lys Gly Ser 770 775 780

    Ile Leu Val Ala Leu Arg Asp Ser Asn Gly Glu His Ile Pro Met His 785 790 795 800

    Ile Arg Glu Ala Ile Tyr Lys Met Lys Asn Asn Phe Asp Ile Ser Ser 805 810 815

    Glu Asp Phe Ile Met Ala Lys Ala Tyr Leu Ala Glu His Asp Val Ala 820 825 830

    Ile Lys Lys Ala Asn Glu Asp Ile Ile Arg Asn Arg Arg Tyr Thr Glu 835 840 845

    Asp Lys Phe Phe Leu Ser Leu Ser Tyr Thr Lys Asn Ala Asp Ile Ser 850 855 860

    Ala Arg Thr Leu Asp Tyr Ile Asn Asp Lys Val Glu Glu Asp Thr Gln 865 870 875 880

    Asp Ser Arg Met Ala Val Ile Val Thr Arg Asn Leu Lys Asp Leu Thr 885 890 895

    Tyr Val Ala Val Val Asp Glu Lys Asn Asn Val Leu Glu Glu Lys Ser 900 905 910

    Leu Asn Glu Ile Asp Gly Val Asn Tyr Arg Glu Leu Leu Lys Glu Arg 915 920 925

    Thr Lys Ile Lys Tyr His Asp Lys Thr Arg Leu Trp Gln Tyr Asp Val 930 935 940

    Ser Ser Lys Gly Leu Lys Glu Ala Tyr Val Glu Leu Ala Val Thr Gln 945 950 955 960

    Ile Ser Lys Leu Ala Thr Lys Tyr Asn Ala Val Val Val Val Glu Ser 965 970 975

    Met Ser Ser Thr Phe Lys Asp Lys Phe Ser Phe Leu Asp Glu Gln Ile 980 985 990

    Phe Lys Ala Phe Glu Ala Arg Leu Cys Ala Arg Met Ser Asp Leu Ser 995 1000 1005

    Phe Asn Thr Ile Lys Glu Gly Glu Ala Gly Ser Ile Ser Asn Pro 1010 1015 1020

    Ile Gln Val Ser Asn Asn Asn Gly Asn Ser Tyr Gln Asp Gly Val 1025 1030 1035

    Ile Tyr Phe Leu Asn Asn Ala Tyr Thr Arg Thr Leu Cys Pro Asp 1040 1045 1050

    Thr Gly Phe Val Asp Val Phe Asp Lys Thr Arg Leu Ile Thr Met 1055 1060 1065

    Gln Ser Lys Arg Gln Phe Phe Ala Lys Met Lys Asp Ile Arg Ile 1070 1075 1080

    Asp Asp Gly Glu Met Leu Phe Thr Phe Asn Leu Glu Glu Tyr Pro 1085 1090 1095

    Thr Lys Arg Leu Leu Asp Arg Lys Glu Trp Thr Val Lys Ile Ala 1100 1105 1110

    Gly Asp Gly Ser Tyr Phe Asp Lys Asp Lys Gly Glu Tyr Val Tyr 1115 1120 1125

    Val Asn Asp Ile Val Arg Glu Gln Ile Ile Pro Ala Leu Leu Glu 1130 1135 1140

    Asp Lys Ala Val Phe Asp Gly Asn Met Ala Glu Lys Phe Leu Asp 1145 1150 1155

    Lys Thr Ala Ile Ser Gly Lys Ser Val Glu Leu Ile Tyr Lys Trp 1160 1165 1170

    Phe Ala Asn Ala Leu Tyr Gly Ile Ile Thr Lys Lys Asp Gly Glu 1175 1180 1185

    Lys Ile Tyr Arg Ser Pro Ile Thr Gly Thr Glu Ile Asp Val Ser 1190 1195 1200

    Lys Asn Thr Thr Tyr Asn Phe Gly Lys Lys Phe Met Phe Lys Gln 1205 1210 1215

    Glu Tyr Arg Gly Asp Gly Asp Phe Leu Asp Ala Phe Leu Asn Tyr 1220 1225 1230

    Met Gln Ala Gln Asp Ile Ala Val

    1235

    1240 <210> 104 <211> 1238 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanoplasma termitum sequence <400> 104

    Met Asn Asn Tyr Asp Glu Phe Thr Lys Leu Tyr Pro Ile Gln Lys Thr 1 5 10 15

    Ile Arg Phe Glu Leu Lys Pro Gln Gly Arg Thr Met Glu His Leu Glu 20 25 30

    Thr Phe Asn Phe Phe Glu Glu Asp Arg Asp Arg Ala Glu Lys Tyr Lys 35 40 45

    Ile Leu Lys Glu Ala Ile Asp Glu Tyr His Lys Lys Phe Ile Asp Glu 50 55 60

    His Leu Thr Asn Met Ser Leu Asp Trp Asn Ser Leu Lys Gln Ile Ser 65 70 75 80

    Glu Lys Tyr Tyr Lys Ser Arg Glu Glu Lys Asp Lys Lys Val Phe Leu 85 90 95

    Ser Glu Gln Lys Arg Met Arg Gln Glu Ile Val Ser Glu Phe Lys Lys 100 105 110

    Asp Asp Arg Phe Lys Asp Leu Phe Ser Lys Lys Leu Phe Ser Glu Leu 115 120 125

    Leu Lys Glu Glu Ile Tyr Lys Lys Gly Asn His Gln Glu Ile Asp Ala 130 135 140

    Leu Lys Ser Phe Asp Lys Phe Ser Gly Tyr Phe Ile Gly Leu His Glu 145 150 155 160

    Asn Arg Lys Asn Met Tyr Ser Asp Gly Asp Glu Ile Thr Ala Ile Ser 165 170 175

    Asn Arg Ile Val Asn Glu Asn Phe Pro Lys Phe Leu Asp Asn Leu Gln 180 185 190

    Lys Tyr Gln Glu Ala Arg Lys Lys Tyr Pro Glu Trp Ile Ile Lys Ala 195 200 205

    Glu Ser Ala Leu Val Ala His Asn Ile Lys Met Asp Glu Val Phe Ser 210 215 220

    Leu Glu Tyr Phe Asn Lys Val Leu Asn Gln Glu Gly Ile Gln Arg Tyr 225 230 235 240

    Asn Leu Ala Leu Gly Gly Tyr Val Thr Lys Ser Gly Glu Lys Met Met 245 250 255

    Gly Leu Asn Asp Ala Leu Asn Leu Ala His Gln Ser Glu Lys Ser Ser 260 265 270

    Lys Gly Arg Ile His Met Thr Pro Leu Phe Lys Gln Ile Leu Ser Glu 275 280 285

    Lys Glu Ser Phe Ser Tyr Ile Pro Asp Val Phe Thr Glu Asp Ser Gln 290 295 300

    Leu Leu Pro Ser Ile Gly Gly Phe Phe Ala Gln Ile Glu Asn Asp Lys

    305

    310

    315

    320

    Asp Gly Asn Ile Phe Asp Arg Ala Leu Glu Leu Ile Ser Ser Tyr Ala 325 330 335

    Glu Tyr Asp Thr Glu Arg Ile Tyr Ile Arg Gln Ala Asp Ile Asn Arg 340 345 350

    Val Ser Asn Val Ile Phe Gly Glu Trp Gly Thr Leu Gly Gly Leu Met 355 360 365

    Arg Glu Tyr Lys Ala Asp Ser Ile Asn Asp Ile Asn Leu Glu Arg Thr 370 375 380

    Cys Lys Lys Val Asp Lys Trp Leu Asp Ser Lys Glu Phe Ala Leu Ser 385 390 395 400

    Asp Val Leu Glu Ala Ile Lys Arg Thr Gly Asn Asn Asp Ala Phe Asn 405 410 415

    Glu Tyr Ile Ser Lys Met Arg Thr Ala Arg Glu Lys Ile Asp Ala Ala 420 425 430

    Arg Lys Glu Met Lys Phe Ile Ser Glu Lys Ile Ser Gly Asp Glu Glu 435 440 445

    Ser Ile His Ile Ile Lys Thr Leu Leu Asp Ser Val Gln Gln Phe Leu 450 455 460

    His Phe Phe Asn Leu Phe Lys Ala Arg Gln Asp Ile Pro Leu Asp Gly 465 470 475 480

    Ala Phe Tyr Ala Glu Phe Asp Glu Val His Ser Lys Leu Phe Ala Ile 485 490 495

    Val Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Lys Asn Asn Leu 500 505 510

    Asn Thr Lys Lys Ile Lys Leu Asn Phe Lys Asn Pro Thr Leu Ala Asn 515 520 525

    Gly Trp Asp Gln Asn Lys Val Tyr Asp Tyr Ala Ser Leu Ile Phe Leu 530 535 540

    Arg Asp Gly Asn Tyr Tyr Leu Gly Ile Ile Asn Pro Lys Arg Lys Lys 545 550 555 560

    Asn Ile Lys Phe Glu Gln Gly Ser Gly Asn Gly Pro Phe Tyr Arg Lys 565 570 575

    Met Val Tyr Lys Gln Ile Pro Gly Pro Asn Lys Asn Leu Pro Arg Val 580 585 590

    Phe Leu Thr Ser Thr Lys Gly Lys Lys Glu Tyr Lys Pro Ser Lys Glu 595 600 605

    Ile Ile Glu Gly Tyr Glu Ala Asp Lys His Ile Arg Gly Asp Lys Phe 610 615 620

    Asp Leu Asp Phe Cys His Lys Leu Ile Asp Phe Phe Lys Glu Ser Ile 625 630 635 640

    Glu Lys His Lys Asp Trp Ser Lys Phe Asn Phe Tyr Phe Ser Pro Thr 645 650 655

    Glu Ser Tyr Gly Asp Ile Ser Glu Phe Tyr Leu Asp Val Glu Lys Gln 660 665 670

    Gly Tyr Arg Met His Phe Glu Asn Ile Ser Ala Glu Thr Ile Asp Glu 675 680 685

    Tyr Val Glu Lys Gly Asp Leu Phe Leu Phe Gln Ile Tyr Asn Lys Asp 690 695 700

    Phe Val Lys Ala Ala Thr Gly Lys Lys Asp Met His Thr Ile Tyr Trp 705 710 715 720

    Asn Ala Ala Phe Ser Pro Glu Asn Leu Gln Asp Val Val Val Lys Leu 725 730 735

    Asn Gly Glu Ala Glu Leu Phe Tyr Arg Asp Lys Ser Asp Ile Lys Glu 740 745 750

    Ile Val His Arg Glu Gly Glu Ile Leu Val Asn Arg Thr Tyr Asn Gly 755 760 765

    Arg Thr Pro Val Pro Asp Lys Ile His Lys Lys Leu Thr Asp Tyr His 770 775 780

    Asn Gly Arg Thr Lys Asp Leu Gly Glu Ala Lys Glu Tyr Leu Asp Lys 785 790 795 800

    Val Arg Tyr Phe Lys Ala His Tyr Asp Ile Thr Lys Asp Arg Arg Tyr 805 810 815

    Leu Asn Asp Lys Ile Tyr Phe His Val Pro Leu Thr Leu Asn Phe Lys 820 825 830

    Ala Asn Gly Lys Lys Asn Leu Asn Lys Met Val Ile Glu Lys Phe Leu 835 840 845

    Ser Asp Glu Lys Ala His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn 850 855 860

    Leu Leu Tyr Tyr Ser Ile Ile Asp Arg Ser Gly Lys Ile Ile Asp Gln 865 870 875 880

    Gln Ser Leu Asn Val Ile Asp Gly Phe Asp Tyr Arg Glu Lys Leu Asn 885 890 895

    Gln Arg Glu Ile Glu Met Lys Asp Ala Arg Gln Ser Trp Asn Ala Ile 900 905 910

    Gly Lys Ile Lys Asp Leu Lys Glu Gly Tyr Leu Ser Lys Ala Val His 915 920 925

    Glu Ile Thr Lys Met Ala Ile Gln Tyr Asn Ala Ile Val Val Met Glu 930 935 940

    Glu Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln 945 950 955 960

    Ile Tyr Gln Lys Phe Glu Asn Met Leu Ile Asp Lys Met Asn Tyr Leu 965 970 975

    Val Phe Lys Asp Ala Pro Asp Glu Ser Pro Gly Gly Val Leu Asn Ala 980 985 990

    Tyr Gln Leu Thr Asn Pro Leu Glu Ser Phe Ala Lys Leu Gly Lys Gln 995 1000 1005

    Thr Gly Ile Leu Phe Tyr Val Pro Ala Ala Tyr Thr Ser Lys Ile 1010 1015 1020

    Asp Pro Thr Thr Gly Phe Val Asn Leu Phe Asn Thr Ser Ser Lys

    1025

    1030

    1035

    Thr Asn Ala Gln Glu Arg Lys Glu Phe Leu Gln Lys Phe Glu Ser 1040 1045 1050

    Ile Ser Tyr Ser Ala Lys Asp Gly Gly Ile Phe Ala Phe Ala Phe 1055 1060 1065

    Asp Tyr Arg Lys Phe Gly Thr Ser Lys Thr Asp His Lys Asn Val 1070 1075 1080

    Trp Thr Ala Tyr Thr Asn Gly Glu Arg Met Arg Tyr Ile Lys Glu 1085 1090 1095

    Lys Lys Arg Asn Glu Leu Phe Asp Pro Ser Lys Glu Ile Lys Glu 1100 1105 1110

    Ala Leu Thr Ser Ser Gly Ile Lys Tyr Asp Gly Gly Gln Asn Ile 1115 1120 1125

    Leu Pro Asp Ile Leu Arg Ser Asn Asn Asn Gly Leu Ile Tyr Thr 1130 1135 1140

    Met Tyr Ser Ser Phe Ile Ala Ala Ile Gln Met Arg Val Tyr Asp 1145 1150 1155

    Gly Lys Glu Asp Tyr Ile Ile Ser Pro Ile Lys Asn Ser Lys Gly 1160 1165 1170

    Glu Phe Phe Arg Thr Asp Pro Lys Arg Arg Glu Leu Pro Ile Asp 1175 1180 1185

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Arg Gly Glu Leu 1190 1195 1200

    Thr Met Arg Ala Ile Ala Glu Lys Phe Asp Pro Asp Ser Glu Lys 1205 1210 1215

    Met Ala Lys Leu Glu Leu Lys His Lys Asp Trp Phe Glu Phe Met 1220 1225 1230

    Gln Thr Arg Gly Asp 1235 <210> 105 <211> 1235 <212> PRT <213> Anaerovibrio sp.

    <400> 105

    Met Val Ala Phe Ile Asp Glu Phe Val Gly Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Ala Arg Pro Val Pro Glu Thr Lys Lys Trp Leu 20 25 30

    Glu Ser Asp Gln Cys Ser Val Leu Phe Asn Asp Gln Lys Arg Asn Glu 35 40 45

    Tyr Tyr Gly Val Leu Lys Glu Leu Leu Asp Asp Tyr Tyr Arg Ala Tyr 50 55 60

    Ile Glu Asp Ala Leu Thr Ser Phe Thr Leu Asp Lys Ala Leu Leu Glu 65 70 75 80

    Asn Ala Tyr Asp Leu Tyr Cys Asn Arg Asp Thr Asn Ala Phe Ser Ser 85 90 95

    Cys Cys Glu Lys Leu Arg Lys Asp Leu Val Lys Ala Phe Gly Asn Leu

    100

    105

    110

    Lys Asp Tyr Leu Leu Gly Ser Asp Gln Leu Lys Asp Leu Val Lys Leu 115 120 125

    Lys Ala Lys Val Asp Ala Pro Ala Gly Lys Gly Lys Lys Lys Ile Glu 130 135 140

    Val Asp Ser Arg Leu Ile Asn Trp Leu Asn Asn Asn Ala Lys Tyr Ser 145 150 155 160

    Ala Glu Asp Arg Glu Lys Tyr Ile Lys Ala Ile Glu Ser Phe Glu Gly 165 170 175

    Phe Val Thr Tyr Leu Thr Asn Tyr Lys Gln Ala Arg Glu Asn Met Phe 180 185 190

    Ser Ser Glu Asp Lys Ser Thr Ala Ile Ala Phe Arg Val Ile Asp Gln 195 200 205

    Asn Met Val Thr Tyr Phe Gly Asn Ile Arg Ile Tyr Glu Lys Ile Lys 210 215 220

    Ala Lys Tyr Pro Glu Leu Tyr Ser Ala Leu Lys Gly Phe Glu Lys Phe 225 230 235 240

    Phe Ser Pro Thr Ala Tyr Ser Glu Ile Leu Ser Gln Ser Lys Ile Asp 245 250 255

    Glu Tyr Asn Tyr Gln Cys Ile Gly Arg Pro Ile Asp Asp Ala Asp Phe 260 265 270

    Lys Gly Val Asn Ser Leu Ile Asn Glu Tyr Arg Gln Lys Asn Gly Ile 275 280 285

    Lys Ala Arg Glu Leu Pro Val Met Ser Met Leu Tyr Lys Gln Ile Leu 290 295 300

    Ser Asp Arg Asp Asn Ser Phe Met Ser Glu Val Ile Asn Arg Asn Glu 305 310 315 320

    Glu Ala Ile Glu Cys Ala Lys Asn Gly Tyr Lys Val Ser Tyr Ala Leu 325 330 335

    Phe Asn Glu Leu Leu Gln Leu Tyr Lys Lys Ile Phe Thr Glu Asp Asn 340 345 350

    Tyr Gly Asn Ile Tyr Val Lys Thr Gln Pro Leu Thr Glu Leu Ser Gln 355 360 365

    Ala Leu Phe Gly Asp Trp Ser Ile Leu Arg Asn Ala Leu Asp Asn Gly 370 375 380

    Lys Tyr Asp Lys Asp Ile Ile Asn Leu Ala Glu Leu Glu Lys Tyr Phe 385 390 395 400

    Ser Glu Tyr Cys Lys Val Leu Asp Ala Asp Asp Ala Ala Lys Ile Gln 405 410 415

    Asp Lys Phe Asn Leu Lys Asp Tyr Phe Ile Gln Lys Asn Ala Leu Asp 420 425 430

    Ala Thr Leu Pro Asp Leu Asp Lys Ile Thr Gln Tyr Lys Pro His Leu 435 440 445

    Asp Ala Met Leu Gln Ala Ile Arg Lys Tyr Lys Leu Phe Ser Met Tyr 450 455 460

    Asn Gly Arg Lys Lys Met Asp Val Pro Glu Asn Gly Ile Asp Phe Ser 465 470 475 480

    Asn Glu Phe Asn Ala Ile Tyr Asp Lys Leu Ser Glu Phe Ser Ile Leu 485 490 495

    Tyr Asp Arg Ile Arg Asn Phe Ala Thr Lys Lys Pro Tyr Ser Asp Glu 500 505 510

    Lys Met Lys Leu Ser Phe Asn Met Pro Thr Met Leu Ala Gly Trp Asp 515 520 525

    Tyr Asn Asn Glu Thr Ala Asn Gly Cys Phe Leu Phe Ile Lys Asp Gly 530 535 540

    Lys Tyr Phe Leu Gly Val Ala Asp Ser Lys Ser Lys Asn Ile Phe Asp 545 550 555 560

    Phe Lys Lys Asn Pro His Leu Leu Asp Lys Tyr Ser Ser Lys Asp Ile 565 570 575

    Tyr Tyr Lys Val Lys Tyr Lys Gln Val Ser Gly Ser Ala Lys Met Leu 580 585 590

    Pro Lys Val Val Phe Ala Gly Ser Asn Glu Lys Ile Phe Gly His Leu 595 600 605

    Ile Ser Lys Arg Ile Leu Glu Ile Arg Glu Lys Lys Leu Tyr Thr Ala 610 615 620

    Ala Ala Gly Asp Arg Lys Ala Val Ala Glu Trp Ile Asp Phe Met Lys 625 630 635 640

    Ser Ala Ile Ala Ile His Pro Glu Trp Asn Glu Tyr Phe Lys Phe Lys 645 650 655

    Phe Lys Asn Thr Ala Glu Tyr Asp Asn Ala Asn Lys Phe Tyr Glu Asp 660 665 670

    Ile Asp Lys Gln Thr Tyr Ser Leu Glu Lys Val Glu Ile Pro Thr Glu 675 680 685

    Tyr Ile Asp Glu Met Val Ser Gln His Lys Leu Tyr Leu Phe Gln Leu 690 695 700

    Tyr Thr Lys Asp Phe Ser Asp Lys Lys Lys Lys Lys Gly Thr Asp Asn 705 710 715 720

    Leu His Thr Met Tyr Trp His Gly Val Phe Ser Asp Glu Asn Leu Lys 725 730 735

    Ala Val Thr Glu Gly Thr Gln Pro Ile Ile Lys Leu Asn Gly Glu Ala 740 745 750

    Glu Met Phe Met Arg Asn Pro Ser Ile Glu Phe Gln Val Thr His Glu 755 760 765

    His Asn Lys Pro Ile Ala Asn Lys Asn Pro Leu Asn Thr Lys Lys Glu 770 775 780

    Ser Val Phe Asn Tyr Asp Leu Ile Lys Asp Lys Arg Tyr Thr Glu Arg 785 790 795 800

    Lys Phe Tyr Phe His Cys Pro Ile Thr Leu Asn Phe Arg Ala Asp Lys 805 810 815

    Pro Ile Lys Tyr Asn Glu Lys Ile Asn Arg Phe Val Glu Asn Asn Pro

    820

    825

    830

    Asp Val Cys Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr 835 840 845

    Tyr Thr Val Ile Asn Gln Thr Gly Asp Ile Leu Glu Gln Gly Ser Leu 850 855 860

    Asn Lys Ile Ser Gly Ser Tyr Thr Asn Asp Lys Gly Glu Lys Val Asn 865 870 875 880

    Lys Glu Thr Asp Tyr His Asp Leu Leu Asp Arg Lys Glu Lys Gly Lys 885 890 895

    His Val Ala Gln Gln Ala Trp Glu Thr Ile Glu Asn Ile Lys Glu Leu 900 905 910

    Lys Ala Gly Tyr Leu Ser Gln Val Val Tyr Lys Leu Thr Gln Leu Met 915 920 925

    Leu Gln Tyr Asn Ala Val Ile Val Leu Glu Asn Leu Asn Val Gly Phe 930 935 940

    Lys Arg Gly Arg Thr Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 945 950 955 960

    Lys Ala Met Ile Asp Lys Leu Asn Tyr Leu Val Phe Lys Asp Arg Gly 965 970 975

    Tyr Glu Met Asn Gly Ser Tyr Ala Lys Gly Leu Gln Leu Thr Asp Lys 980 985 990

    Phe Glu Ser Phe Asp Lys Ile Gly Lys Gln Thr Gly Cys Ile Tyr Tyr 995 1000 1005

    Val Ile Pro Ser Tyr Thr Ser His Ile Asp Pro Lys Thr Gly Phe 1010 1015 1020

    Val Asn Leu Leu Asn Ala Lys Leu Arg Tyr Glu Asn Ile Thr Lys 1025 1030 1035

    Ala Gln Asp Thr Ile Arg Lys Phe Asp Ser Ile Ser Tyr Asn Ala 1040 1045 1050

    Lys Ala Asp Tyr Phe Glu Phe Ala Phe Asp Tyr Arg Ser Phe Gly 1055 1060 1065

    Val Asp Met Ala Arg Asn Glu Trp Val Val Cys Thr Cys Gly Asp 1070 1075 1080

    Leu Arg Trp Glu Tyr Ser Ala Lys Thr Arg Glu Thr Lys Ala Tyr 1085 1090 1095

    Ser Val Thr Asp Arg Leu Lys Glu Leu Phe Lys Ala His Gly Ile 1100 1105 1110

    Asp Tyr Val Gly Gly Glu Asn Leu Val Ser His Ile Thr Glu Val 1115 1120 1125

    Ala Asp Lys His Phe Leu Ser Thr Leu Leu Phe Tyr Leu Arg Leu 1130 1135 1140

    Val Leu Lys Met Arg Tyr Thr Val Ser Gly Thr Glu Asn Glu Asn 1145 1150 1155

    Asp Phe Ile Leu Ser Pro Val Glu Tyr Ala Pro Gly Lys Phe Phe 1160 1165 1170

    Asp Ser Arg Glu Ala Thr Ser Thr Glu Pro Met Asn Ala Asp Ala 1175 1180 1185

    Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Met Thr Ile Arg 1190 1195 1200

    Gly Ile Glu Asp Gly Lys Leu His Asn Tyr Gly Lys Gly Gly Glu 1205 1210 1215

    Asn Ala Ala Trp Phe Lys Phe Met Gln Asn Gln Glu Tyr Lys Asn 1220 1225 1230

    Asn Gly 1235 <210> 106 <211> 1233 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 106

    Met Asp Tyr Gly Asn Gly Gln Phe Glu Arg Arg Ala Pro Leu Thr Lys 1 5 10 15

    Thr Ile Thr Leu Arg Leu Lys Pro Ile Gly Glu Thr Arg Glu Thr Ile 20 25 30

    Arg Glu Gln Lys Leu Leu Glu Gln Asp Ala Ala Phe Arg Lys Leu Val 35 40 45

    Glu Thr Val Thr Pro Ile Val Asp Asp Cys Ile Arg Lys Ile Ala Asp 50 55 60

    Asn Ala Leu Cys His Phe Gly Thr Glu Tyr Asp Phe Ser Cys Leu Gly 65 70 75 80

    Asn Ala Ile Ser Lys Asn Asp Ser Lys Ala Ile Lys Lys Glu Thr Glu 85 90 95

    Lys Val Glu Lys Leu Leu Ala Lys Val Leu Thr Glu Asn Leu Pro Asp 100 105 110

    Gly Leu Arg Lys Val Asn Asp Ile Asn Ser Ala Ala Phe Ile Gln Asp 115 120 125

    Thr Leu Thr Ser Phe Val Gln Asp Asp Ala Asp Lys Arg Val Leu Ile 130 135 140

    Gln Glu Leu Lys Gly Lys Thr Val Leu Met Gln Arg Phe Leu Thr Thr 145 150 155 160

    Arg Ile Thr Ala Leu Thr Val Trp Leu Pro Asp Arg Val Phe Glu Asn 165 170 175

    Phe Asn Ile Phe Ile Glu Asn Ala Glu Lys Met Arg Ile Leu Leu Asp 180 185 190

    Ser Pro Leu Asn Glu Lys Ile Met Lys Phe Asp Pro Asp Ala Glu Gln 195 200 205

    Tyr Ala Ser Leu Glu Phe Tyr Gly Gln Cys Leu Ser Gln Lys Asp Ile 210 215 220

    Asp Ser Tyr Asn Leu Ile Ile Ser Gly Ile Tyr Ala Asp Asp Glu Val 225 230 235 240

    Lys Asn Pro Gly Ile Asn Glu Ile Val Lys Glu Tyr Asn Gln Gln Ile 245 250 255

    Arg Gly Asp Lys Asp Glu Ser Pro Leu Pro Lys Leu Lys Lys Leu His 260 265 270

    Lys Gln Ile Leu Met Pro Val Glu Lys Ala Phe Phe Val Arg Val Leu 275 280 285

    Ser Asn Asp Ser Asp Ala Arg Ser Ile Leu Glu Lys Ile Leu Lys Asp 290 295 300

    Thr Glu Met Leu Pro Ser Lys Ile Ile Glu Ala Met Lys Glu Ala Asp 305 310 315 320

    Ala Gly Asp Ile Ala Val Tyr Gly Ser Arg Leu His Glu Leu Ser His 325 330 335

    Val Ile Tyr Gly Asp His Gly Lys Leu Ser Gln Ile Ile Tyr Asp Lys 340 345 350

    Glu Ser Lys Arg Ile Ser Glu Leu Met Glu Thr Leu Ser Pro Lys Glu 355 360 365

    Arg Lys Glu Ser Lys Lys Arg Leu Glu Gly Leu Glu Glu His Ile Arg 370 375 380

    Lys Ser Thr Tyr Thr Phe Asp Glu Leu Asn Arg Tyr Ala Glu Lys Asn 385 390 395 400

    Val Met Ala Ala Tyr Ile Ala Ala Val Glu Glu Ser Cys Ala Glu Ile 405 410 415

    Met Arg Lys Glu Lys Asp Leu Arg Thr Leu Leu Ser Lys Glu Asp Val 420 425 430

    Lys Ile Arg Gly Asn Arg His Asn Thr Leu Ile Val Lys Asn Tyr Phe 435 440 445

    Asn Ala Trp Thr Val Phe Arg Asn Leu Ile Arg Ile Leu Arg Arg Lys 450 455 460

    Ser Glu Ala Glu Ile Asp Ser Asp Phe Tyr Asp Val Leu Asp Asp Ser 465 470 475 480

    Val Glu Val Leu Ser Leu Thr Tyr Lys Gly Glu Asn Leu Cys Arg Ser 485 490 495

    Tyr Ile Thr Lys Lys Ile Gly Ser Asp Leu Lys Pro Glu Ile Ala Thr 500 505 510

    Tyr Gly Ser Ala Leu Arg Pro Asn Ser Arg Trp Trp Ser Pro Gly Glu 515 520 525

    Lys Phe Asn Val Lys Phe His Thr Ile Val Arg Arg Asp Gly Arg Leu 530 535 540

    Tyr Tyr Phe Ile Leu Pro Lys Gly Ala Lys Pro Val Glu Leu Glu Asp 545 550 555 560

    Met Asp Gly Asp Ile Glu Cys Leu Gln Met Arg Lys Ile Pro Asn Pro 565 570 575

    Thr Ile Phe Leu Pro Lys Leu Val Phe Lys Asp Pro Glu Ala Phe Phe 580 585 590

    Arg Asp Asn Pro Glu Ala Asp Glu Phe Val Phe Leu Ser Gly Met Lys

    595

    600

    605

    Ala Pro Val Thr Ile Thr Arg Glu Thr Tyr Glu Ala Tyr Arg Tyr Lys 610 615 620

    Leu Tyr Thr Val Gly Lys Leu Arg Asp Gly Glu Val Ser Glu Glu Glu 625 630 635 640

    Tyr Lys Arg Ala Leu Leu Gln Val Leu Thr Ala Tyr Lys Glu Phe Leu 645 650 655

    Glu Asn Arg Met Ile Tyr Ala Asp Leu Asn Phe Gly Phe Lys Asp Leu 660 665 670

    Glu Glu Tyr Lys Asp Ser Ser Glu Phe Ile Lys Gln Val Glu Thr His 675 680 685

    Asn Thr Phe Met Cys Trp Ala Lys Val Ser Ser Ser Gln Leu Asp Asp 690 695 700

    Leu Val Lys Ser Gly Asn Gly Leu Leu Phe Glu Ile Trp Ser Glu Arg 705 710 715 720

    Leu Glu Ser Tyr Tyr Lys Tyr Gly Asn Glu Lys Val Leu Arg Gly Tyr 725 730 735

    Glu Gly Val Leu Leu Ser Ile Leu Lys Asp Glu Asn Leu Val Ser Met 740 745 750

    Arg Thr Leu Leu Asn Ser Arg Pro Met Leu Val Tyr Arg Pro Lys Glu 755 760 765

    Ser Ser Lys Pro Met Val Val His Arg Asp Gly Ser Arg Val Val Asp 770 775 780

    Arg Phe Asp Lys Asp Gly Lys Tyr Ile Pro Pro Glu Val His Asp Glu 785 790 795 800

    Leu Tyr Arg Phe Phe Asn Asn Leu Leu Ile Lys Glu Lys Leu Gly Glu 805 810 815

    Lys Ala Arg Lys Ile Leu Asp Asn Lys Lys Val Lys Val Lys Val Leu 820 825 830

    Glu Ser Glu Arg Val Lys Trp Ser Lys Phe Tyr Asp Glu Gln Phe Ala 835 840 845

    Val Thr Phe Ser Val Lys Lys Asn Ala Asp Cys Leu Asp Thr Thr Lys 850 855 860

    Asp Leu Asn Ala Glu Val Met Glu Gln Tyr Ser Glu Ser Asn Arg Leu 865 870 875 880

    Ile Leu Ile Arg Asn Thr Thr Asp Ile Leu Tyr Tyr Leu Val Leu Asp 885 890 895

    Lys Asn Gly Lys Val Leu Lys Gln Arg Ser Leu Asn Ile Ile Asn Asp 900 905 910

    Gly Ala Arg Asp Val Asp Trp Lys Glu Arg Phe Arg Gln Val Thr Lys 915 920 925

    Asp Arg Asn Glu Gly Tyr Asn Glu Trp Asp Tyr Ser Arg Thr Ser Asn 930 935 940

    Asp Leu Lys Glu Val Tyr Leu Asn Tyr Ala Leu Lys Glu Ile Ala Glu 945 950 955 960

    Ala Val Ile Glu Tyr Asn Ala Ile Leu Ile Ile Glu Lys Met Ser Asn 965 970 975

    Ala Phe Lys Asp Lys Tyr Ser Phe Leu Asp Asp Val Thr Phe Lys Gly 980 985 990

    Phe Glu Thr Lys Leu Leu Ala Lys Leu Ser Asp Leu His Phe Arg Gly 995 1000 1005

    Ile Lys Asp Gly Glu Pro Cys Ser Phe Thr Asn Pro Leu Gln Leu 1010 1015 1020

    Cys Gln Asn Asp Ser Asn Lys Ile Leu Gln Asp Gly Val Ile Phe 1025 1030 1035

    Met Val Pro Asn Ser Met Thr Arg Ser Leu Asp Pro Asp Thr Gly 1040 1045 1050

    Phe Ile Phe Ala Ile Asn Asp His Asn Ile Arg Thr Lys Lys Ala 1055 1060 1065

    Lys Leu Asn Phe Leu Ser Lys Phe Asp Gln Leu Lys Val Ser Ser 1070 1075 1080

    Glu Gly Cys Leu Ile Met Lys Tyr Ser Gly Asp Ser Leu Pro Thr 1085 1090 1095

    His Asn Thr Asp Asn Arg Val Trp Asn Cys Cys Cys Asn His Pro 1100 1105 1110

    Ile Thr Asn Tyr Asp Arg Glu Thr Lys Lys Val Glu Phe Ile Glu 1115 1120 1125

    Glu Pro Val Glu Glu Leu Ser Arg Val Leu Glu Glu Asn Gly Ile 1130 1135 1140

    Glu Thr Asp Thr Glu Leu Asn Lys Leu Asn Glu Arg Glu Asn Val 1145 1150 1155

    Pro Gly Lys Val Val Asp Ala Ile Tyr Ser Leu Val Leu Asn Tyr 1160 1165 1170

    Leu Arg Gly Thr Val Ser Gly Val Ala Gly Gln Arg Ala Val Tyr 1175 1180 1185

    Tyr Ser Pro Val Thr Gly Lys Lys Tyr Asp Ile Ser Phe Ile Gln 1190 1195 1200

    Ala Met Asn Leu Asn Arg Lys Cys Asp Tyr Tyr Arg Ile Gly Ser 1205 1210 1215

    Lys Glu Arg Gly Glu Trp Thr Asp Phe Val Ala Gln Leu Ile Asn 1220 1225 1230 <210> 107 <211> 1231 <212> PRT <213> Butyrivibrio fibrisolvens <400> 107

    Met Tyr Tyr Glu Ser Leu Thr Lys Leu Tyr Pro Ile Lys Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Val Pro Ile Gly Lys Thr Leu Glu Asn Ile Lys Lys 20 25 30

    Asn Asn Ile Leu Glu Ala Asp Glu Asp Arg Lys Ile Ala Tyr Ile Arg 35 40 45

    Val Lys Ala Ile Met Asp Asp Tyr His Lys Arg Leu Ile Asn Glu Ala 50 55 60

    Leu Ser Gly Phe Ala Leu Ile Asp Leu Asp Lys Ala Ala Asn Leu Tyr 65 70 75 80

    Leu Ser Arg Ser Lys Ser Ala Asp Asp Ile Glu Ser Phe Ser Arg Phe 85 90 95

    Gln Asp Lys Leu Arg Lys Ala Ile Ala Lys Arg Leu Arg Glu His Glu 100 105 110

    Asn Phe Gly Lys Ile Gly Asn Lys Asp Ile Ile Pro Leu Leu Gln Lys 115 120 125

    Leu Ser Glu Asn Glu Asp Asp Tyr Asn Ala Leu Glu Ser Phe Lys Asn 130 135 140

    Phe Tyr Thr Tyr Phe Glu Ser Tyr Asn Asp Val Arg Leu Asn Leu Tyr 145 150 155 160

    Ser Asp Lys Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn Glu 165 170 175

    Asn Leu Pro Arg Phe Leu Asp Asn Ile Arg Ala Tyr Asp Ala Val Gln 180 185 190

    Lys Ala Gly Ile Thr Ser Glu Glu Leu Ser Ser Glu Ala Gln Asp Gly 195 200 205

    Leu Phe Leu Val Asn Thr Phe Asn Asn Val Leu Ile Gln Asp Gly Ile 210 215 220

    Asn Thr Tyr Asn Glu Asp Ile Gly Lys Leu Asn Val Ala Ile Asn Leu 225 230 235 240

    Tyr Asn Gln Lys Asn Ala Ser Val Gln Gly Phe Arg Lys Val Pro Lys 245 250 255

    Met Lys Val Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ser Phe 260 265 270

    Ile Asp Glu Phe Glu Ser Asp Thr Glu Leu Leu Asp Ser Leu Glu Ser 275 280 285

    His Tyr Ala Asn Leu Ala Lys Tyr Phe Gly Ser Asn Lys Val Gln Leu 290 295 300

    Leu Phe Thr Ala Leu Arg Glu Ser Lys Gly Val Asn Val Tyr Val Lys 305 310 315 320

    Asn Asp Ile Ala Lys Thr Ser Phe Ser Asn Val Val Phe Gly Ser Trp 325 330 335

    Ser Arg Ile Asp Glu Leu Ile Asn Gly Glu Tyr Asp Asp Asn Asn Asn 340 345 350

    Arg Lys Lys Asp Glu Lys Tyr Tyr Asp Lys Arg Gln Lys Glu Leu Lys 355 360 365

    Lys Asn Lys Ser Tyr Thr Ile Glu Lys Ile Ile Thr Leu Ser Thr Glu 370 375 380

    Asp Val Asp Val Ile Gly Lys Tyr Ile Glu Lys Leu Glu Ser Asp Ile 385 390 395 400

    Asp Asp Ile Arg Phe Lys Gly Lys Asn Phe Tyr Glu Ala Val Leu Cys

    405

    410

    415

    Gly His Asp Arg Ser Lys Lys Leu Ser Lys Asn Lys Gly Ala Val Glu 420 425 430

    Ala Ile Lys Gly Tyr Leu Asp Ser Val Lys Asp Phe Glu Arg Asp Leu 435 440 445

    Lys Leu Ile Asn Gly Ser Gly Gln Glu Leu Glu Lys Asn Leu Val Val 450 455 460

    Tyr Gly Glu Gln Glu Ala Val Leu Ser Glu Leu Ser Gly Ile Asp Ser 465 470 475 480

    Leu Tyr Asn Met Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe Ser Thr 485 490 495

    Glu Lys Ile Lys Leu Asn Phe Asn Lys Pro Thr Phe Leu Asp Gly Trp 500 505 510

    Asp Tyr Gly Asn Glu Glu Ala Tyr Leu Gly Phe Phe Met Ile Lys Glu 515 520 525

    Gly Asn Tyr Phe Leu Ala Val Met Asp Ala Asn Trp Asn Lys Glu Phe 530 535 540

    Arg Asn Ile Pro Ser Val Asp Lys Ser Asp Cys Tyr Lys Lys Val Ile 545 550 555 560

    Tyr Lys Gln Ile Ser Ser Pro Glu Lys Ser Ile Gln Asn Leu Met Val 565 570 575

    Ile Asp Gly Lys Thr Val Lys Lys Asn Gly Arg Lys Glu Lys Glu Gly 580 585 590

    Ile His Ser Gly Glu Asn Leu Ile Leu Glu Glu Leu Lys Asn Thr Tyr 595 600 605

    Leu Pro Lys Lys Ile Asn Asp Ile Arg Lys Arg Arg Ser Tyr Leu Asn 610 615 620

    Gly Asp Thr Phe Ser Lys Lys Asp Leu Thr Glu Phe Ile Gly Tyr Tyr 625 630 635 640

    Lys Gln Arg Val Ile Glu Tyr Tyr Asn Gly Tyr Ser Phe Tyr Phe Lys 645 650 655

    Ser Asp Asp Asp Tyr Ala Ser Phe Lys Glu Phe Gln Glu Asp Val Gly 660 665 670

    Arg Gln Ala Tyr Gln Ile Ser Tyr Val Asp Val Pro Val Ser Phe Val 675 680 685

    Asp Asp Leu Ile Asn Ser Gly Lys Leu Tyr Leu Phe Arg Val Tyr Asn 690 695 700

    Lys Asp Phe Ser Glu Tyr Ser Lys Gly Arg Leu Asn Leu His Thr Leu 705 710 715 720

    Tyr Phe Lys Met Leu Phe Asp Glu Arg Asn Leu Lys Asn Val Val Tyr 725 730 735

    Lys Leu Asn Gly Gln Ala Glu Val Phe Tyr Arg Pro Ser Ser Ile Lys 740 745 750

    Lys Glu Glu Leu Ile Val His Arg Ala Gly Glu Glu Ile Lys Asn Lys 755 760 765

    Asn Pro Lys Arg Ala Ala Gln Lys Pro Thr Arg Arg Leu Asp Tyr Asp 770 775 780

    Ile Val Lys Asp Arg Arg Tyr Ser Gln Asp Lys Phe Met Leu His Thr 785 790 795 800

    Ser Ile Ile Met Asn Phe Gly Ala Glu Glu Asn Val Ser Phe Asn Asp 805 810 815

    Ile Val Asn Gly Val Leu Arg Asn Glu Asp Lys Val Asn Val Ile Gly 820 825 830

    Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asp Pro 835 840 845

    Glu Gly Lys Ile Leu Glu Gln Arg Ser Leu Asn Cys Ile Thr Asp Ser 850 855 860

    Asn Leu Asp Ile Glu Thr Asp Tyr His Arg Leu Leu Asp Glu Lys Glu 865 870 875 880

    Ser Asp Arg Lys Ile Ala Arg Arg Asp Trp Thr Thr Ile Glu Asn Ile 885 890 895

    Lys Glu Leu Lys Ala Gly Tyr Leu Ser Gln Val Val His Ile Val Ala 900 905 910

    Glu Leu Val Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn 915 920 925

    Phe Gly Phe Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln 930 935 940

    Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Met Asp 945 950 955 960

    Lys Ser Arg Glu Gln Leu Ser Pro Glu Lys Ile Ser Gly Ala Leu Asn 965 970 975

    Ala Leu Gln Leu Thr Pro Asp Phe Lys Ser Phe Lys Val Leu Gly Lys 980 985 990

    Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile 995 1000 1005

    Asp Pro Met Thr Gly Phe Ala Asn Leu Phe Tyr Val Lys Tyr Glu 1010 1015 1020

    Asn Val Asp Lys Ala Lys Glu Phe Phe Ser Lys Phe Asp Ser Ile 1025 1030 1035

    Lys Tyr Asn Lys Asp Gly Lys Asn Trp Asn Thr Lys Gly Tyr Phe 1040 1045 1050

    Glu Phe Ala Phe Asp Tyr Lys Lys Phe Thr Asp Arg Ala Tyr Gly 1055 1060 1065

    Arg Val Ser Glu Trp Thr Val Cys Thr Val Gly Glu Arg Ile Ile 1070 1075 1080

    Lys Phe Lys Asn Lys Glu Lys Asn Asn Ser Tyr Asp Asp Lys Val 1085 1090 1095

    Ile Asp Leu Thr Asn Ser Leu Lys Glu Leu Phe Asp Ser Tyr Lys 1100 1105 1110

    Val Thr Tyr Glu Ser Glu Val Asp Leu Lys Asp Ala Ile Leu Ala

    1115

    1120

    1125

    Ile Asp Asp Pro Ala Phe Tyr Arg Asp Leu Thr Arg Arg Leu Gln 1130 1135 1140

    Gln Thr Leu Gln Met Arg Asn Ser Ser Cys Asp Gly Ser Arg Asp 1145 1150 1155

    Tyr Ile Ile Ser Pro Val Lys Asn Ser Lys Gly Glu Phe Phe Cys 1160 1165 1170

    Ser Asp Asn Asn Asp Asp Thr Thr Pro Asn Asp Ala Asp Ala Asn 1175 1180 1185

    Gly Ala Phe Asn Ile Ala Arg Lys Gly Leu Trp Val Leu Asn Glu 1190 1195 1200

    Ile Arg Asn Ser Glu Glu Gly Ser Lys Ile Asn Leu Ala Met Ser 1205 1210 1215

    Asn Ala Gln Trp Leu Glu Tyr Ala Gln Asp Asn Thr Ile 1220 1225 1230 <210> 108 <211> 1230 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 108

    Met His Glu Asn Asn Gly Lys Ile Ala Asp Asn Phe Ile Gly Ile Tyr

    1 5 10 15

    Pro Val Ser Lys Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr 20 25 30

    Gln Glu Tyr Ile Glu Lys His Gly Ile Leu Asp Glu Asp Leu Lys Arg 35 40 45

    Ala Gly Asp Tyr Lys Ser Val Lys Lys Ile Ile Asp Ala Tyr His Lys 50 55 60

    Tyr Phe Ile Asp Glu Ala Leu Asn Gly Ile Gln Leu Asp Gly Leu Lys 65 70 75 80

    Asn Tyr Tyr Glu Leu Tyr Glu Lys Lys Arg Asp Asn Asn Glu Glu Lys 85 90 95

    Glu Phe Gln Lys Ile Gln Met Ser Leu Arg Lys Gln Ile Val Lys Arg 100 105 110

    Phe Ser Glu His Pro Gln Tyr Lys Tyr Leu Phe Lys Lys Glu Leu Ile 115 120 125

    Lys Asn Val Leu Pro Glu Phe Thr Lys Asp Asn Ala Glu Glu Gln Thr 130 135 140

    Leu Val Lys Ser Phe Gln Glu Phe Thr Thr Tyr Phe Glu Gly Phe His 145 150 155 160

    Gln Asn Arg Lys Asn Met Tyr Ser Asp Glu Glu Lys Ser Thr Ala Ile 165 170 175

    Ala Tyr Arg Val Val His Gln Asn Leu Pro Lys Tyr Ile Asp Asn Met 180 185 190

    Arg Ile Phe Ser Met Ile Leu Asn Thr Asp Ile Arg Ser Asp Leu Thr

    195

    200

    205

    Glu Leu Phe Asn Asn Leu Lys Thr Lys Met Asp Ile Thr Ile Val Glu 210 215 220

    Glu Tyr Phe Ala Ile Asp Gly Phe Asn Lys Val Val Asn Gln Lys Gly 225 230 235 240

    Ile Asp Val Tyr Asn Thr Ile Leu Gly Ala Phe Ser Thr Asp Asp Asn 245 250 255

    Thr Lys Ile Lys Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn Gln Lys 260 265 270

    Asn Lys Ala Lys Leu Pro Lys Leu Lys Pro Leu Phe Lys Gln Ile Leu 275 280 285

    Ser Asp Arg Asp Lys Ile Ser Phe Ile Pro Glu Gln Phe Asp Ser Asp 290 295 300

    Thr Glu Val Leu Glu Ala Val Asp Met Phe Tyr Asn Arg Leu Leu Gln 305 310 315 320

    Phe Val Ile Glu Asn Glu Gly Gln Ile Thr Ile Ser Lys Leu Leu Thr 325 330 335

    Asn Phe Ser Ala Tyr Asp Leu Asn Lys Ile Tyr Val Lys Asn Asp Thr 340 345 350

    Thr Ile Ser Ala Ile Ser Asn Asp Leu Phe Asp Asp Trp Ser Tyr Ile 355 360 365

    Ser Lys Ala Val Arg Glu Asn Tyr Asp Ser Glu Asn Val Asp Lys Asn 370 375 380

    Lys Arg Ala Ala Ala Tyr Glu Glu Lys Lys Glu Lys Ala Leu Ser Lys 385 390 395 400

    Ile Lys Met Tyr Ser Ile Glu Glu Leu Asn Phe Phe Val Lys Lys Tyr 405 410 415

    Ser Cys Asn Glu Cys His Ile Glu Gly Tyr Phe Glu Arg Arg Ile Leu 420 425 430

    Glu Ile Leu Asp Lys Met Arg Tyr Ala Tyr Glu Ser Cys Lys Ile Leu 435 440 445

    His Asp Lys Gly Leu Ile Asn Asn Ile Ser Leu Cys Gln Asp Arg Gln 450 455 460

    Ala Ile Ser Glu Leu Lys Asp Phe Leu Asp Ser Ile Lys Glu Val Gln 465 470 475 480

    Trp Leu Leu Lys Pro Leu Met Ile Gly Gln Glu Gln Ala Asp Lys Glu 485 490 495

    Glu Ala Phe Tyr Thr Glu Leu Leu Arg Ile Trp Glu Glu Leu Glu Pro 500 505 510

    Ile Thr Leu Leu Tyr Asn Lys Val Arg Asn Tyr Val Thr Lys Lys Pro 515 520 525

    Tyr Thr Leu Glu Lys Val Lys Leu Asn Phe Tyr Lys Ser Thr Leu Leu 530 535 540

    Asp Gly Trp Asp Lys Asn Lys Glu Lys Asp Asn Leu Gly Ile Ile Leu 545 550 555 560

    Leu Lys Asp Gly Gln Tyr Tyr Leu Gly Ile Met Asn Arg Arg Asn Asn 565 570 575

    Lys Ile Ala Asp Asp Ala Pro Leu Ala Lys Thr Asp Asn Val Tyr Arg 580 585 590

    Lys Met Glu Tyr Lys Leu Leu Thr Lys Val Ser Ala Asn Leu Pro Arg 595 600 605

    Ile Phe Leu Lys Asp Lys Tyr Asn Pro Ser Glu Glu Met Leu Glu Lys 610 615 620

    Tyr Glu Lys Gly Thr His Leu Lys Gly Glu Asn Phe Cys Ile Asp Asp 625 630 635 640

    Cys Arg Glu Leu Ile Asp Phe Phe Lys Lys Gly Ile Lys Gln Tyr Glu 645 650 655

    Asp Trp Gly Gln Phe Asp Phe Lys Phe Ser Asp Thr Glu Ser Tyr Asp 660 665 670

    Asp Ile Ser Ala Phe Tyr Lys Glu Val Glu His Gln Gly Tyr Lys Ile 675 680 685

    Thr Phe Arg Asp Ile Asp Glu Thr Tyr Ile Asp Ser Leu Val Asn Glu 690 695 700

    Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Tyr 705 710 715 720

    Ser Lys Gly Thr Lys Asn Leu His Thr Leu Tyr Trp Glu Met Leu Phe 725 730 735

    Ser Gln Gln Asn Leu Gln Asn Ile Val Tyr Lys Leu Asn Gly Asn Ala 740 745 750

    Glu Ile Phe Tyr Arg Lys Ala Ser Ile Asn Gln Lys Asp Val Val Val 755 760 765

    His Lys Ala Asp Leu Pro Ile Lys Asn Lys Asp Pro Gln Asn Ser Lys 770 775 780

    Lys Glu Ser Met Phe Asp Tyr Asp Ile Ile Lys Asp Lys Arg Phe Thr 785 790 795 800

    Cys Asp Lys Tyr Gln Phe His Val Pro Ile Thr Met Asn Phe Lys Ala 805 810 815

    Leu Gly Glu Asn His Phe Asn Arg Lys Val Asn Arg Leu Ile His Asp 820 825 830

    Ala Glu Asn Met His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu 835 840 845

    Ile Tyr Leu Cys Met Ile Asp Met Lys Gly Asn Ile Val Lys Gln Ile 850 855 860

    Ser Leu Asn Glu Ile Ile Ser Tyr Asp Lys Asn Lys Leu Glu His Lys 865 870 875 880

    Arg Asn Tyr His Gln Leu Leu Lys Thr Arg Glu Asp Glu Asn Lys Ser 885 890 895

    Ala Arg Gln Ser Trp Gln Thr Ile His Thr Ile Lys Glu Leu Lys Glu 900 905 910

    Gly Tyr Leu Ser Gln Val Ile His Val Ile Thr Asp Leu Met Val Glu

    915

    920

    925

    Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly Phe Lys Gln 930 935 940

    Gly Arg Gln Lys Phe Glu Arg Gln Val Tyr Gln Lys Phe Glu Lys Met 945 950 955 960

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Ser Lys Gly Met Asp 965 970 975

    Glu Asp Gly Gly Leu Leu His Ala Tyr Gln Leu Thr Asp Glu Phe Lys 980 985 990

    Ser Phe Lys Gln Leu Gly Lys Gln Ser Gly Phe Leu Tyr Tyr Ile Pro 995 1000 1005

    Ala Trp Asn Thr Ser Lys Leu Asp Pro Thr Thr Gly Phe Val Asn 1010 1015 1020

    Leu Phe Tyr Thr Lys Tyr Glu Ser Val Glu Lys Ser Lys Glu Phe 1025 1030 1035

    Ile Asn Asn Phe Thr Ser Ile Leu Tyr Asn Gln Glu Arg Glu Tyr 1040 1045 1050

    Phe Glu Phe Leu Phe Asp Tyr Ser Ala Phe Thr Ser Lys Ala Glu 1055 1060 1065

    Gly Ser Arg Leu Lys Trp Thr Val Cys Ser Lys Gly Glu Arg Val 1070 1075 1080

    Glu Thr Tyr Arg Asn Pro Lys Lys Asn Asn Glu Trp Asp Thr Gln 1085 1090 1095

    Lys Ile Asp Leu Thr Phe Glu Leu Lys Lys Leu Phe Asn Asp Tyr 1100 1105 1110

    Ser Ile Ser Leu Leu Asp Gly Asp Leu Arg Glu Gln Met Gly Lys 1115 1120 1125

    Ile Asp Lys Ala Asp Phe Tyr Lys Lys Phe Met Lys Leu Phe Ala 1130 1135 1140

    Leu Ile Val Gln Met Arg Asn Ser Asp Glu Arg Glu Asp Lys Leu 1145 1150 1155

    Ile Ser Pro Val Leu Asn Lys Tyr Gly Ala Phe Phe Glu Thr Gly 1160 1165 1170

    Lys Asn Glu Arg Met Pro Leu Asp Ala Asp Ala Asn Gly Ala Tyr 1175 1180 1185

    Asn Ile Ala Arg Lys Gly Leu Trp Ile Ile Glu Lys Ile Lys Asn 1190 1195 1200

    Thr Asp Val Glu Gln Leu Asp Lys Val Lys Leu Thr Ile Ser Asn 1205 1210 1215

    Lys Glu Trp Leu Gln Tyr Ala Gln Glu His Ile Leu 1220 1225 1230 <210> 109 <211> 1228 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 109

    Met Ser Lys Leu Glu Lys Phe Thr Asn Cys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Lys Ala Ile Pro Val Gly Lys Thr Gln Glu Asn Ile Asp 20 25 30

    Asn Lys Arg Leu Leu Val Glu Asp Glu Lys Arg Ala Glu Asp Tyr Lys 35 40 45

    Gly Val Lys Lys Leu Leu Asp Arg Tyr Tyr Leu Ser Phe Ile Asn Asp 50 55 60

    Val Leu His Ser Ile Lys Leu Lys Asn Leu Asn Asn Tyr Ile Ser Leu 65 70 75 80

    Phe Arg Lys Lys Thr Arg Thr Glu Lys Glu Asn Lys Glu Leu Glu Asn 85 90 95

    Leu Glu Ile Asn Leu Arg Lys Glu Ile Ala Lys Ala Phe Lys Gly Asn 100 105 110

    Glu Gly Tyr Lys Ser Leu Phe Lys Lys Asp Ile Ile Glu Thr Ile Leu 115 120 125

    Pro Glu Phe Leu Asp Asp Lys Asp Glu Ile Ala Leu Val Asn Ser Phe 130 135 140

    Asn Gly Phe Thr Thr Ala Phe Thr Gly Phe Phe Asp Asn Arg Glu Asn 145 150 155 160

    Met Phe Ser Glu Glu Ala Lys Ser Thr Ser Ile Ala Phe Arg Cys Ile 165 170 175

    Asn Glu Asn Leu Thr Arg Tyr Ile Ser Asn Met Asp Ile Phe Glu Lys 180 185 190

    Val Asp Ala Ile Phe Asp Lys His Glu Val Gln Glu Ile Lys Glu Lys 195 200 205

    Ile Leu Asn Ser Asp Tyr Asp Val Glu Asp Phe Phe Glu Gly Glu Phe 210 215 220

    Phe Asn Phe Val Leu Thr Gln Glu Gly Ile Asp Val Tyr Asn Ala Ile 225 230 235 240

    Ile Gly Gly Phe Val Thr Glu Ser Gly Glu Lys Ile Lys Gly Leu Asn 245 250 255

    Glu Tyr Ile Asn Leu Tyr Asn Gln Lys Thr Lys Gln Lys Leu Pro Lys 260 265 270

    Phe Lys Pro Leu Tyr Lys Gln Val Leu Ser Asp Arg Glu Ser Leu Ser 275 280 285

    Phe Tyr Gly Glu Gly Tyr Thr Ser Asp Glu Glu Val Leu Glu Val Phe 290 295 300

    Arg Asn Thr Leu Asn Lys Asn Ser Glu Ile Phe Ser Ser Ile Lys Lys 305 310 315 320

    Leu Glu Lys Leu Phe Lys Asn Phe Asp Glu Tyr Ser Ser Ala Gly Ile 325 330 335

    Phe Val Lys Asn Gly Pro Ala Ile Ser Thr Ile Ser Lys Asp Ile Phe 340 345 350

    Gly Glu Trp Asn Val Ile Arg Asp Lys Trp Asn Ala Glu Tyr Asp Asp 355 360 365

    Ile His Leu Lys Lys Lys Ala Val Val Thr Glu Lys Tyr Glu Asp Asp 370 375 380

    Arg Arg Lys Ser Phe Lys Lys Ile Gly Ser Phe Ser Leu Glu Gln Leu 385 390 395 400

    Gln Glu Tyr Ala Asp Ala Asp Leu Ser Val Val Glu Lys Leu Lys Glu 405 410 415

    Ile Ile Ile Gln Lys Val Asp Glu Ile Tyr Lys Val Tyr Gly Ser Ser 420 425 430

    Glu Lys Leu Phe Asp Ala Asp Phe Val Leu Glu Lys Ser Leu Lys Lys 435 440 445

    Asn Asp Ala Val Val Ala Ile Met Lys Asp Leu Leu Asp Ser Val Lys 450 455 460

    Ser Phe Glu Asn Tyr Ile Lys Ala Phe Phe Gly Glu Gly Lys Glu Thr 465 470 475 480

    Asn Arg Asp Glu Ser Phe Tyr Gly Asp Phe Val Leu Ala Tyr Asp Ile 485 490 495

    Leu Leu Lys Val Asp His Ile Tyr Asp Ala Ile Arg Asn Tyr Val Thr 500 505 510

    Gln Lys Pro Tyr Ser Lys Asp Lys Phe Lys Leu Tyr Phe Gln Asn Pro 515 520 525

    Gln Phe Met Gly Gly Trp Asp Lys Asp Lys Glu Thr Asp Tyr Arg Ala 530 535 540

    Thr Ile Leu Arg Tyr Gly Ser Lys Tyr Tyr Leu Ala Ile Met Asp Lys 545 550 555 560

    Lys Tyr Ala Lys Cys Leu Gln Lys Ile Asp Lys Asp Asp Val Asn Gly 565 570 575

    Asn Tyr Glu Lys Ile Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met 580 585 590

    Leu Pro Lys Val Phe Phe Ser Lys Lys Trp Met Ala Tyr Tyr Asn Pro 595 600 605

    Ser Glu Asp Ile Gln Lys Ile Tyr Lys Asn Gly Thr Phe Lys Lys Gly 610 615 620

    Asp Met Phe Asn Leu Asn Asp Cys His Lys Leu Ile Asp Phe Phe Lys 625 630 635 640

    Asp Ser Ile Ser Arg Tyr Pro Lys Trp Ser Asn Ala Tyr Asp Phe Asn 645 650 655

    Phe Ser Glu Thr Glu Lys Tyr Lys Asp Ile Ala Gly Phe Tyr Arg Glu 660 665 670

    Val Glu Glu Gln Gly Tyr Lys Val Ser Phe Glu Ser Ala Ser Lys Lys 675 680 685

    Glu Val Asp Lys Leu Val Glu Glu Gly Lys Leu Tyr Met Phe Gln Ile 690 695 700

    Tyr Asn Lys Asp Phe Ser Asp Lys Ser His Gly Thr Pro Asn Leu His

    705

    710

    715

    720

    Thr Met Tyr Phe Lys Leu Leu Phe Asp Glu Asn Asn His Gly Gln Ile 725 730 735

    Arg Leu Ser Gly Gly Ala Glu Leu Phe Met Arg Arg Ala Ser Leu Lys 740 745 750

    Lys Glu Glu Leu Val Val His Pro Ala Asn Ser Pro Ile Ala Asn Lys 755 760 765

    Asn Pro Asp Asn Pro Lys Lys Thr Thr Thr Leu Ser Tyr Asp Val Tyr 770 775 780

    Lys Asp Lys Arg Phe Ser Glu Asp Gln Tyr Glu Leu His Ile Pro Ile 785 790 795 800

    Ala Ile Asn Lys Cys Pro Lys Asn Ile Phe Lys Ile Asn Thr Glu Val 805 810 815

    Arg Val Leu Leu Lys His Asp Asp Asn Pro Tyr Val Ile Gly Ile Asp 820 825 830

    Arg Gly Glu Arg Asn Leu Leu Tyr Ile Val Val Val Asp Gly Lys Gly 835 840 845

    Asn Ile Val Glu Gln Tyr Ser Leu Asn Glu Ile Ile Asn Asn Phe Asn 850 855 860

    Gly Ile Arg Ile Lys Thr Asp Tyr His Ser Leu Leu Asp Lys Lys Glu 865 870 875 880

    Lys Glu Arg Phe Glu Ala Arg Gln Asn Trp Thr Ser Ile Glu Asn Ile 885 890 895

    Lys Glu Leu Lys Ala Gly Tyr Ile Ser Gln Val Val His Lys Ile Cys 900 905 910

    Glu Leu Val Glu Lys Tyr Asp Ala Val Ile Ala Leu Glu Asp Leu Asn 915 920 925

    Ser Gly Phe Lys Asn Ser Arg Val Lys Val Glu Lys Gln Val Tyr Gln 930 935 940

    Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Met Val Asp Lys 945 950 955 960

    Lys Ser Asn Pro Cys Ala Thr Gly Gly Ala Leu Lys Gly Tyr Gln Ile 965 970 975

    Thr Asn Lys Phe Glu Ser Phe Lys Ser Met Ser Thr Gln Asn Gly Phe 980 985 990

    Ile Phe Tyr Ile Pro Ala Trp Leu Thr Ser Lys Ile Asp Pro Ser Thr 995 1000 1005

    Gly Phe Val Asn Leu Leu Lys Thr Lys Tyr Thr Ser Ile Ala Asp 1010 1015 1020

    Ser Lys Lys Phe Ile Ser Ser Phe Asp Arg Ile Met Tyr Val Pro 1025 1030 1035

    Glu Glu Asp Leu Phe Glu Phe Ala Leu Asp Tyr Lys Asn Phe Ser 1040 1045 1050

    Arg Thr Asp Ala Asp Tyr Ile Lys Lys Trp Lys Leu Tyr Ser Tyr 1055 1060 1065

    Gly Asn Arg Ile Arg Ile Phe Arg Asn Pro Lys Lys Asn Asn Val 1070 1075 1080

    Phe Asp Trp Glu Glu Val Cys Leu Thr Ser Ala Tyr Lys Glu Leu 1085 1090 1095

    Phe Asn Lys Tyr Gly Ile Asn Tyr Gln Gln Gly Asp Ile Arg Ala 1100 1105 1110

    Leu Leu Cys Glu Gln Ser Asp Lys Ala Phe Tyr Ser Ser Phe Met 1115 1120 1125

    Ala Leu Met Ser Leu Met Leu Gln Met Arg Asn Ser Ile Thr Gly 1130 1135 1140

    Arg Thr Asp Val Asp Phe Leu Ile Ser Pro Val Lys Asn Ser Asp 1145 1150 1155

    Gly Ile Phe Tyr Asp Ser Arg Asn Tyr Glu Ala Gln Glu Asn Ala 1160 1165 1170

    Ile Leu Pro Lys Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala 1175 1180 1185

    Arg Lys Val Leu Trp Ala Ile Gly Gln Phe Lys Lys Ala Glu Asp 1190 1195 1200

    Leu Glu Tyr Ala Gln Thr Ser Val Lys His 1220 1225

    Glu Lys Leu Asp Lys Val Lys Ile Ala Ile Ser Asn Lys Glu Trp

    1205 1210 1215 <210> 110 <211> 1227 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 110

    Met Asp Ala Lys Glu Phe Thr Gly Gln Tyr Pro Leu Ser Lys Thr Leu 1 5 10 15

    Arg Phe Glu Leu Arg Pro Ile Gly Arg Thr Trp Asp Asn Leu Glu Ala 20 25 30

    Ser Gly Tyr Leu Ala Glu Asp Arg His Arg Ala Glu Cys Tyr Pro Arg 35 40 45

    Ala Lys Glu Leu Leu Asp Asp Asn His Arg Ala Phe Leu Asn Arg Val 50 55 60

    Leu Pro Gln Ile Asp Met Asp Trp His Pro Ile Ala Glu Ala Phe Cys 65 70 75 80

    Lys Val His Lys Asn Pro Gly Asn Lys Glu Leu Ala Gln Asp Tyr Asn 85 90 95

    Leu Gln Leu Ser Lys Arg Arg Lys Glu Ile Ser Ala Tyr Leu Gln Asp 100 105 110

    Ala Asp Gly Tyr Lys Gly Leu Phe Ala Lys Pro Ala Leu Asp Glu Ala 115 120 125

    Met Lys Ile Ala Lys Glu Asn Gly Asn Glu Ser Asp Ile Glu Val Leu 130 135 140

    Glu Ala Phe Asn Gly Phe Ser Val Tyr Phe Thr Gly Tyr His Glu Ser 145 150 155 160

    Arg Glu Asn Ile Tyr Ser Asp Glu Asp Met Val Ser Val Ala Tyr Arg 165 170 175

    Ile Thr Glu Asp Asn Phe Pro Arg Phe Val Ser Asn Ala Leu Ile Phe 180 185 190

    Asp Lys Leu Asn Glu Ser His Pro Asp Ile Ile Ser Glu Val Ser Gly 195 200 205

    Asn Leu Gly Val Asp Asp Ile Gly Lys Tyr Phe Asp Val Ser Asn Tyr 210 215 220

    Asn Asn Phe Leu Ser Gln Ala Gly Ile Asp Asp Tyr Asn His Ile Ile 225 230 235 240

    Gly Gly His Thr Thr Glu Asp Gly Leu Ile Gln Ala Phe Asn Val Val 245 250 255

    Leu Asn Leu Arg His Gln Lys Asp Pro Gly Phe Glu Lys Ile Gln Phe 260 265 270

    Lys Gln Leu Tyr Lys Gln Ile Leu Ser Val Arg Thr Ser Lys Ser Tyr 275 280 285

    Ile Pro Lys Gln Phe Asp Asn Ser Lys Glu Met Val Asp Cys Ile Cys 290 295 300

    Asp Tyr Val Ser Lys Ile Glu Lys Ser Glu Thr Val Glu Arg Ala Leu 305 310 315 320

    Lys Leu Val Arg Asn Ile Ser Ser Phe Asp Leu Arg Gly Ile Phe Val 325 330 335

    Asn Lys Lys Asn Leu Arg Ile Leu Ser Asn Lys Leu Ile Gly Asp Trp 340 345 350

    Asp Ala Ile Glu Thr Ala Leu Met His Ser Ser Ser Ser Glu Asn Asp 355 360 365

    Lys Lys Ser Val Tyr Asp Ser Ala Glu Ala Phe Thr Leu Asp Asp Ile 370 375 380

    Phe Ser Ser Val Lys Lys Phe Ser Asp Ala Ser Ala Glu Asp Ile Gly 385 390 395 400

    Asn Arg Ala Glu Asp Ile Cys Arg Val Ile Ser Glu Thr Ala Pro Phe 405 410 415

    Ile Asn Asp Leu Arg Ala Val Asp Leu Asp Ser Leu Asn Asp Asp Gly 420 425 430

    Tyr Glu Ala Ala Val Ser Lys Ile Arg Glu Ser Leu Glu Pro Tyr Met 435 440 445

    Asp Leu Phe His Glu Leu Glu Ile Phe Ser Val Gly Asp Glu Phe Pro 450 455 460

    Lys Cys Ala Ala Phe Tyr Ser Glu Leu Glu Glu Val Ser Glu Gln Leu 465 470 475 480

    Ile Glu Ile Ile Pro Leu Phe Asn Lys Ala Arg Ser Phe Cys Thr Arg 485 490 495

    Lys Arg Tyr Ser Thr Asp Lys Ile Lys Val Asn Leu Lys Phe Pro Thr

    500

    505

    510

    Leu Ala Asp Gly Trp Asp Leu Asn Lys Glu Arg Asp Asn Lys Ala Ala 515 520 525

    Ile Leu Arg Lys Asp Gly Lys Tyr Tyr Leu Ala Ile Leu Asp Met Lys 530 535 540

    Lys Asp Leu Ser Ser Ile Arg Thr Ser Asp Glu Asp Glu Ser Ser Phe 545 550 555 560

    Glu Lys Met Glu Tyr Lys Leu Leu Pro Ser Pro Val Lys Met Leu Pro 565 570 575

    Lys Ile Phe Val Lys Ser Lys Ala Ala Lys Glu Lys Tyr Gly Leu Thr 580 585 590

    Asp Arg Met Leu Glu Cys Tyr Asp Lys Gly Met His Lys Ser Gly Ser 595 600 605

    Ala Phe Asp Leu Gly Phe Cys His Glu Leu Ile Asp Tyr Tyr Lys Arg 610 615 620

    Cys Ile Ala Glu Tyr Pro Gly Trp Asp Val Phe Asp Phe Lys Phe Arg 625 630 635 640

    Glu Thr Ser Asp Tyr Gly Ser Met Lys Glu Phe Asn Glu Asp Val Ala 645 650 655

    Gly Ala Gly Tyr Tyr Met Ser Leu Arg Lys Ile Pro Cys Ser Glu Val 660 665 670

    Tyr Arg Leu Leu Asp Glu Lys Ser Ile Tyr Leu Phe Gln Ile Tyr Asn 675 680 685

    Lys Asp Tyr Ser Glu Asn Ala His Gly Asn Lys Asn Met His Thr Met 690 695 700

    Tyr Trp Glu Gly Leu Phe Ser Pro Gln Asn Leu Glu Ser Pro Val Phe 705 710 715 720

    Lys Leu Ser Gly Gly Ala Glu Leu Phe Phe Arg Lys Ser Ser Ile Pro 725 730 735

    Asn Asp Ala Lys Thr Val His Pro Lys Gly Ser Val Leu Val Pro Arg 740 745 750

    Asn Asp Val Asn Gly Arg Arg Ile Pro Asp Ser Ile Tyr Arg Glu Leu 755 760 765

    Thr Arg Tyr Phe Asn Arg Gly Asp Cys Arg Ile Ser Asp Glu Ala Lys 770 775 780

    Ser Tyr Leu Asp Lys Val Lys Thr Lys Lys Ala Asp His Asp Ile Val 785 790 795 800

    Lys Asp Arg Arg Phe Thr Val Asp Lys Met Met Phe His Val Pro Ile 805 810 815

    Ala Met Asn Phe Lys Ala Ile Ser Lys Pro Asn Leu Asn Lys Lys Val 820 825 830

    Ile Asp Gly Ile Ile Asp Asp Gln Asp Leu Lys Ile Ile Gly Ile Asp 835 840 845

    Arg Gly Glu Arg Asn Leu Ile Tyr Val Thr Met Val Asp Arg Lys Gly 850 855 860

    Asn Ile Leu Tyr Gln Asp Ser Leu Asn Ile Leu Asn Gly Tyr Asp Tyr 865 870 875 880

    Arg Lys Ala Leu Asp Val Arg Glu Tyr Asp Asn Lys Glu Ala Arg Arg 885 890 895

    Asn Trp Thr Lys Val Glu Gly Ile Arg Lys Met Lys Glu Gly Tyr Leu 900 905 910

    Ser Leu Ala Val Ser Lys Leu Ala Asp Met Ile Ile Glu Asn Asn Ala 915 920 925

    Ile Ile Val Met Glu Asp Leu Asn His Gly Phe Lys Ala Gly Arg Ser 930 935 940

    Lys Ile Glu Lys Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 945 950 955 960

    Lys Leu Gly Tyr Met Val Leu Lys Asp Lys Ser Ile Asp Gln Ser Gly 965 970 975

    Gly Ala Leu His Gly Tyr Gln Leu Ala Asn His Val Thr Thr Leu Ala 980 985 990

    Ser Val Gly Lys Gln Cys Gly Val Ile Phe Tyr Ile Pro Ala Ala Phe 995 1000 1005

    Thr Ser Lys Ile Asp Pro Thr Thr Gly Phe Ala Asp Leu Phe Ala 1010 1015 1020

    Leu Ser Asn Val Lys Asn Val Ala Ser Met Arg Glu Phe Phe Ser 1025 1030 1035

    Lys Met Lys Ser Val Ile Tyr Asp Lys Ala Glu Gly Lys Phe Ala 1040 1045 1050

    Phe Thr Phe Asp Tyr Leu Asp Tyr Asn Val Lys Ser Glu Cys Gly 1055 1060 1065

    Arg Thr Leu Trp Thr Val Tyr Thr Val Gly Glu Arg Phe Thr Tyr 1070 1075 1080

    Ser Arg Val Asn Arg Glu Tyr Val Arg Lys Val Pro Thr Asp Ile 1085 1090 1095

    Ile Tyr Asp Ala Leu Gln Lys Ala Gly Ile Ser Val Glu Gly Asp 1100 1105 1110

    Leu Arg Asp Arg Ile Ala Glu Ser Asp Gly Asp Thr Leu Lys Ser 1115 1120 1125

    Ile Phe Tyr Ala Phe Lys Tyr Ala Leu Asp Met Arg Val Glu Asn 1130 1135 1140

    Arg Glu Glu Asp Tyr Ile Gln Ser Pro Val Lys Asn Ala Ser Gly 1145 1150 1155

    Glu Phe Phe Cys Ser Lys Asn Ala Gly Lys Ser Leu Pro Gln Asp 1160 1165 1170

    Ser Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Lys Gly Ile Leu 1175 1180 1185

    Gln Leu Arg Met Leu Ser Glu Gln Tyr Asp Pro Asn Ala Glu Ser 1190 1195 1200

    Ile Arg Leu Pro Leu Ile Thr Asn Lys Ala Trp Leu Thr Phe Met

    1205

    1210

    1215

    Gln Ser Gly Met Lys Thr Trp Lys Asn 1220 1225 <210> 111 <211> 1224 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 111

    Met Gly Leu Tyr Asp Gly Phe Val Asn Arg Tyr Ser Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Arg Thr Arg Glu Tyr Ile Glu 20 25 30

    Thr Asn Gly Ile Leu Ser Asp Asp Glu Glu Arg Ala Lys Asp Tyr Lys 35 40 45

    Thr Ile Lys Arg Leu Ile Asp Glu Tyr His Lys Asp Tyr Ile Ser Arg 50 55 60

    Cys Leu Lys Asn Val Asn Ile Ser Cys Leu Glu Glu Tyr Tyr His Leu 65 70 75 80

    Tyr Asn Ser Ser Asn Arg Asp Lys Arg His Glu Glu Leu Asp Ala Leu 85 90 95

    Ser Asp Gln Met Arg Gly Glu Ile Ala Ser Phe Leu Thr Gly Asn Asp 100 105 110

    Glu Tyr Lys Glu Gln Lys Ser Arg Asp Ile Ile Ile Asn Glu Arg Ile 115 120 125

    Ile Asn Phe Ala Ser Thr Asp Glu Glu Leu Ala Ala Val Lys Arg Phe 130 135 140

    Arg Lys Phe Thr Ser Tyr Phe Thr Gly Phe Phe Thr Asn Arg Glu Asn 145 150 155 160

    Met Tyr Ser Ala Glu Lys Lys Ser Thr Ala Ile Ala His Arg Ile Ile 165 170 175

    Asp Val Asn Leu Pro Lys Tyr Val Asp Asn Ile Lys Ala Phe Asn Thr 180 185 190

    Ala Ile Glu Ala Gly Val Phe Asp Ile Ala Glu Phe Glu Ser Asn Phe 195 200 205

    Lys Ala Ile Thr Asp Glu His Glu Val Ser Asp Leu Leu Asp Ile Thr 210 215 220

    Lys Tyr Ser Arg Phe Ile Arg Asn Glu Asp Ile Ile Ile Tyr Asn Thr 225 230 235 240

    Leu Leu Gly Gly Ile Ser Met Lys Asp Glu Lys Ile Gln Gly Leu Asn 245 250 255

    Glu Leu Ile Asn Leu His Asn Gln Lys His Pro Gly Lys Lys Val Pro 260 265 270

    Leu Leu Lys Val Leu Tyr Lys Gln Ile Leu Gly Asp Ser Gln Thr His 275 280 285

    Ser Phe Val Asp Asp Gln Phe Glu Asp Asp Gln Gln Val Ile Asn Ala

    290

    295

    300

    Val Lys Ala Val Thr Asp Thr Phe Ser Glu Thr Leu Leu Gly Ser Leu 305 310 315 320

    Lys Ile Ile Ile Asn Asn Ile Gly His Tyr Asp Leu Asp Arg Ile Tyr 325 330 335

    Ile Lys Ala Gly Gln Asp Ile Thr Thr Leu Ser Lys Arg Ala Leu Asn 340 345 350

    Asp Trp His Ile Ile Thr Glu Cys Leu Glu Ser Glu Tyr Asp Asp Lys 355 360 365

    Phe Pro Lys Asn Lys Lys Ser Asp Thr Tyr Glu Glu Met Arg Asn Arg 370 375 380

    Tyr Val Lys Ser Phe Lys Ser Phe Ser Ile Gly Arg Leu Asn Ser Leu 385 390 395 400

    Val Thr Thr Tyr Thr Glu Gln Ala Cys Phe Leu Glu Asn Tyr Leu Gly 405 410 415

    Ser Phe Gly Gly Asp Thr Asp Lys Asn Cys Leu Thr Asp Phe Thr Asn 420 425 430

    Ser Leu Met Glu Val Glu His Leu Leu Asn Ser Glu Tyr Pro Val Thr 435 440 445

    Asn Arg Leu Ile Thr Asp Tyr Glu Ser Val Arg Ile Leu Lys Arg Leu 450 455 460

    Leu Asp Ser Glu Met Glu Val Ile His Phe Leu Lys Pro Leu Leu Gly 465 470 475 480

    Asn Gly Asn Glu Ser Asp Lys Asp Leu Val Phe Tyr Gly Glu Phe Glu 485 490 495

    Ala Glu Tyr Glu Lys Leu Leu Pro Val Ile Lys Val Tyr Asn Arg Val 500 505 510

    Arg Asn Tyr Leu Thr Arg Lys Pro Phe Ser Thr Glu Lys Ile Lys Leu 515 520 525

    Asn Phe Asn Ser Pro Thr Leu Leu Cys Gly Trp Ser Gln Ser Lys Glu 530 535 540

    Lys Glu Tyr Met Gly Val Ile Leu Arg Lys Asp Gly Gln Tyr Tyr Leu 545 550 555 560

    Gly Ile Met Thr Pro Ser Asn Lys Lys Ile Phe Ser Glu Ala Pro Lys 565 570 575

    Pro Asp Glu Asp Cys Tyr Glu Lys Met Val Leu Arg Tyr Ile Pro His 580 585 590

    Pro Tyr Gln Met Leu Pro Lys Val Phe Phe Ser Lys Ser Asn Ile Ala 595 600 605

    Phe Phe Asn Pro Ser Asp Glu Ile Leu Arg Ile Lys Lys Gln Glu Ser 610 615 620

    Phe Lys Lys Gly Lys Ser Phe Asn Arg Asp Asp Cys His Lys Phe Ile 625 630 635 640

    Asp Phe Tyr Lys Asp Ser Ile Asn Arg His Glu Glu Trp Arg Lys Phe 645 650 655

    Asn Phe Lys Phe Ser Asp Thr Asp Ser Tyr Glu Asp Ile Ser Arg Phe 660 665 670

    Tyr Lys Glu Val Glu Asn Gln Ala Phe Ser Met Ser Phe Thr Lys Ile 675 680 685

    Pro Thr Val Tyr Ile Asp Ser Leu Val Asp Glu Gly Lys Leu Tyr Leu 690 695 700

    Phe Lys Leu His Asn Lys Asp Phe Ser Glu His Ser Lys Gly Lys Pro 705 710 715 720

    Asn Leu His Thr Val Tyr Trp Asn Ala Leu Phe Ser Glu Tyr Asn Leu 725 730 735

    Gln Asn Thr Val Tyr Gln Leu Asn Gly Ser Ala Glu Ile Phe Phe Arg 740 745 750

    Lys Ala Ser Ile Pro Glu Asn Glu Arg Val Ile His Lys Lys Asn Val 755 760 765

    Pro Ile Thr Arg Lys Val Ala Glu Leu Asn Gly Lys Lys Glu Val Ser 770 775 780

    Val Phe Pro Tyr Asp Ile Ile Lys Asn Arg Arg Tyr Thr Val Asp Lys 785 790 795 800

    Phe Gln Phe His Val Pro Leu Lys Met Asn Phe Lys Ala Asp Glu Lys 805 810 815

    Lys Arg Ile Asn Asp Asp Val Ile Glu Ala Ile Arg Ser Asn Lys Gly 820 825 830

    Ile His Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Leu 835 840 845

    Ser Leu Ile Asn Glu Glu Gly Arg Ile Ile Glu Gln Arg Ser Leu Asn 850 855 860

    Ile Ile Asp Ser Gly Glu Gly His Thr Gln Asn Tyr Arg Asp Leu Leu 865 870 875 880

    Asp Ser Arg Glu Lys Asp Arg Glu Lys Ala Arg Glu Asn Trp Gln Glu 885 890 895

    Ile Gln Glu Ile Lys Asp Leu Lys Thr Gly Tyr Leu Ser Gln Ala Ile 900 905 910

    His Thr Ile Thr Lys Trp Met Lys Glu Tyr Asn Ala Ile Ile Val Leu 915 920 925

    Glu Asp Leu Asn Asp Arg Phe Thr Asn Gly Arg Lys Lys Val Glu Lys 930 935 940

    Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr 945 950 955 960

    Tyr Val Asp Lys Asp Glu Glu Phe Asp Arg Met Gly Gly Thr His Arg 965 970 975

    Ala Leu Gln Leu Thr Glu Lys Phe Glu Ser Phe Gln Lys Leu Gly Arg 980 985 990

    Gln Thr Gly Phe Ile Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Leu 995 1000 1005

    Asp Pro Thr Thr Gly Phe Val Asp Leu Leu Tyr Pro Lys Tyr Lys

    1010

    1015

    1020

    Ser Val Asp Ala Thr Lys Asp Phe Ile Lys Lys Phe Asp Phe Ile 1025 1030 1035

    Arg Phe Asn Ser Glu Lys Asn Tyr Phe Glu Phe Gly Leu His Tyr 1040 1045 1050

    Ser Asn Phe Thr Glu Arg Ala Ile Gly Cys Arg Asp Glu Trp Ile 1055 1060 1065

    Leu Cys Ser Tyr Gly Asn Arg Ile Val Asn Phe Arg Asn Ala Ala 1070 1075 1080

    Lys Asn Asn Ser Trp Asp Tyr Lys Glu Ile Asp Ile Thr Lys Gln 1085 1090 1095

    Leu Leu Asp Leu Phe Glu Lys Asn Gly Ile Asp Val Lys Gln Glu 1100 1105 1110

    Asn Leu Ile Asp Ser Ile Cys Glu Met Lys Asp Lys Pro Phe Phe 1115 1120 1125

    Lys Ser Leu Ile Ala Asn Ile Lys Leu Ile Leu Gln Ile Arg Asn 1130 1135 1140

    Ser Ala Ser Gly Thr Asp Ile Asp Tyr Met Ile Ser Pro Ala Met 1145 1150 1155

    Asn Asp Arg Gly Glu Phe Phe Asp Thr Arg Lys Gly Leu Gln Gln 1160 1165 1170

    Leu Pro Leu Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Lys 1175 1180 1185

    Lys Gly Leu Trp Ile Val Asp Gln Ile Arg Asn Thr Thr Gly Asn 1190 1195 1200

    Asn Val Lys Met Ala Met Ser Asn Arg Glu Trp Met His Phe Ala 1205 1210 1215

    Gln Glu Ser Arg Leu Ala 1220 <210> 112 <211> 1214 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    candidate division WS6 bacterium sequence <400> 112

    Met Lys Asn Val Phe Gly Gly Phe Thr Asn Leu Tyr Ser Leu Thr Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Thr Ser Lys Thr Gln Lys Leu Met 20 25 30

    Lys Arg Asn Asn Val Ile Gln Thr Asp Glu Glu Ile Asp Lys Leu Tyr 35 40 45

    His Asp Glu Met Lys Pro Ile Leu Asp Glu Ile His Arg Arg Phe Ile 50 55 60

    Asn Asp Ala Leu Ala Gln Lys Ile Phe Ile Ser Ala Ser Leu Asp Asn 65 70 75 80

    Phe Leu Lys Val Val Lys Asn Tyr Lys Val Glu Ser Ala Lys Lys Asn

    Ile Lys Gln Asn Gln Val Lys Leu Leu Gln Lys Glu Ile Thr Ile Lys 100 105 110

    Thr Leu Gly Leu Arg Arg Glu Val Val Ser Gly Phe Ile Thr Val Ser 115 120 125

    Lys Lys Trp Lys Asp Lys Tyr Val Gly Leu Gly Ile Lys Leu Lys Gly 130 135 140

    Asp Gly Tyr Lys Val Leu Thr Glu Gln Ala Val Leu Asp Ile Leu Lys 145 150 155 160

    Ile Glu Phe Pro Asn Lys Ala Lys Tyr Ile Asp Lys Phe Arg Gly Phe 165 170 175

    Trp Thr Tyr Phe Ser Gly Phe Asn Glu Asn Arg Lys Asn Tyr Tyr Ser 180 185 190

    Glu Glu Asp Lys Ala Thr Ser Ile Ala Asn Arg Ile Val Asn Glu Asn 195 200 205

    Leu Ser Arg Tyr Ile Asp Asn Ile Ile Ala Phe Glu Glu Ile Leu Gln 210 215 220

    Lys Ile Pro Asn Leu Lys Lys Phe Lys Gln Asp Leu Asp Ile Thr Ser 225 230 235 240

    Tyr Asn Tyr Tyr Leu Asn Gln Ala Gly Ile Asp Lys Tyr Asn Lys Ile 245 250 255

    Ile Gly Gly Tyr Ile Val Asp Lys Asp Lys Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Lys Val Asn Leu Tyr Thr Gln Gln Thr Lys Lys Lys Leu Pro Lys 275 280 285

    Leu Lys Phe Leu Phe Lys Gln Ile Gly Ser Glu Arg Lys Gly Phe Gly 290 295 300

    Ile Phe Glu Ile Lys Glu Gly Lys Glu Trp Glu Gln Leu Gly Asp Leu 305 310 315 320

    Phe Lys Leu Gln Arg Thr Lys Ile Asn Ser Asn Gly Arg Glu Lys Gly 325 330 335

    Leu Phe Asp Ser Leu Arg Thr Met Tyr Arg Glu Phe Phe Asp Glu Ile 340 345 350

    Lys Arg Asp Ser Asn Ser Gln Ala Arg Tyr Ser Leu Asp Lys Ile Tyr 355 360 365

    Phe Asn Lys Ala Ser Val Asn Thr Ile Ser Asn Ser Trp Phe Thr Asn 370 375 380

    Trp Asn Lys Phe Ala Glu Leu Leu Asn Ile Lys Glu Asp Lys Lys Asn 385 390 395 400

    Gly Glu Lys Lys Ile Pro Glu Gln Ile Ser Ile Glu Asp Ile Lys Asp 405 410 415

    Ser Leu Ser Ile Ile Pro Lys Glu Asn Leu Glu Glu Leu Phe Lys Leu 420 425 430

    Thr Asn Arg Glu Lys His Asp Arg Thr Arg Phe Phe Gly Ser Asn Ala 435 440 445

    Trp Val Thr Phe Leu Asn Ile Trp Gln Asn Glu Ile Glu Glu Ser Phe 450 455 460

    Asn Lys Leu Glu Glu Lys Glu Lys Asp Phe Lys Lys Asn Ala Ala Ile 465 470 475 480

    Lys Phe Gln Lys Asn Asn Leu Val Gln Lys Asn Tyr Ile Lys Glu Val 485 490 495

    Cys Asp Arg Met Leu Ala Ile Glu Arg Met Ala Lys Tyr His Leu Pro 500 505 510

    Lys Asp Ser Asn Leu Ser Arg Glu Glu Asp Phe Tyr Trp Ile Ile Asp 515 520 525

    Asn Leu Ser Glu Gln Arg Glu Ile Tyr Lys Tyr Tyr Asn Ala Phe Arg 530 535 540

    Asn Tyr Ile Ser Lys Lys Pro Tyr Asn Lys Ser Lys Met Lys Leu Asn 545 550 555 560

    Phe Glu Asn Gly Asn Leu Leu Gly Gly Trp Ser Asp Gly Gln Glu Arg 565 570 575

    Asn Lys Ala Gly Val Ile Leu Arg Asn Gly Asn Lys Tyr Tyr Leu Gly 580 585 590

    Val Leu Ile Asn Arg Gly Ile Phe Arg Thr Asp Lys Ile Asn Asn Glu 595 600 605

    Ile Tyr Arg Thr Gly Ser Ser Lys Trp Glu Arg Leu Ile Leu Ser Asn 610 615 620

    Leu Lys Phe Gln Thr Leu Ala Gly Lys Gly Phe Leu Gly Lys His Gly 625 630 635 640

    Val Ser Tyr Gly Asn Met Asn Pro Glu Lys Ser Val Pro Ser Leu Gln 645 650 655

    Lys Phe Ile Arg Glu Asn Tyr Leu Lys Lys Tyr Pro Gln Leu Thr Glu 660 665 670

    Val Ser Asn Thr Lys Phe Leu Ser Lys Lys Asp Phe Asp Ala Ala Ile 675 680 685

    Lys Glu Ala Leu Lys Glu Cys Phe Thr Met Asn Phe Ile Asn Ile Ala 690 695 700

    Glu Asn Lys Leu Leu Glu Ala Glu Asp Lys Gly Asp Leu Tyr Leu Phe 705 710 715 720

    Glu Ile Thr Asn Lys Asp Phe Ser Gly Lys Lys Ser Gly Lys Asp Asn 725 730 735

    Ile His Thr Ile Tyr Trp Lys Tyr Leu Phe Ser Glu Ser Asn Cys Lys 740 745 750

    Ser Pro Ile Ile Gly Leu Asn Gly Gly Ala Glu Ile Phe Phe Arg Glu 755 760 765

    Gly Gln Lys Asp Lys Leu His Thr Lys Leu Asp Lys Lys Gly Lys Lys 770 775 780

    Val Phe Asp Ala Lys Arg Tyr Ser Glu Asp Lys Leu Phe Phe His Val 785 790 795 800

    Ser Ile Thr Ile Asn Tyr Gly Lys Pro Lys Asn Ile Lys Phe Arg Asp

    805

    810

    815

    Ile Ile Asn Gln Leu Ile Thr Ser Met Asn Val Asn Ile Ile Gly Ile 820 825 830

    Asp Arg Gly Glu Lys His Leu Leu Tyr Tyr Ser Val Ile Asp Ser Asn 835 840 845

    Gly Ile Ile Leu Lys Gln Gly Ser Leu Asn Lys Ile Arg Val Gly Asp 850 855 860

    Lys Glu Val Asp Phe Asn Lys Lys Leu Thr Glu Arg Ala Asn Glu Met 865 870 875 880

    Lys Lys Ala Arg Gln Ser Trp Glu Gln Ile Gly Asn Ile Lys Asn Phe 885 890 895

    Lys Glu Gly Tyr Leu Ser Gln Ala Ile His Glu Ile Tyr Gln Leu Met 900 905 910

    Ile Lys Tyr Asn Ala Ile Ile Val Leu Glu Asp Leu Asn Thr Glu Phe 915 920 925

    Lys Ala Lys Arg Leu Ser Lys Val Glu Lys Ser Val Tyr Lys Lys Phe 930 935 940

    Glu Leu Lys Leu Ala Arg Lys Leu Asn His Leu Ile Leu Lys Asp Arg 945 950 955 960

    Asn Thr Asn Glu Ile Gly Gly Val Leu Lys Ala Tyr Gln Leu Thr Pro 965 970 975

    Thr Ile Gly Gly Gly Asp Val Ser Lys Phe Glu Lys Ala Lys Gln Trp 980 985 990

    Gly Met Met Phe Tyr Val Arg Ala Asn Tyr Thr Ser Thr Thr Asp Pro 995 1000 1005

    Val Thr Gly Trp Arg Lys His Leu Tyr Ile Ser Asn Phe Ser Asn 1010 1015 1020

    Asn Ser Val Ile Lys Ser Phe Phe Asp Pro Thr Asn Arg Asp Thr 1025 1030 1035

    Gly Ile Glu Ile Phe Tyr Ser Gly Lys Tyr Arg Ser Trp Gly Phe 1040 1045 1050

    Arg Tyr Val Gln Lys Glu Thr Gly Lys Lys Trp Glu Leu Phe Ala 1055 1060 1065

    Thr Lys Glu Leu Glu Arg Phe Lys Tyr Asn Gln Thr Thr Lys Leu 1070 1075 1080

    Cys Glu Lys Ile Asn Leu Tyr Asp Lys Phe Glu Glu Leu Phe Lys 1085 1090 1095

    Gly Ile Asp Lys Ser Ala Asp Ile Tyr Ser Gln Leu Cys Asn Val 1100 1105 1110

    Leu Asp Phe Arg Trp Lys Ser Leu Val Tyr Leu Trp Asn Leu Leu 1115 1120 1125

    Asn Gln Ile Arg Asn Val Asp Lys Asn Ala Glu Gly Asn Lys Asn 1130 1135 1140

    Asp Phe Ile Gln Ser Pro Val Tyr Pro Phe Phe Asp Ser Arg Lys 1145 1150 1155

    Thr Asp Gly Lys Thr Glu Pro Ile Asn Gly Asp Ala Asn Gly Ala 1160 1165 1170

    Leu Asn Ile Ala Arg Lys Gly Leu Met Leu Val Glu Arg Ile Lys 1175 1180 1185

    Asn Asn Pro Glu Lys Tyr Glu Gln Leu Ile Arg Asp Thr Glu Trp 1190 1195 1200

    Asp Ala Trp Ile Gln Asn Phe Asn Lys Val Asn 1205 1210 <210> 113 <211> 1200 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 113

    Met Tyr Tyr Glu Ser Leu Thr Lys Gln Tyr Pro Val Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Ile Pro Ile Gly Lys Thr Leu Asp Asn Ile Arg Gln 20 25 30

    Asn Asn Ile Leu Glu Ser Asp Val Lys Arg Lys Gln Asn Tyr Glu His 35 40 45

    Val Lys Gly Ile Leu Asp Glu Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Cys Thr Leu Pro Ser Leu Lys Ile Ala Ala Glu Ile Tyr 65 70 75 80

    Leu Lys Asn Gln Lys Glu Val Ser Asp Arg Glu Asp Phe Asn Lys Thr 85 90 95

    Gln Asp Leu Leu Arg Lys Glu Val Val Glu Lys Leu Lys Ala His Glu 100 105 110

    Asn Phe Thr Lys Ile Gly Lys Lys Asp Ile Leu Asp Leu Leu Glu Lys 115 120 125

    Leu Pro Ser Ile Ser Glu Asp Asp Tyr Asn Ala Leu Glu Ser Phe Arg 130 135 140

    Asn Phe Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Glu Asn Leu 145 150 155 160

    Tyr Ser Asp Lys Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn 165 170 175

    Glu Asn Phe Pro Lys Phe Leu Asp Asn Val Lys Ser Tyr Arg Phe Val 180 185 190

    Lys Thr Ala Gly Ile Leu Ala Asp Gly Leu Gly Glu Glu Glu Gln Asp 195 200 205

    Ser Leu Phe Ile Val Glu Thr Phe Asn Lys Thr Leu Thr Gln Asp Gly 210 215 220

    Ile Asp Thr Tyr Asn Ser Gln Val Gly Lys Ile Asn Ser Ser Ile Asn 225 230 235 240

    Leu Tyr Asn Gln Lys Asn Gln Lys Ala Asn Gly Phe Arg Lys Ile Pro 245 250 255

    Lys Met Lys Met Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ser 260 265 270

    Phe Ile Asp Glu Phe Gln Ser Asp Glu Val Leu Ile Asp Asn Val Glu 275 280 285

    Ser Tyr Gly Ser Val Leu Ile Glu Ser Leu Lys Ser Ser Lys Val Ser 290 295 300

    Ala Phe Phe Asp Ala Leu Arg Glu Ser Lys Gly Lys Asn Val Tyr Val 305 310 315 320

    Lys Asn Asp Leu Ala Lys Thr Ala Met Ser Asn Ile Val Phe Glu Asn 325 330 335

    Trp Arg Thr Phe Asp Asp Leu Leu Asn Gln Glu Tyr Asp Leu Ala Asn 340 345 350

    Glu Asn Lys Lys Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Glu 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Ser Leu Glu His Leu Cys Asn Leu Ser 370 375 380

    Glu Asp Ser Cys Asn Leu Ile Glu Asn Tyr Ile His Gln Ile Ser Asp 385 390 395 400

    Asp Ile Glu Asn Ile Ile Ile Asn Asn Glu Thr Phe Leu Arg Ile Val 405 410 415

    Ile Asn Glu His Asp Arg Ser Arg Lys Leu Ala Lys Asn Arg Lys Ala 420 425 430

    Val Lys Ala Ile Lys Asp Phe Leu Asp Ser Ile Lys Val Leu Glu Arg 435 440 445

    Glu Leu Lys Leu Ile Asn Ser Ser Gly Gln Glu Leu Glu Lys Asp Leu 450 455 460

    Ile Val Tyr Ser Ala His Glu Glu Leu Leu Val Glu Leu Lys Gln Val 465 470 475 480

    Asp Ser Leu Tyr Asn Met Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe 485 490 495

    Ser Thr Glu Lys Val Lys Leu Asn Phe Asn Arg Ser Thr Leu Leu Asn 500 505 510

    Gly Trp Asp Arg Asn Lys Glu Thr Asp Asn Leu Gly Val Leu Leu Leu 515 520 525

    Lys Asp Gly Lys Tyr Tyr Leu Gly Ile Met Asn Thr Ser Ala Asn Lys 530 535 540

    Ala Phe Val Asn Pro Pro Val Ala Lys Thr Glu Lys Val Phe Lys Lys 545 550 555 560

    Val Asp Tyr Lys Leu Leu Pro Val Pro Asn Gln Met Leu Pro Lys Val 565 570 575

    Phe Phe Ala Lys Ser Asn Ile Asp Phe Tyr Asn Pro Ser Ser Glu Ile 580 585 590

    Tyr Ser Asn Tyr Lys Lys Gly Thr His Lys Lys Gly Asn Met Phe Ser 595 600 605

    Leu Glu Asp Cys His Asn Leu Ile Asp Phe Phe Lys Glu Ser Ile Ser

    610

    615

    620

    Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser Asp Thr Ala 625 630 635 640

    Ser Tyr Asn Asp Ile Ser Glu Phe Tyr Arg Glu Val Glu Lys Gln Gly 645 650 655

    Tyr Lys Leu Thr Tyr Thr Asp Ile Asp Glu Thr Tyr Ile Asn Asp Leu 660 665 670

    Ile Glu Arg Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 675 680 685

    Ser Met Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met 690 695 700

    Met Leu Phe Asp Gln Arg Asn Ile Asp Asp Val Val Tyr Lys Leu Asn 705 710 715 720

    Gly Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ser Glu Asp Glu 725 730 735

    Leu Ile Ile His Lys Ala Gly Glu Glu Ile Lys Asn Lys Asn Pro Asn 740 745 750

    Arg Ala Arg Thr Lys Glu Thr Ser Thr Phe Ser Tyr Asp Ile Val Lys 755 760 765

    Asp Lys Arg Tyr Ser Lys Asp Lys Phe Thr Leu His Ile Pro Ile Thr 770 775 780

    Met Asn Phe Gly Val Asp Glu Val Lys Arg Phe Asn Asp Ala Val Asn 785 790 795 800

    Ser Ala Ile Arg Ile Asp Glu Asn Val Asn Val Ile Gly Ile Asp Arg 805 810 815

    Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asp Ser Lys Gly Asn 820 825 830

    Ile Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Lys Glu Tyr Asp 835 840 845

    Ile Glu Thr Asp Tyr His Ala Leu Leu Asp Glu Arg Glu Gly Gly Arg 850 855 860

    Asp Lys Ala Arg Lys Asp Trp Asn Thr Val Glu Asn Ile Arg Asp Leu 865 870 875 880

    Lys Ala Gly Tyr Leu Ser Gln Val Val Asn Val Val Ala Lys Leu Val 885 890 895

    Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe 900 905 910

    Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 915 920 925

    Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg 930 935 940

    Glu Gln Thr Ser Pro Lys Glu Leu Gly Gly Ala Leu Asn Ala Leu Gln 945 950 955 960

    Leu Thr Ser Lys Phe Lys Ser Phe Lys Glu Leu Gly Lys Gln Ser Gly 965 970 975

    Val Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr 980 985 990

    Thr Gly Phe Ala Asn Leu Phe Tyr Met Lys Cys Glu Asn Val Glu Lys 995 1000 1005

    Ser Lys Arg Phe Phe Asp Gly Phe Asp Phe Ile Arg Phe Asn Ala 1010 1015 1020

    Leu Glu Asn Val Phe Glu Phe Gly Phe Asp Tyr Arg Ser Phe Thr 1025 1030 1035

    Gln Arg Ala Cys Gly Ile Asn Ser Lys Trp Thr Val Cys Thr Asn 1040 1045 1050

    Gly Glu Arg Ile Ile Lys Tyr Arg Asn Pro Asp Lys Asn Asn Met 1055 1060 1065

    Phe Asp Glu Lys Val Val Val Val Thr Asp Glu Met Lys Asn Leu 1070 1075 1080

    Phe Glu Gln Tyr Lys Ile Pro Tyr Glu Asp Gly Arg Asn Val Lys 1085 1090 1095

    Asp Met Ile Ile Ser Asn Glu Glu Ala Glu Phe Tyr Arg Arg Leu 1100 1105 1110

    Tyr Arg Leu Leu Gln Gln Thr Leu Gln Met Arg Asn Ser Thr Ser 1115 1120 1125

    Asp Gly Thr Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Lys Arg 1130 1135 1140

    Glu Ala Tyr Phe Asn Ser Glu Leu Ser Asp Gly Ser Val Pro Lys 1145 1150 1155

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1160 1165 1170

    Trp Val Leu Glu Gln Ile Arg Gln Lys Ser Glu Gly Glu Lys Ile 1175 1180 1185

    Asn Leu Ala Met Thr Asn Ala Glu Trp Leu Glu Tyr 1190 1195 1200 <210> 114 <211> 1206 <212> PRT <213> Butyrivibrio sp.

    <400> 114

    Met Tyr Tyr Gln Asn Leu Thr Lys Lys Tyr Pro Val Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Ile Pro Ile Gly Lys Thr Leu Glu Asn Ile Arg Lys 20 25 30

    Asn Asn Ile Leu Glu Ser Asp Val Lys Arg Lys Gln Asp Tyr Glu His 35 40 45

    Val Lys Gly Ile Met Asp Glu Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Tyr Met Leu Pro Ser Leu Asn Gln Ala Ala Glu Ile Tyr 65 70 75 80

    Leu Lys Lys His Val Asp Val Glu Asp Arg Glu Glu Phe Lys Lys Thr 85 90 95

    Gln Asp Leu Leu Arg Arg Glu Val Thr Gly Arg Leu Lys Glu His Glu 100 105 110

    Asn Tyr Thr Lys Ile Gly Lys Lys Asp Ile Leu Asp Leu Leu Glu Lys 115 120 125

    Leu Pro Ser Ile Ser Glu Glu Asp Tyr Asn Ala Leu Glu Ser Phe Arg 130 135 140

    Asn Phe Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Glu Asn Leu 145 150 155 160

    Tyr Ser Asp Glu Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn 165 170 175

    Glu Asn Leu Pro Lys Phe Leu Asp Asn Ile Lys Ser Tyr Ala Phe Val 180 185 190

    Lys Ala Ala Gly Val Leu Ala Asp Cys Ile Glu Glu Glu Glu Gln Asp 195 200 205

    Ala Leu Phe Met Val Glu Thr Phe Asn Met Thr Leu Thr Gln Glu Gly 210 215 220

    Ile Asp Met Tyr Asn Tyr Gln Ile Gly Lys Val Asn Ser Ala Ile Asn 225 230 235 240

    Leu Tyr Asn Gln Lys Asn His Lys Val Glu Glu Phe Lys Lys Ile Pro 245 250 255

    Lys Met Lys Val Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Val 260 265 270

    Phe Ile Gly Glu Phe Lys Asp Asp Glu Thr Leu Leu Ser Ser Ile Gly 275 280 285

    Ala Tyr Gly Asn Val Leu Met Thr Tyr Leu Lys Ser Glu Lys Ile Asn 290 295 300

    Ile Phe Phe Asp Ala Leu Arg Glu Ser Glu Gly Lys Asn Val Tyr Val 305 310 315 320

    Lys Asn Asp Leu Ser Lys Thr Thr Met Ser Asn Ile Val Phe Gly Ser 325 330 335

    Trp Ser Ala Phe Asp Glu Leu Leu Asn Gln Glu Tyr Asp Leu Ala Asn 340 345 350

    Glu Asn Lys Lys Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Glu 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Thr Leu Glu Gln Met Ser Asn Leu Ser 370 375 380

    Lys Glu Asp Ile Ser Pro Ile Glu Asn Tyr Ile Glu Arg Ile Ser Glu 385 390 395 400

    Asp Ile Glu Lys Ile Cys Ile Tyr Asn Gly Glu Phe Glu Lys Ile Val 405 410 415

    Val Asn Glu His Asp Ser Ser Arg Lys Leu Ser Lys Asn Ile Lys Ala 420 425 430

    Val Lys Val Ile Lys Asp Tyr Leu Asp Ser Ile Lys Glu Leu Glu His 435 440 445

    Asp Ile Lys Leu Ile Asn Gly Ser Gly Gln Glu Leu Glu Lys Asn Leu

    450

    455

    460

    Val Val Tyr Val Gly Gln Glu Glu Ala Leu Glu Gln Leu Arg Pro Val 465 470 475 480

    Asp Ser Leu Tyr Asn Leu Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe 485 490 495

    Ser Thr Glu Lys Val Lys Leu Asn Phe Asn Lys Ser Thr Leu Leu Asn 500 505 510

    Gly Trp Asp Lys Asn Lys Glu Thr Asp Asn Leu Gly Ile Leu Phe Phe 515 520 525

    Lys Asp Gly Lys Tyr Tyr Leu Gly Ile Met Asn Thr Thr Ala Asn Lys 530 535 540

    Ala Phe Val Asn Pro Pro Ala Ala Lys Thr Glu Asn Val Phe Lys Lys 545 550 555 560

    Val Asp Tyr Lys Leu Leu Pro Gly Ser Asn Lys Met Leu Pro Lys Val 565 570 575

    Phe Phe Ala Lys Ser Asn Ile Gly Tyr Tyr Asn Pro Ser Thr Glu Leu 580 585 590

    Tyr Ser Asn Tyr Lys Lys Gly Thr His Lys Lys Gly Pro Ser Phe Ser 595 600 605

    Ile Asp Asp Cys His Asn Leu Ile Asp Phe Phe Lys Glu Ser Ile Lys 610 615 620

    Lys His Glu Asp Trp Ser Lys Phe Gly Phe Glu Phe Ser Asp Thr Ala 625 630 635 640

    Asp Tyr Arg Asp Ile Ser Glu Phe Tyr Arg Glu Val Glu Lys Gln Gly 645 650 655

    Tyr Lys Leu Thr Phe Thr Asp Ile Asp Glu Ser Tyr Ile Asn Asp Leu 660 665 670

    Ile Glu Lys Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 675 680 685

    Ser Glu Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met 690 695 700

    Met Leu Phe Asp Gln Arg Asn Leu Asp Asn Val Val Tyr Lys Leu Asn 705 710 715 720

    Gly Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ala Glu Asn Glu 725 730 735

    Leu Val Ile His Lys Ala Gly Glu Gly Ile Lys Asn Lys Asn Pro Asn 740 745 750

    Arg Ala Lys Val Lys Glu Thr Ser Thr Phe Ser Tyr Asp Ile Val Lys 755 760 765

    Asp Lys Arg Tyr Ser Lys Tyr Lys Phe Thr Leu His Ile Pro Ile Thr 770 775 780

    Met Asn Phe Gly Val Asp Glu Val Arg Arg Phe Asn Asp Val Ile Asn 785 790 795 800

    Asn Ala Leu Arg Thr Asp Asp Asn Val Asn Val Ile Gly Ile Asp Arg 805 810 815

    Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asn Ser Glu Gly Lys 820 825 830

    Ile Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Lys Glu Tyr Asp 835 840 845

    Ile Glu Thr Asn Tyr His Ala Leu Leu Asp Glu Arg Glu Asp Asp Arg 850 855 860

    Asn Lys Ala Arg Lys Asp Trp Asn Thr Ile Glu Asn Ile Lys Glu Leu 865 870 875 880

    Lys Thr Gly Tyr Leu Ser Gln Val Val Asn Val Val Ala Lys Leu Val 885 890 895

    Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe 900 905 910

    Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 915 920 925

    Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg 930 935 940

    Glu Gln Val Ser Pro Glu Lys Met Gly Gly Ala Leu Asn Ala Leu Gln 945 950 955 960

    Leu Thr Ser Lys Phe Lys Ser Phe Ala Glu Leu Gly Lys Gln Ser Gly 965 970 975

    Ile Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr 980 985 990

    Thr Gly Phe Val Asn Leu Phe Tyr Ile Lys Tyr Glu Asn Ile Glu Lys 995 1000 1005

    Ala Lys Gln Phe Phe Asp Gly Phe Asp Phe Ile Arg Phe Asn Lys 1010 1015 1020

    Lys Asp Asp Met Phe Glu Phe Ser Phe Asp Tyr Lys Ser Phe Thr 1025 1030 1035

    Gln Lys Ala Cys Gly Ile Arg Ser Lys Trp Ile Val Tyr Thr Asn 1040 1045 1050

    Gly Glu Arg Ile Ile Lys Tyr Pro Asn Pro Glu Lys Asn Asn Leu 1055 1060 1065

    Phe Asp Glu Lys Val Ile Asn Val Thr Asp Glu Ile Lys Gly Leu 1070 1075 1080

    Phe Lys Gln Tyr Arg Ile Pro Tyr Glu Asn Gly Glu Asp Ile Lys 1085 1090 1095

    Glu Ile Ile Ile Ser Lys Ala Glu Ala Asp Phe Tyr Lys Arg Leu 1100 1105 1110

    Phe Arg Leu Leu His Gln Thr Leu Gln Met Arg Asn Ser Thr Ser 1115 1120 1125

    Asp Gly Thr Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Asp Arg 1130 1135 1140

    Gly Glu Phe Phe Cys Ser Glu Phe Ser Glu Gly Thr Met Pro Lys 1145 1150 1155

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu

    1160

    1165

    1170

    Trp Val Leu Glu Gln Ile Arg Gln Lys Asp Glu Gly Glu Lys Val 1175 1180 1185

    Asn Leu Ser Met Thr Asn Ala Glu Trp Leu Lys Tyr Ala Gln Leu 1190 1195 1200

    His Leu Leu 1205 <210> 115 <211> 1206 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 115

    Met Glu Asn Tyr Tyr Asp Ser Leu Thr Arg Gln Tyr Pro Val Thr Lys 1 5 10 15

    Thr Ile Arg Gln Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile 20 25 30

    Lys Asn Ala Glu Ile Ile Glu Ala Asp Lys Gln Lys Lys Glu Ala Tyr 35 40 45

    Val Lys Val Lys Glu Leu Met Asp Glu Phe His Lys Ser Ile Ile Glu 50 55 60

    Lys Ser Leu Val Gly Ile Lys Leu Asp Gly Leu Ser Glu Phe Glu Lys 65 70 75 80

    Leu Tyr Lys Ile Lys Thr Lys Thr Asp Glu Asp Lys Asn Arg Ile Ser 85 90 95

    Glu Leu Phe Tyr Tyr Met Arg Lys Gln Ile Ala Asp Ala Leu Lys Asn 100 105 110

    Ser Arg Asp Tyr Gly Tyr Val Asp Asn Lys Asp Leu Ile Glu Lys Ile 115 120 125

    Leu Pro Glu Arg Val Lys Asp Glu Asn Ser Leu Asn Ala Leu Ser Cys 130 135 140

    Phe Lys Gly Phe Thr Thr Tyr Phe Thr Asp Tyr Tyr Lys Asn Arg Lys 145 150 155 160

    Asn Ile Tyr Ser Asp Glu Glu Lys His Ser Thr Val Gly Tyr Arg Cys 165 170 175

    Ile Asn Glu Asn Leu Leu Ile Phe Met Ser Asn Ile Glu Val Tyr Gln 180 185 190

    Ile Tyr Lys Lys Ala Asn Ile Lys Asn Asp Asn Tyr Asp Glu Glu Thr 195 200 205

    Leu Asp Lys Thr Phe Met Ile Glu Ser Phe Asn Glu Cys Leu Thr Gln 210 215 220

    Ser Gly Val Glu Ala Tyr Asn Ser Val Val Ala Ser Ile Lys Thr Ala 225 230 235 240

    Thr Asn Leu Tyr Ile Gln Lys Asn Asn Lys Glu Glu Asn Phe Val Arg 245 250 255

    Val Pro Lys Met Lys Val Leu Phe Lys Gln Ile Leu Ser Asp Arg Thr

    260

    265

    270

    Ser Leu Phe Asp Gly Leu Ile Ile Glu Ser Asp Asp Glu Leu Leu Asp 275 280 285

    Lys Leu Cys Ser Phe Ser Ala Glu Val Asp Lys Phe Leu Pro Ile Asn 290 295 300

    Ile Asp Arg Tyr Ile Lys Thr Leu Met Asp Ser Asn Asn Gly Thr Gly 305 310 315 320

    Ile Tyr Val Lys Asn Asp Ser Ser Leu Thr Thr Leu Ser Asn Tyr Leu 325 330 335

    Thr Asp Ser Trp Ser Ser Ile Arg Asn Ala Phe Asn Glu Asn Tyr Asp 340 345 350

    Ala Lys Tyr Thr Gly Lys Val Asn Asp Lys Tyr Glu Glu Lys Arg Glu 355 360 365

    Lys Ala Tyr Lys Ser Asn Asp Ser Phe Glu Leu Asn Tyr Ile Gln Asn 370 375 380

    Leu Leu Gly Ile Asn Val Ile Asp Lys Tyr Ile Glu Arg Ile Asn Phe 385 390 395 400

    Asp Ile Lys Glu Ile Cys Glu Ala Tyr Lys Glu Met Thr Lys Asn Cys 405 410 415

    Phe Glu Asp His Asp Lys Thr Lys Lys Leu Gln Lys Asn Ile Lys Ala 420 425 430

    Val Ala Ser Ile Lys Ser Tyr Leu Asp Ser Leu Lys Asn Ile Glu Arg 435 440 445

    Asp Ile Lys Leu Leu Asn Gly Thr Gly Leu Glu Ser Arg Asn Glu Phe 450 455 460

    Phe Tyr Gly Glu Gln Ser Thr Val Leu Glu Glu Ile Thr Lys Val Asp 465 470 475 480

    Glu Leu Tyr Asn Ile Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe Ser 485 490 495

    Thr Glu Lys Met Lys Leu Asn Phe Asn Asn Pro Gln Leu Leu Gly Gly 500 505 510

    Trp Asp Val Asn Lys Glu Arg Asp Cys Tyr Gly Val Ile Leu Ile Lys 515 520 525

    Asp Asn Asn Tyr Tyr Leu Gly Ile Met Asp Lys Ser Ala Asn Lys Ser 530 535 540

    Phe Leu Asn Ile Lys Glu Ser Lys Asn Glu Asn Ala Tyr Lys Lys Val 545 550 555 560

    Asn Cys Lys Leu Leu Pro Gly Pro Asn Lys Met Phe Pro Lys Val Phe 565 570 575

    Phe Ala Lys Ser Asn Ile Asp Tyr Tyr Asp Pro Thr His Glu Ile Lys 580 585 590

    Lys Leu Tyr Asp Lys Gly Thr Phe Lys Lys Gly Asn Ser Phe Asn Leu 595 600 605

    Glu Asp Cys His Lys Leu Ile Asp Phe Tyr Lys Glu Ser Ile Lys Lys 610 615 620

    Asn Asp Asp Trp Lys Asn Phe Asn Phe Asn Phe Ser Asp Thr Lys Asp 625 630 635 640

    Tyr Glu Asp Ile Ser Gly Phe Phe Arg Glu Val Glu Ala Gln Asn Tyr 645 650 655

    Lys Ile Thr Tyr Thr Asn Val Ser Cys Asp Phe Ile Glu Ser Leu Val 660 665 670

    Asp Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 675 680 685

    Glu Tyr Ala Thr Gly Asn Leu Asn Leu His Thr Leu Tyr Leu Lys Met 690 695 700

    Leu Phe Asp Glu Arg Asn Leu Lys Asp Leu Cys Ile Lys Met Asn Gly 705 710 715 720

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Leu Asp Glu Asp Lys 725 730 735

    Val Val His Lys Ala Asn Gln Lys Ile Thr Asn Lys Asn Thr Asn Ser 740 745 750

    Lys Lys Lys Glu Ser Ile Phe Ser Tyr Asp Ile Val Lys Asp Lys Arg 755 760 765

    Tyr Thr Val Asp Lys Phe Phe Ile His Leu Pro Ile Thr Leu Asn Tyr 770 775 780

    Lys Glu Gln Asn Val Ser Arg Phe Asn Asp Tyr Ile Arg Glu Ile Leu 785 790 795 800

    Lys Lys Ser Lys Asn Ile Arg Val Ile Gly Ile Asp Arg Gly Glu Arg 805 810 815

    Asn Leu Leu Tyr Val Val Val Cys Asp Ser Asp Gly Ser Ile Leu Tyr 820 825 830

    Gln Arg Ser Ile Asn Glu Ile Val Ser Gly Ser His Lys Thr Asp Tyr 835 840 845

    His Lys Leu Leu Asp Asn Lys Glu Lys Glu Arg Leu Ser Ser Arg Arg 850 855 860

    Asp Trp Lys Thr Ile Glu Asn Ile Lys Asp Leu Lys Ala Gly Tyr Met 865 870 875 880

    Ser Gln Val Val Asn Glu Ile Tyr Asn Leu Ile Leu Lys Tyr Asn Ala 885 890 895

    Ile Val Val Leu Glu Asp Leu Asn Ile Gly Phe Lys Asn Gly Arg Lys 900 905 910

    Lys Val Glu Lys Gln Val Tyr Gln Asn Phe Glu Lys Ala Leu Ile Asp 915 920 925

    Lys Leu Asn Tyr Leu Cys Ile Asp Lys Thr Arg Glu Gln Leu Ser Pro 930 935 940

    Ser Ser Pro Gly Gly Val Leu Asn Ala Tyr Gln Leu Thr Ala Lys Phe 945 950 955 960

    Glu Ser Phe Glu Lys Ile Gly Lys Gln Thr Gly Cys Ile Phe Tyr Val 965 970 975

    Pro Ala Tyr Leu Thr Ser Gln Ile Asp Pro Thr Thr Gly Phe Val Asn

    980

    985

    990

    Leu Phe Tyr Gln Lys Asp Thr Ser Lys Gln Gly Leu Gln Leu Phe Phe 995 1000 1005

    Arg Lys Phe Lys Lys Ile Asn Phe Asp Lys Val Ala Ser Asn Phe 1010 1015 1020

    Glu Phe Val Phe Asp Tyr Asn Asp Phe Thr Asn Lys Ala Glu Gly 1025 1030 1035

    Thr Lys Thr Asn Trp Thr Ile Ser Thr Gln Gly Thr Arg Ile Ala 1040 1045 1050

    Lys Tyr Arg Ser Asp Asp Ala Asn Gly Lys Trp Ile Ser Arg Thr 1055 1060 1065

    Val His Pro Thr Asp Ile Ile Lys Glu Ala Leu Asn Arg Glu Lys 1070 1075 1080

    Ile Asn Tyr Asn Asp Gly His Asp Leu Ile Asp Glu Ile Val Ser 1085 1090 1095

    Ile Glu Lys Ser Ala Val Leu Lys Glu Ile Tyr Tyr Gly Phe Lys 1100 1105 1110

    Leu Thr Leu Gln Leu Arg Asn Ser Thr Leu Ala Asn Glu Glu Glu 1115 1120 1125

    Gln Glu Asp Tyr Ile Ile Ser Pro Val Lys Asn Ser Ser Gly Asn 1130 1135 1140

    Tyr Phe Asp Ser Arg Ile Thr Ser Lys Glu Leu Pro Cys Asp Ala 1145 1150 1155

    Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Ala 1160 1165 1170

    Leu Glu Gln Ile Arg Asn Ser Glu Asn Val Ser Lys Val Lys Leu 1175 1180 1185

    Ala Ile Ser Asn Lys Glu Trp Phe Glu Tyr Thr Gln Asn Asn Ile 1190 1195 1200

    Pro Ser Leu 1205 <210> 116 <211> 1205 <212> PRT <213> Oribacterium sp.

    <400> 116

    Met Tyr Tyr Asp Gly Leu Thr Lys Gln Tyr Ala Leu Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Val Pro Ile Gly Lys Thr Leu Asp Asn Ile Lys Lys 20 25 30

    Asn Arg Ile Leu Glu Ala Asp Ile Lys Arg Lys Ser Asp Tyr Glu His 35 40 45

    Val Lys Lys Leu Met Asp Met Tyr His Lys Lys Ile Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Phe Lys Leu Ser Val Leu Glu Asp Ala Ala Asp Ile Tyr 65 70 75 80

    Phe Asn Lys Gln Asn Asp Glu Arg Asp Ile Asp Ala Phe Leu Lys Ile

    Gln Asp Lys Leu Arg Lys Glu Ile Val Glu Gln Leu Lys Gly His Thr 100 105 110

    Asp Tyr Ser Lys Val Gly Asn Lys Asp Phe Leu Gly Leu Leu Lys Ala 115 120 125

    Ala Ser Thr Glu Glu Asp Arg Ile Leu Ile Glu Ser Phe Asp Asn Phe 130 135 140

    Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Ser Asn Leu Tyr Ser 145 150 155 160

    Ala Glu Asp Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn Glu Asn 165 170 175

    Leu Pro Lys Phe Phe Asp Asn Ile Lys Ala Tyr Arg Thr Val Arg Asn 180 185 190

    Ala Gly Val Ile Ser Gly Asp Met Ser Ile Val Glu Gln Asp Glu Leu 195 200 205

    Phe Glu Val Asp Thr Phe Asn His Thr Leu Thr Gln Tyr Gly Ile Asp 210 215 220

    Thr Tyr Asn His Met Ile Gly Gln Leu Asn Ser Ala Ile Asn Leu Tyr 225 230 235 240

    Asn Gln Lys Met His Gly Ala Gly Ser Phe Lys Lys Leu Pro Lys Met 245 250 255

    Lys Glu Leu Tyr Lys Gln Leu Leu Thr Glu Arg Glu Glu Glu Phe Ile 260 265 270

    Glu Glu Tyr Thr Asp Asp Glu Val Leu Ile Thr Ser Val His Asn Tyr 275 280 285

    Val Ser Tyr Leu Ile Asp Tyr Leu Asn Ser Asp Lys Val Glu Ser Phe 290 295 300

    Phe Asp Thr Leu Arg Lys Ser Asp Gly Lys Glu Val Phe Ile Lys Asn 305 310 315 320

    Asp Val Ser Lys Thr Thr Met Ser Asn Ile Leu Phe Asp Asn Trp Ser 325 330 335

    Thr Ile Asp Asp Leu Ile Asn His Glu Tyr Asp Ser Ala Pro Glu Asn 340 345 350

    Val Lys Lys Thr Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Asp 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Ser Leu Ser Lys Ile Ala Ala Leu Cys 370 375 380

    Arg Asp Thr Thr Ile Leu Glu Lys Tyr Ile Arg Arg Leu Val Asp Asp 385 390 395 400

    Ile Glu Lys Ile Tyr Thr Ser Asn Asn Val Phe Ser Asp Ile Val Leu 405 410 415

    Ser Lys His Asp Arg Ser Lys Lys Leu Ser Lys Asn Thr Asn Ala Val 420 425 430

    Gln Ala Ile Lys Asn Met Leu Asp Ser Ile Lys Asp Phe Glu His Asp 435 440 445

    Val Met Leu Ile Asn Gly Ser Gly Gln Glu Ile Lys Lys Asn Leu Asn 450 455 460

    Val Tyr Ser Glu Gln Glu Ala Leu Ala Gly Ile Leu Arg Gln Val Asp 465 470 475 480

    His Ile Tyr Asn Leu Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe Ser 485 490 495

    Thr Glu Lys Ile Lys Leu Asn Phe Asn Arg Pro Thr Phe Leu Asp Gly 500 505 510

    Trp Asp Lys Asn Lys Glu Glu Ala Asn Leu Gly Ile Leu Leu Ile Lys 515 520 525

    Asp Asn Arg Tyr Tyr Leu Gly Ile Met Asn Thr Ser Ser Asn Lys Ala 530 535 540

    Phe Val Asn Pro Pro Lys Ala Ile Ser Asn Asp Ile Tyr Lys Lys Val 545 550 555 560

    Asp Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met Leu Pro Lys Val Phe 565 570 575

    Phe Ala Thr Lys Asn Ile Ala Tyr Tyr Ala Pro Ser Glu Glu Leu Leu 580 585 590

    Ser Lys Tyr Arg Lys Gly Thr His Lys Lys Gly Asp Ser Phe Ser Ile 595 600 605

    Asp Asp Cys Arg Asn Leu Ile Asp Phe Phe Lys Ser Ser Ile Asn Lys 610 615 620

    Asn Thr Asp Trp Ser Thr Phe Gly Phe Asn Phe Ser Asp Thr Asn Ser 625 630 635 640

    Tyr Asn Asp Ile Ser Asp Phe Tyr Arg Glu Val Glu Lys Gln Gly Tyr 645 650 655

    Lys Leu Ser Phe Thr Asp Ile Asp Ala Cys Tyr Ile Lys Asp Leu Val 660 665 670

    Asp Asn Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 675 680 685

    Pro Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Lys Met 690 695 700

    Leu Phe Asp Gln Arg Asn Leu Asp Asn Val Val Tyr Lys Leu Asn Gly 705 710 715 720

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Glu Ser Asp Glu Gln 725 730 735

    Ile Ile His Lys Ser Gly Gln Asn Ile Lys Asn Lys Asn Gln Lys Arg 740 745 750

    Ser Asn Cys Lys Lys Thr Ser Thr Phe Asp Tyr Asp Ile Val Lys Asp 755 760 765

    Arg Arg Tyr Cys Lys Asp Lys Phe Met Leu His Leu Pro Ile Thr Val 770 775 780

    Asn Phe Gly Thr Asn Glu Ser Gly Lys Phe Asn Glu Leu Val Asn Asn 785 790 795 800

    Ala Ile Arg Ala Asp Lys Asp Val Asn Val Ile Gly Ile Asp Arg Gly

    805

    810

    815

    Glu Arg Asn Leu Leu Tyr Val Val Val Val Asp Pro Cys Gly Lys Ile 820 825 830

    Ile Glu Gln Ile Ser Leu Asn Thr Ile Val Asp Lys Glu Tyr Asp Ile 835 840 845

    Glu Thr Asp Tyr His Gln Leu Leu Asp Glu Lys Glu Gly Ser Arg Asp 850 855 860

    Lys Ala Arg Lys Asp Trp Asn Thr Ile Glu Asn Ile Lys Glu Leu Lys 865 870 875 880

    Glu Gly Tyr Leu Ser Gln Val Val Asn Ile Ile Ala Lys Leu Val Leu 885 890 895

    Lys Tyr Asp Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe Lys 900 905 910

    Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys 915 920 925

    Met Leu Ile Asp Lys Met Asn Tyr Leu Val Leu Asp Lys Ser Arg Lys 930 935 940

    Gln Glu Ser Pro Gln Lys Pro Gly Gly Ala Leu Asn Ala Leu Gln Leu 945 950 955 960

    Thr Ser Ala Phe Lys Ser Phe Lys Glu Leu Gly Lys Gln Thr Gly Ile 965 970 975

    Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr Thr 980 985 990

    Gly Phe Ala Asn Leu Phe Tyr Ile Lys Tyr Glu Ser Val Asp Lys Ala 995 1000 1005

    Arg Asp Phe Phe Ser Lys Phe Asp Phe Ile Arg Tyr Asn Gln Met 1010 1015 1020

    Asp Asn Tyr Phe Glu Phe Gly Phe Asp Tyr Lys Ser Phe Thr Glu 1025 1030 1035

    Arg Ala Ser Gly Cys Lys Ser Lys Trp Ile Ala Cys Thr Asn Gly 1040 1045 1050

    Glu Arg Ile Val Lys Tyr Arg Asn Ser Asp Lys Asn Asn Ser Phe 1055 1060 1065

    Asp Asp Lys Thr Val Ile Leu Thr Asp Glu Tyr Arg Ser Leu Phe 1070 1075 1080

    Asp Lys Tyr Leu Gln Asn Tyr Ile Asp Glu Asp Asp Leu Lys Asp 1085 1090 1095

    Gln Ile Leu Gln Ile Asp Ser Ala Asp Phe Tyr Lys Asn Leu Ile 1100 1105 1110

    Lys Leu Phe Gln Leu Thr Leu Gln Met Arg Asn Ser Ser Ser Asp 1115 1120 1125

    Gly Lys Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Tyr Arg Glu 1130 1135 1140

    Glu Phe Phe Cys Ser Glu Phe Ser Asp Asp Thr Phe Pro Arg Asp 1145 1150 1155

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp 1160 1165 1170

    Val Ile Lys Gln Ile Arg Glu Thr Lys Ser Gly Thr Lys Ile Asn 1175 1180 1185

    Leu Ala Met Ser Asn Ser Glu Trp Leu Glu Tyr Ala Gln Cys Asn 1190 1195 1200

    Leu Leu 1205 <210> 117 <211> 1125 <212> PRT <213> Pseudobutyrivibrio ruminis <400> 117

    Phe Asn Leu Ser Lys Glu Lys Asn Ser Val Asp Ala Phe Ser Lys Cys 1 5 10 15

    Gln Asp Lys Leu Arg Lys Glu Ile Val Ser Leu Leu Lys Asn His Glu 20 25 30

    Asn Phe Pro Lys Ile Gly Asn Lys Glu Ile Ile Lys Leu Leu Gln Ser 35 40 45

    Leu Tyr Asp Asn Asp Thr Asp Tyr Lys Ala Leu Asp Ser Phe Ser Asn 50 55 60

    Phe Tyr Thr Tyr Phe Ser Ser Tyr Asn Glu Val Arg Lys Asn Leu Tyr 65 70 75 80

    Ser Asp Glu Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn Glu 85 90 95

    Asn Leu Pro Lys Phe Leu Asp Asn Ile Lys Ala Tyr Ala Ile Ala Lys 100 105 110

    Lys Ala Gly Val Arg Ala Glu Gly Leu Ser Glu Glu Asp Gln Asp Cys 115 120 125

    Leu Phe Ile Ile Glu Thr Phe Glu Arg Thr Leu Thr Gln Asp Gly Ile 130 135 140

    Asp Asn Tyr Asn Ala Ala Ile Gly Lys Leu Asn Thr Ala Ile Asn Leu 145 150 155 160

    Phe Asn Gln Gln Asn Lys Lys Gln Glu Gly Phe Arg Lys Val Pro Gln 165 170 175

    Met Lys Cys Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ala Phe 180 185 190

    Ile Asp Glu Phe Ser Asp Asp Glu Asp Leu Ile Thr Asn Ile Glu Ser 195 200 205

    Phe Ala Glu Asn Met Asn Val Phe Leu Asn Ser Glu Ile Ile Thr Asp 210 215 220

    Phe Lys Ile Ala Leu Val Glu Ser Asp Gly Ser Leu Val Tyr Ile Lys 225 230 235 240

    Asn Asp Val Ser Lys Thr Ser Phe Ser Asn Ile Val Phe Gly Ser Trp 245 250 255

    Asn Ala Ile Asp Glu Lys Leu Ser Asp Glu Tyr Asp Leu Ala Asn Ser 260 265 270

    Lys Lys Lys Lys Asp Glu Lys Tyr Tyr Glu Lys Arg Gln Lys Glu Leu 275 280 285

    Lys Lys Asn Lys Ser Tyr Asp Leu Glu Thr Ile Ile Gly Leu Phe Asp 290 295 300

    Asp Asn Ser Asp Val Ile Gly Lys Tyr Ile Glu Lys Leu Glu Ser Asp 305 310 315 320

    Ile Thr Ala Ile Ala Glu Ala Lys Asn Asp Phe Asp Glu Ile Val Leu 325 330 335

    Arg Lys His Asp Lys Asn Lys Ser Leu Arg Lys Asn Thr Asn Ala Val 340 345 350

    Glu Ala Ile Lys Ser Tyr Leu Asp Thr Val Lys Asp Phe Glu Arg Asp 355 360 365

    Ile Lys Leu Ile Asn Gly Ser Gly Gln Glu Val Glu Lys Asn Leu Val 370 375 380

    Val Tyr Ala Glu Gln Glu Asn Ile Leu Ala Glu Ile Lys Asn Val Asp 385 390 395 400

    Ser Leu Tyr Asn Met Ser Arg Asn Tyr Leu Thr Gln Lys Pro Phe Ser 405 410 415

    Thr Glu Lys Phe Lys Leu Asn Phe Asn Arg Ala Thr Leu Leu Asn Gly 420 425 430

    Trp Asp Lys Asn Lys Glu Thr Asp Asn Leu Gly Ile Leu Phe Glu Lys 435 440 445

    Asp Gly Met Tyr Tyr Leu Gly Ile Met Asn Thr Lys Ala Asn Lys Ile 450 455 460

    Phe Val Asn Ile Pro Lys Ala Thr Ser Asn Asp Val Tyr His Lys Val 465 470 475 480

    Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met Leu Pro Lys Val Phe 485 490 495

    Phe Ala Gln Ser Asn Leu Asp Tyr Tyr Lys Pro Ser Glu Glu Leu Leu 500 505 510

    Ala Lys Tyr Lys Ala Gly Thr His Lys Lys Gly Asp Asn Phe Ser Leu 515 520 525

    Glu Asp Cys His Ala Leu Ile Asp Phe Phe Lys Ala Ser Ile Glu Lys 530 535 540

    His Pro Asp Trp Ser Ser Phe Gly Phe Glu Phe Ser Glu Thr Cys Thr 545 550 555 560

    Tyr Glu Asp Leu Ser Gly Phe Tyr Arg Glu Val Glu Lys Gln Gly Tyr 565 570 575

    Lys Ile Thr Tyr Thr Asp Val Asp Ala Asp Tyr Ile Thr Ser Leu Val 580 585 590

    Glu Arg Asp Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 595 600 605

    Pro Tyr Ser Lys Gly Asn Leu Asn Leu His Thr Ile Tyr Leu Gln Met 610 615 620

    Leu Phe Asp Gln Arg Asn Leu Asn Asn Val Val Tyr Lys Leu Asn Gly

    625

    630

    635

    640

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Asn Asp Glu Glu Val 645 650 655

    Ile Ile His Lys Ala Gly Glu Glu Ile Lys Asn Lys Asn Ser Lys Arg 660 665 670

    Ala Val Asp Lys Pro Thr Ser Lys Phe Gly Tyr Asp Ile Ile Lys Asp 675 680 685

    Arg Arg Tyr Ser Lys Asp Lys Phe Met Leu His Ile Pro Val Thr Met 690 695 700

    Asn Phe Gly Val Asp Glu Thr Arg Arg Phe Asn Asp Val Val Asn Asp 705 710 715 720

    Ala Leu Arg Asn Asp Glu Lys Val Arg Val Ile Gly Ile Asp Arg Gly 725 730 735

    Glu Arg Asn Leu Leu Tyr Val Val Val Val Asp Thr Asp Gly Thr Ile 740 745 750

    Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Asn Glu Tyr Ser Ile 755 760 765

    Glu Thr Asp Tyr His Lys Leu Leu Asp Glu Lys Glu Gly Asp Arg Asp 770 775 780

    Arg Ala Arg Lys Asn Trp Thr Thr Ile Glu Asn Ile Lys Glu Leu Lys 785 790 795 800

    Glu Gly Tyr Leu Ser Gln Val Val Asn Val Ile Ala Lys Leu Val Leu 805 810 815

    Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe Lys 820 825 830

    Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys 835 840 845

    Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg Lys 850 855 860

    Gln Asp Lys Pro Glu Glu Phe Gly Gly Ala Leu Asn Ala Leu Gln Leu 865 870 875 880

    Thr Ser Lys Phe Thr Ser Phe Lys Asp Met Gly Lys Gln Thr Gly Ile 885 890 895

    Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr Thr 900 905 910

    Gly Phe Ala Asn Leu Phe Tyr Val Lys Tyr Glu Asn Val Glu Lys Ala 915 920 925

    Lys Glu Phe Phe Ser Arg Phe Asp Ser Ile Ser Tyr Asn Asn Glu Ser 930 935 940

    Gly Tyr Phe Glu Phe Ala Phe Asp Tyr Lys Lys Phe Thr Asp Arg Ala 945 950 955 960

    Cys Gly Ala Arg Ser Gln Trp Thr Val Cys Thr Tyr Gly Glu Arg Ile 965 970 975

    Ile Lys Phe Arg Asn Thr Glu Lys Asn Asn Ser Phe Asp Asp Lys Thr 980 985 990

    Ile Val Leu Ser Glu Glu Phe Lys Glu Leu Phe Ser Ile Tyr Gly Ile 995 1000 1005

    Ser Tyr Glu Asp Gly Ala Glu Leu Lys Asn Lys Ile Met Ser Val 1010 1015 1020

    Asp Glu Ala Asp Phe Phe Arg Ser Leu Thr Arg Leu Phe Gln Gln 1025 1030 1035

    Thr Met Gln Met Arg Asn Ser Ser Asn Asp Val Thr Arg Asp Tyr 1040 1045 1050

    Ile Ile Ser Pro Ile Met Asn Asp Arg Gly Glu Phe Phe Asn Ser 1055 1060 1065

    Glu Ala Cys Asp Ala Ser Lys Pro Lys Asp Ala Asp Ala Asn Gly 1070 1075 1080

    Ala Phe Asn Ile Ala Arg Lys Gly Leu Trp Val Leu Glu Gln Ile 1085 1090 1095

    Arg Asn Thr Pro Ser Gly Asp Lys Leu Asn Leu Ala Met Ser Asn 1100 1105 1110

    Ala Glu Trp Leu Glu Tyr Ala Gln Arg Asn Gln Ile 1115 1120 1125 <210> 118 <211> 1154 <212> PRT <213> Proteocatella sphenisci <400> 118

    Met Glu Asn Phe Lys Asn Leu Tyr Pro Ile Asn Lys Thr Leu Arg Phe

    1 5 10 15

    Glu Leu Arg Pro Tyr Gly Lys Thr Leu Glu Asn Phe Lys Lys Ser Gly 20 25 30

    Leu Leu Glu Lys Asp Ala Phe Lys Ala Asn Ser Arg Arg Ser Met Gln 35 40 45

    Ala Ile Ile Asp Glu Lys Phe Lys Glu Thr Ile Glu Glu Arg Leu Lys 50 55 60

    Tyr Thr Glu Phe Ser Glu Cys Asp Leu Gly Asn Met Thr Ser Lys Asp 65 70 75 80

    Lys Lys Ile Thr Asp Lys Ala Ala Thr Asn Leu Lys Lys Gln Val Ile 85 90 95

    Leu Ser Phe Asp Asp Glu Ile Phe Asn Asn Tyr Leu Lys Pro Asp Lys 100 105 110

    Asn Ile Asp Ala Leu Phe Lys Asn Asp Pro Ser Asn Pro Val Ile Ser 115 120 125

    Thr Phe Lys Gly Phe Thr Thr Tyr Phe Val Asn Phe Phe Glu Ile Arg 130 135 140

    Lys His Ile Phe Lys Gly Glu Ser Ser Gly Ser Met Ala Tyr Arg Ile 145 150 155 160

    Ile Asp Glu Asn Leu Thr Thr Tyr Leu Asn Asn Ile Glu Lys Ile Lys 165 170 175

    Lys Leu Pro Glu Glu Leu Lys Ser Gln Leu Glu Gly Ile Asp Gln Ile 180 185 190

    Asp Lys Leu Asn Asn Tyr Asn Glu Phe Ile Thr Gln Ser Gly Ile Thr 195 200 205

    His Tyr Asn Glu Ile Ile Gly Gly Ile Ser Lys Ser Glu Asn Val Lys 210 215 220

    Ile Gln Gly Ile Asn Glu Gly Ile Asn Leu Tyr Cys Gln Lys Asn Lys 225 230 235 240

    Val Lys Leu Pro Arg Leu Thr Pro Leu Tyr Lys Met Ile Leu Ser Asp 245 250 255

    Arg Val Ser Asn Ser Phe Val Leu Asp Thr Ile Glu Asn Asp Thr Glu 260 265 270

    Leu Ile Glu Met Ile Ser Asp Leu Ile Asn Lys Thr Glu Ile Ser Gln 275 280 285

    Asp Val Ile Met Ser Asp Ile Gln Asn Ile Phe Ile Lys Tyr Lys Gln 290 295 300

    Leu Gly Asn Leu Pro Gly Ile Ser Tyr Ser Ser Ile Val Asn Ala Ile 305 310 315 320

    Cys Ser Asp Tyr Asp Asn Asn Phe Gly Asp Gly Lys Arg Lys Lys Ser 325 330 335

    Tyr Glu Asn Asp Arg Lys Lys His Leu Glu Thr Asn Val Tyr Ser Ile 340 345 350

    Asn Tyr Ile Ser Glu Leu Leu Thr Asp Thr Asp Val Ser Ser Asn Ile 355 360 365

    Lys Met Arg Tyr Lys Glu Leu Glu Gln Asn Tyr Gln Val Cys Lys Glu 370 375 380

    Asn Phe Asn Ala Thr Asn Trp Met Asn Ile Lys Asn Ile Lys Gln Ser 385 390 395 400

    Glu Lys Thr Asn Leu Ile Lys Asp Leu Leu Asp Ile Leu Lys Ser Ile 405 410 415

    Gln Arg Phe Tyr Asp Leu Phe Asp Ile Val Asp Glu Asp Lys Asn Pro 420 425 430

    Ser Ala Glu Phe Tyr Thr Trp Leu Ser Lys Asn Ala Glu Lys Leu Asp 435 440 445

    Phe Glu Phe Asn Ser Val Tyr Asn Lys Ser Arg Asn Tyr Leu Thr Arg 450 455 460

    Lys Gln Tyr Ser Asp Lys Lys Ile Lys Leu Asn Phe Asp Ser Pro Thr 465 470 475 480

    Leu Ala Lys Gly Trp Asp Ala Asn Lys Glu Ile Asp Asn Ser Thr Ile 485 490 495

    Ile Met Arg Lys Phe Asn Asn Asp Arg Gly Asp Tyr Asp Tyr Phe Leu 500 505 510

    Gly Ile Trp Asn Lys Ser Thr Pro Ala Asn Glu Lys Ile Ile Pro Leu 515 520 525

    Glu Asp Asn Gly Leu Phe Glu Lys Met Gln Tyr Lys Leu Tyr Pro Asp 530 535 540

    Pro Ser Lys Met Leu Pro Lys Gln Phe Leu Ser Lys Ile Trp Lys Ala

    545

    550

    555

    560

    Lys His Pro Thr Thr Pro Glu Phe Asp Lys Lys Tyr Lys Glu Gly Arg 565 570 575

    His Lys Lys Gly Pro Asp Phe Glu Lys Glu Phe Leu His Glu Leu Ile 580 585 590

    Asp Cys Phe Lys His Gly Leu Val Asn His Asp Glu Lys Tyr Gln Asp 595 600 605

    Val Phe Gly Phe Asn Leu Arg Asn Thr Glu Asp Tyr Asn Ser Tyr Thr 610 615 620

    Glu Phe Leu Glu Asp Val Glu Arg Cys Asn Tyr Asn Leu Ser Phe Asn 625 630 635 640

    Lys Ile Ala Asp Thr Ser Asn Leu Ile Asn Asp Gly Lys Leu Tyr Val 645 650 655

    Phe Gln Ile Trp Ser Lys Asp Phe Ser Ile Asp Ser Lys Gly Thr Lys 660 665 670

    Asn Leu Asn Thr Ile Tyr Phe Glu Ser Leu Phe Ser Glu Glu Asn Met 675 680 685

    Ile Glu Lys Met Phe Lys Leu Ser Gly Glu Ala Glu Ile Phe Tyr Arg 690 695 700

    Pro Ala Ser Leu Asn Tyr Cys Glu Asp Ile Ile Lys Lys Gly His His 705 710 715 720

    His Ala Glu Leu Lys Asp Lys Phe Asp Tyr Pro Ile Ile Lys Asp Lys 725 730 735

    Arg Tyr Ser Gln Asp Lys Phe Phe Phe His Val Pro Met Val Ile Asn 740 745 750

    Tyr Lys Ser Glu Lys Leu Asn Ser Lys Ser Leu Asn Asn Arg Thr Asn 755 760 765

    Glu Asn Leu Gly Gln Phe Thr His Ile Ile Gly Ile Asp Arg Gly Glu 770 775 780

    Arg His Leu Ile Tyr Leu Thr Val Val Asp Val Ser Thr Gly Glu Ile 785 790 795 800

    Val Glu Gln Lys His Leu Asp Glu Ile Ile Asn Thr Asp Thr Lys Gly 805 810 815

    Val Glu His Lys Thr His Tyr Leu Asn Lys Leu Glu Glu Lys Ser Lys 820 825 830

    Thr Arg Asp Asn Glu Arg Lys Ser Trp Glu Ala Ile Glu Thr Ile Lys 835 840 845

    Glu Leu Lys Glu Gly Tyr Ile Ser His Val Ile Asn Glu Ile Gln Lys 850 855 860

    Leu Gln Glu Lys Tyr Asn Ala Leu Ile Val Met Glu Asn Leu Asn Tyr 865 870 875 880

    Gly Phe Lys Asn Ser Arg Ile Lys Val Glu Lys Gln Val Tyr Gln Lys 885 890 895

    Phe Glu Thr Ala Leu Ile Lys Lys Phe Asn Tyr Ile Ile Asp Lys Lys 900 905 910

    Asp Pro Glu Thr Tyr Ile His Gly Tyr Gln Leu Thr Asn Pro Ile Thr 915 920 925

    Thr Leu Asp Lys Ile Gly Asn Gln Ser Gly Ile Val Leu Tyr Ile Pro 930 935 940

    Ala Trp Asn Thr Ser Lys Ile Asp Pro Val Thr Gly Phe Val Asn Leu 945 950 955 960

    Leu Tyr Ala Asp Asp Leu Lys Tyr Lys Asn Gln Glu Gln Ala Lys Ser 965 970 975

    Phe Ile Gln Lys Ile Asp Asn Ile Tyr Phe Glu Asn Gly Glu Phe Lys 980 985 990

    Phe Asp Ile Asp Phe Ser Lys Trp Asn Asn Arg Tyr Ser Ile Ser Lys 995 1000 1005

    Thr Lys Trp Thr Leu Thr Ser Tyr Gly Thr Arg Ile Gln Thr Phe 1010 1015 1020

    Arg Asn Pro Gln Lys Asn Asn Lys Trp Asp Ser Ala Glu Tyr Asp 1025 1030 1035

    Leu Thr Glu Glu Phe Lys Leu Ile Leu Asn Ile Asp Gly Thr Leu 1040 1045 1050

    Lys Ser Gln Asp Val Glu Thr Tyr Lys Lys Phe Met Ser Leu Phe 1055 1060 1065

    Lys Leu Met Leu Gln Leu Arg Asn Ser Val Thr Gly Thr Asp Ile 1070 1075 1080

    Asp Tyr Met Ile Ser Pro Val Thr Asp Lys Thr Gly Thr His Phe 1085 1090 1095

    Asp Ser Arg Glu Asn Ile Lys Asn Leu Pro Ala Asp Ala Asp Ala 1100 1105 1110

    Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Ile Met Ala Ile Glu 1115 1120 1125

    Asn Ile Met Asn Gly Ile Ser Asp Pro Leu Lys Ile Ser Asn Glu 1130 1135 1140

    Asp Tyr Leu Lys Tyr Ile Gln Asn Gln Gln Glu 1145 1150 <210> 119 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 119 ttagagaagt catttaataa ggccactgtt aaaa 34 <210> 120 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 120 ttcgagaagu cauuuaauaa ggccacuguu aaaa <210> 121 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 121 ttcgagaagu cauuuaauaa ggccacuguu aaaa 34 <210> 122 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 122 ttcgagaagu cauuuaauaa ggccacuguu aaaa 34 <210> 123 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 123 ttcgagaagu cauuuaauaa ggccacuguu aaaa 34 <210> 124 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 124 ctgatggtcc atgtctgtta ctcg 24 <210> 125 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 125 ctgggactca ggcgggtcac 20 <210> 126 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 126 cctcacacaa cagcttcatg tcagc <210> 127 <211> 3960 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 127 atggccccaa agaagaagcg gaaggtcggt atccacggag tcccagcagc cggtagtaac 60 atcaaaaact ttaccgggct ctaccccctc agcaaaactt tgcgctttga actcaagcct 120 attggcaaaa ccaaggaaaa catcgagaaa aatggcatcc tgaccaagga cgagcaacgg 180 gctaaagact acctcatagt caaaggcttt attgacgagt atcacaagca gttcatcaaa 240 gacaggcttt gggactttaa attgcctctc gaaagtgagg gggagaagaa cagtctcgaa 300 gaataccagg aactgtacga gctcactaag cgcaacgatg cccaggaggc cgacttcacc 360 gagattaaag ataaccttcg cagctctatt accgaacagc tcacgaagtc tggatctgcg 420 tacgatcgga tttttaaaaa agagttcatt agagaagacc tggtcaactt cctcgaagat 480 gaaaaagata aaaatatcgt gaaacagttc gaggacttta ctacatattt tacgggtttt 540 tatgaaaata ggaagaacat gtactctagc gaagagaagt ccacggccat cgcataccgg 600 cttatccatc agaatctgcc aaaattcatg gacaacatga gaagttttgc caaaattgca 660 aattccagtg tttccgagca ctttagcgac atctatgaaa gctggaagga atatctgaat 720 gtaaatagca tcgaggaaat cttccagctc gactatttta gcgaaacctt gactcagcca 780 catattgagg tgtataacta tattatcggg aagaaagtcc tggaagacgg aaccgagata 840 aagggcatca acgagtatgt gaacctctac aatcagcagc agaaagataa gagtaaacga 900 ctgcctttcc tggtgccact gtataagcaa attttgtctg atagggaaaa actctcctgg 960 attgctgaag agttcgacag cgacaagaag atgctgagcg ctatcaccga gtcttacaac 1020 cacctgcaca acgtgttgat gggtaacgag aacgaaagcc tgcgaaatct gctgctgaat 1080 attaaggact ataacctgga gaaaattaat atcacaaacg acttgtctct caccgaaatc 1140 tcccagaatc tttttggccg atatgatgta ttcacaaatg ggatcaaaaa caagctgaga 1200 gtgttgactc caaggaagaa aaaggagacg gacgaaaatt ttgaggaccg cattaacaaa 1260 atttttaaga cccagaagtc cttcagcatc gcttttctga acaagctgcc tcagcccgaa 1320 atggaggatg ggaagccccg gaacattgag gactatttca ttacacaggg ggcgattaac 1380 accaaatcta tacagaaaga agatatcttc gcccaaattg agaatgcata cgaggatgca 1440 caggtgttcc tgcaaattaa ggacaccgac aacaaactta gccagaacaa gacggcggtg 1500 gaaaagatca aaactttgct ggacgccttg aaggaactcc agcacttcat caaaccgctg 1560 ctgggctctg gggaggagaa cgagaaagac gaactgttct acggttcctt cctggccatc 1620 tgggacgaac tggacaccat tacaccactt tataacaaag tgagaaattg gctgacccga 1680 aaaccatatt caacagaaaa aatcaaattg aatttcgaca acgctcagct gctgggaggg 1740 tgggatgtca ataaagaaca cgactgtgca ggtatcttgt tgcggaaaaa cgatagctac 1800 tatctcggaa ttatcaataa gaaaaccaac cacatctttg atacggatat tacgccatca 1860 gatggcgagt gctatgacaa aatcgactac aagctccttc ccggggcgaa caaaatgctt 1920 ccaaaggtgt tttttagtaa gtcccgaatc aaagagttcg agccatcaga ggccataatc 1980 aattgctata agaaggggac acacaaaaaa ggaaaaaact ttaacctgac ggactgtcac 2040 cgcctgatca acttttttaa gacctcaatc gagaaacacg aggattggtc aaaattcgga 2100 ttcaagttct ccgataccga aacgtatgag gatattagcg gtttttatag agaggtcgag 2160 cagcagggat acaggctgac gagccatcca gtcagtgcca gctatataca tagtctggtc 2220 aaggaaggaa aactgtacct cttccaaatc tggaacaagg acttttctca attctccaag 2280 gggaccccta acttgcacac tctctattgg aagatgctgt ttgacaaacg gaatcttagc 2340 gatgtggttt ataagctgaa tggccaggct gaagtgttct atagaaagag ctccattgaa 2400 caccagaacc gaattatcca ccccgctcag catcccatca caaataagaa tgagcttaac 2460 aaaaagcaca ctagcacctt caaatacgat atcatcaaag atcgcagata cacggtggat 2520 aaattccagt tccatgtgcc cattactata aattttaagg cgaccgggca gaacaacatc 2580 aacccaatcg tccaagaggt gattcgccaa aacggtatca cccacatcat aggcatcgat 2640 cgaggtgaac gccatcttct gtacctctct ctcatcgatt tgaaaggcaa catcatcaag 2700 cagatgactc tcaacgaaat tattaatgag tataagggtg tgacctataa gaccaactac 2760 cataacctcc tggagaagag ggagaaggag cggaccgagg ccagacactc ctggagtagt 2820 attgaaagca taaaagaact gaaggatgga tacatgtcac aggtgattca caaaattacg 2880 gacatgatgg ttaagtacaa tgcgattgtg gtcctggagg acctcaacgg ggggtttatg 2940 cgaggccgcc agaaggtcga gaagcaggtg taccagaaat ttgaaaaaaa gttgatcgac 3000 aagctgaact atctcgttga caagaaactc gacgctaacg aggtcggcgg agtactgaat 3060 gcttatcagc tgaccaacaa gttcgagtct ttcaagaaga ttgggaaaca aagcggattt 3120 ttgttctaca tccccgcctg gaacacaagc aaaatcgatc ctataacagg gttcgttaat 3180 ctgttcaaca ccaggtacga gtctatcaag gagacaaaag ttttttggtc taagtttgat 3240 attatccgat acaataaaga gaagaattgg ttcgagttcg tcttcgatta caataccttt 3300 acgactaaag cggagggaac acgcactaag tggactctgt gcacccacgg cactcgcatc 3360 cagacattcc ggaacccaga aaagaatgcc cagtgggaca ataaagagat caatttgact 3420 gagtccttca aagctctgtt tgaaaagtac aagatcgata tcaccagtaa tctcaaggaa 3480 tccatcatgc aggaaaccga gaagaagttc ttccaggaac tgcataatct gctccacctg 3540 accctgcaga tgaggaatag cgttactgga accgacatag actatttgat cagccccgtt 3600 gccgatgagg atggaaattt ctatgatagt cgcataaatg gcaaaaattt tccggagaat 3660 gccgatgcca atggcgcgta caacatcgca cgaaagggtc tgatgcttat tcggcagatc 3720 aagcaagcag atccacagaa gaaattcaag tttgagacaa tcaccaataa agactggctg 3780 aaattcgccc aagacaagcc ctatcttaaa gatggcagcg ggaaaaggcc ggcggccacg 3840 aaaaaggccg gccaggcaaa aaagaaaaag ggatcctacc catacgatgt tccagattac 3900 gcttatccct acgacgtgcc tgattatgca tacccatacg atgtccccga ctatgcctaa 3960 <210> 128 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 128 cctcactcct gctcggtgaa ttt 23 <210> 129 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 129 ctgatggtcc atgtctgtta ctc 23 <210> 130 <211> 6 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic

    6xHis tag <400> 130

    His His His His His His

    1 5 <210> 131 <211> 31 <212> DNA <213> Francisella novicida <400> 131 gagaagtcat ttaataaggc cactgttaaa a <210> 132 <211> 30 <212> DNA <213> Francisella novicida <400> 132 gctactattc ctgtgccttc agataattca <210> 133 <211> 27 <212> DNA <213> Francisella novicida <400> 133 gtctagagcc ttttgtatta gtagccg <210> 134 <211> 98 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (30)..(37) <223> a, c, t, g, unknown or other <400> 134 ggccagtgaa ttcgagctcg gtacccgggn nnnnnnngag aagtcattta ataaggccac tgttaaaaag cttggcgtaa tcatggtcat agctgttt 98 <210> 135 <211> 98 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (61)..(68) <223> a, c, t, g, unknown or other <400> 135 ggccagtgaa ttcgagctcg gtacccgggg agaagtcatt taataaggcc actgttaaaa nnnnnnnnag cttggcgtaa tcatggtcat agctgttt 98 <210> 136 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 136 gctgacatga agctgttgtg tgagg <210> 137 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 137 ggccagtgaa ttcgagctcg g 21 <210> 138 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 138 caatttcaca caggaaacag ctatgacc <210> 139 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 139 cggggctggc ttaactatgc g 21 <210> 140 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 140 gcccaatacg caaaccgcct 20 <210> 141 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 141 ccatcccctt ctgtgaatgt 20 <210> 142 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 142 tctccgtgtc tccaatctcc 20 <210> 143 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 143 ctgggactca ggcgggtcac 20 <210> 144 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <400> 144 gctgacatga agctgttgtg tgagg 25 <210> 145 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 145 gagaagtcat ttaataaggc cact 24 <210> 146 <211> 22 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 146 gagaagtcat ttaataaggc ca 22 <210> 147 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 147 gagaagtcat ttaataaggc 20 <210> 148 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 148 gagaagtcat ttaataag 18 <210> 149 <211> 17 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 149 gagaagtcat ttaataa 17 <210> 150 <211> 16 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 150 gagaagtcat ttaata <210> 151 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 151 gataagtcat ttaataaggc cact <210> 152 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 152 gagaaggcat ttaataaggc cact <210> 153 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 153 gagaagtcat gtaataaggc cact <210> 154 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 154 gagaagtcat ttaagaaggc cact <210> 155 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 155 gagaagtcat ttaataagtc cact <210> 156 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 156 gagaagtcat ttaataaggc caat <210> 157 <211> 42 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 157 atttctactg ttgtagatga gaagtcattt aataaggcca ct <210> 158 <211> 41 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 158 tttctactgt tgtagatgag aagtcattta ataaggccac t <210> 159 <211> 40 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 159 ttctactgtt gtagatgaga agtcatttaa taaggccact <210> 160 <211> 39 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 160 tctactgttg tagatgagaa gtcatttaat aaggccact <210> 161 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 161 ctgttgtaga tgagaagtca tttaataagg ccact <210> 162 <211> 31 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 162 tgtagatgag aagtcattta ataaggccac t <210> 163 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 163 aatttctgct gttgcagat 19 <210> 164 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 164 aatttccact gttgtggat 19 <210> 165 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 165 aattcctact gttgtaggt 19 <210> 166 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 166 aatttatact gttgtagat 19 <210> 167 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 167 aatttcgact gttgtagat 19 <210> 168 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 168 aatttctagt gttgtagat 19 <210> 169 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 169 aatttctact attgtagat 19 <210> 170 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 170 aatttctact gctgtagat 19 <210> 171 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 171 aatttctact ttgtagat 18 <210> 172 <211> 17 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 172 aatttctact tgtagat 17 <210> 173 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 173 aatttctact tttgtagaa 19 <210> 174 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 174 aatttctact tttgtagac 19 <210> 175 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 175 taatttctac tgttgtagat 20 <210> 176 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 176 cctcactcct gctcggtgaa ttt 23 <210> 177 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 177 taatttctac tgttgtagat 20 <210> 178 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 178 aggagtgttc agtctccgtg aac 23 <210> 179 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 179 taatttctac tgttgtagat 20 <210> 180 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 180 ctgatggtcc atgtctgtta ctc 23 <210> 181 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 181 taatttctac tgttgtagat <210> 182 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 182 tttcccttca gctaaaataa agg 23 <210> 183 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 183 taatttctac taagtgtaga t 21 <210> 184 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 184 cctcactcct gctcggtgaa ttt 23 <220>

    <210> 185 <211> 21 <212> DNA <213> Artificial Sequence <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 185 taatttctac taagtgtaga t 21 <210> 186 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 186 aggagtgttc agtctccgtg aac 23 <210> 187 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 187 taatttctac taagtgtaga t 21 <210> 188 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 188 ctgatggtcc atgtctgtta ctc 23 <210> 189 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 189 taatttctac taagtgtaga t 21 <210> 190 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 190 tttcccttca gctaaaataa agg 23 <210> 191 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 191 tcactcctgc tcggtgaatt 20 <210> 192 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 192 aaccctctgg ggaccgtttg 20 <210> 193 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 193 agtacgttaa tgtttcctga 20 <210> 194 <400> 194

    000 <210> 195 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 195 taatttctac tgttgtagat 20 <210> 196 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 196 agaaatgcat ggttctcatg c 21 <210> 197 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 197 aaaattacct agtaattagg t 21 <210> 198 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 198 ggatttctac ttttgtagat 20 <210> 199 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 199 aaatttctac ttttgtagat <210> 200 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 200 cgcgcccacg cggggcgcga c 21 <210> 201 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 201 taatttctac tcttgtagat 20 <210> 202 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 202 gaatttctac tattgtagat 20 <210> 203 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 203 gaatctctac tctttgtaga t 21 <210> 204 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 204 taatttctac tttgtagat 19 <210> 205 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 205 aaatttctac tgtttgtaga t 21 <210> 206 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 206 gaatttctac ttttgtagat <210> 207 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 207 taatttctac taagtgtaga t 21 <210> 208 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 208 taatttctac tattgtagat 20 <210> 209 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 209 taatttctac ttcggtagat 20 <210> 210 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 210 taatttctac tattgtagat 20 <210> 211 <211> 6569 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 211 catcaaggaa ttggttctaa gcttatagaa gcaatgatta aggaagccaa aaaaaataat 60 attgatgcaa tatttgtctt aggtcatcca agttattatc caaaatttgg ttttaaacca 120 gccacagaat atcagataaa atgtgaatat gatgtcccag cggatgtttt tatggtacta 180 gatttgtcag ctaaactagc tagtttaaaa ggacaaactg tctactatgc cgatgagttt 240 ggcaaaattt tttagatcta caaaattata aactaaataa agattcttat aataacttta 300 tatataatcg aaatgtagag aattttataa ggagtcttta tcatgtcaat ttatcaagaa 360 tttgttaata aatatagttt aagtaaaact ctaagatttg agttaatccc acagggtaaa 420 acacttgaaa acataaaagc aagaggtttg attttagatg atgagaaaag agctaaagac 480 tacaaaaagg ctaaacaaat aattgataaa tatcatcagt tttttataga ggagatatta 540 agttcggttt gtattagcga agatttatta caaaactatt ctgatgttta ttttaaactt 600 aaaaagagtg atgatgataa tctacaaaaa gattttaaaa gtgcaaaaga tacgataaag 660 aaacaaatat ctgaatatat aaaggactca gagaaattta agaatttgtt taatcaaaac 720 cttatcgatg ctaaaaaagg gcaagagtca gatttaattc tatggctaaa gcaatctaag 780 gataatggta tagaactatt taaagccaat agtgatatca cagatataga tgaggcgtta 840 gaaataatca aatcttttaa aggttggaca acttatttta agggttttca tgaaaataga 900 aaaaatgttt atagtagcaa tgatattcct acatctatta tttataggat agtagatgat 960 aatttgccta aatttctaga aaataaagct aagtatgaga gtttaaaaga caaagctcca 1020 gaagctataa actatgaaca aattaaaaaa gatttggcag aagagctaac ctttgatatt 1080 gactacaaaa catctgaagt taatcaaaga gttttttcac ttgatgaagt ttttgagata 1140 gcaaacttta ataattatct aaatcaaagt ggtattacta aatttaatac tattattggt 1200 ggtaaatttg taaatggtga aaatacaaag agaaaaggta taaatgaata tataaatcta 1260 tactcacagc aaataaatga taaaacactc aaaaaatata aaatgagtgt tttatttaag 1320 caaattttaa gtgatacaga atctaaatct tttgtaattg ataagttaga agatgatagt 1380 gatgtagtta caacgatgca aagtttttat gagcaaatag cagcttttaa aacagtagaa 1440 gaaaaatcta ttaaagaaac actatcttta ttatttgatg atttaaaagc tcaaaaactt 1500 gatttgagta aaatttattt taaaaatgat aaatctctta ctgatctatc acaacaagtt 1560 tttgatgatt atagtgttat tggtacagcg gtactagaat atataactca acaaatagca 1620 cctaaaaatc ttgataaccc tagtaagaaa gagcaagaat taatagccaa aaaaactgaa 1680 aaagcaaaat acttatctct agaaactata aagcttgcct tagaagaatt taataagcat 1740 agagatatag ataaacagtg taggtttgaa gaaatacttg caaactttgc ggctattccg 1800 atgatatttg atgaaatagc tcaaaacaaa gacaatttgg cacagatatc tatcaaatat 1860 caaaatcaag gtaaaaaaga cctacttcaa gctagtgcgg aagatgatgt taaagctatc 1920 aaggatcttt tagatcaaac taataatctc ttacataaac taaaaatatt tcatattagt 1980 cagtcagaag ataaggcaaa tattttagac aaggatgagc atttttatct agtatttgag 2040 gagtgctact ttgagctagc gaatatagtg cctctttata acaaaattag aaactatata 2100 actcaaaagc catatagtga tgagaaattt aagctcaatt ttgagaactc gactttggct 2160 aatggttggg ataaaaataa agagcctgac aatacggcaa ttttatttat caaagatgat 2220 aaatattatc tgggtgtgat gaataagaaa aataacaaaa tatttgatga taaagctatc 2280 aaagaaaata aaggcgaggg ttataaaaaa attgtttata aacttttacc tggcgcaaat 2340 aaaatgttac ctaaggtttt cttttctgct aaatctataa aattttataa tcctagtgaa 2400 gatatactta gaataagaaa tcattccaca catacaaaaa atggtagtcc tcaaaaagga 2460 tatgaaaaat ttgagtttaa tattgaagat tgccgaaaat ttatagattt ttataaacag 2520 tctataagta agcatccgga gtggaaagat tttggattta gattttctga tactcaaaga 2580 tataattcta tagatgaatt ttatagagaa gttgaaaatc aaggctacaa actaactttt 2640 gaaaatatat cagagagcta tattgatagc gtagttaatc agggtaaatt gtacctattc 2700 caaatctata ataaagattt ttcagcttat agcaaagggc gaccaaatct acatacttta 2760 tattggaaag cgctgtttga tgagagaaat cttcaagatg tggtttataa gctaaatggt 2820 gaggcagagc ttttttatcg taaacaatca atacctaaaa aaatcactca cccagctaaa 2880 gaggcaatag ctaataaaaa caaagataat cctaaaaaag agagtgtttt tgaatatgat 2940 ttaatcaaag ataaacgctt tactgaagat aagtttttct ttcactgtcc tattacaatc 3000 aattttaaat ctagtggagc taataagttt aatgatgaaa tcaatttatt gctaaaagaa 3060 aaagcaaatg atgttcatat attaagtata gatagaggtg aaagacattt agcttactat 3120 actttggtag atggtaaagg caatatcatc aaacaagata ctttcaacat cattggtaat 3180 gatagaatga aaacaaacta ccatgataag cttgctgcaa tagagaaaga tagggattca 3240 gctaggaaag actggaaaaa gataaataac atcaaagaga tgaaagaggg ctatctatct 3300 caggtagttc atgaaatagc taagctagtt atagagtata atgctattgt ggtttttgag 3360 gatttaaatt ttggatttaa aagagggcgt ttcaaggtag agaagcaggt ctatcaaaag 3420 ttagaaaaaa tgctaattga gaaactaaac tatctagttt tcaaagataa tgagtttgat 3480 aaaactgggg gagtgcttag agcttatcag ctaacagcac cttttgagac ttttaaaaag 3540 atgggtaaac aaacaggtat tatctactat gtaccagctg gttttacttc aaaaatttgt 3600 cctgtaactg gttttgtaaa tcagttatat cctaagtatg aaagtgtcag caaatctcaa 3660 gagttcttta gtaagtttga caagatttgt tataaccttg ataagggcta ttttgagttt 3720 agttttgatt ataaaaactt tggtgacaag gctgccaaag gcaagtggac tatagctagc 3780 tttgggagta gattgattaa ctttagaaat tcagataaaa atcataattg ggatactcga 3840 gaagtttatc caactaaaga gttggagaaa ttgctaaaag attattctat cgaatatggg 3900 catggcgaat gtatcaaagc agctatttgc ggtgagagcg acaaaaagtt ttttgctaag 3960 ctaactagtg tcctaaatac tatcttacaa atgcgtaact caaaaacagg tactgagtta 4020 gattatctaa tttcaccagt agcagatgta aatggcaatt tctttgattc gcgacaggcg 4080 ccaaaaaata tgcctcaaga tgctgatgcc aatggtgctt atcatattgg gctaaaaggt 4140 ctgatgctac taggtaggat caaaaataat caagagggca aaaaactcaa tttggttatc 4200 aaaaatgaag agtattttga gttcgtgcag aataggaata actaattcat tcaagaatat 4260 attaccctgt cagtttagcg actattacct ctttaataat ttgcagggga attattttag 4320 taatagtaat atacacaaga gttattgatt atatggaaaa ttatatttag ataacatggt 4380 taaatgattt tatattctgt ccttactcga tatatttgca taatatctat agtaatgcct 4440 cagatactac atactattca tctagccaaa caaaagggcg cgatgctcat aaaagtatcg 4500 ataaaggaat ctatagtacc aaaaaagatg acctgatcgg tatcgatgtt attaaccata 4560 aatatggttt ggttggtaaa attgatgttt ttcataaaga taagggctta cttgtggaga 4620 gaaaaaggca aatcaagact atctatgatg gctataaata tcagctttat gcgcaatatt 4680 tttgtctcca agagatgggc tatgatgtca aagccattaa attttattcg atggttgata 4740 ataaatcata cccaatagct ataccaactt cagctgagtt agaaaagttt gaaaaacata 4800 ttcaaacaat caagcaatat aatccaatgg ataactcatt taggcaaaat attgaaaagt 4860 gtaaattttg tatatatgca aacttatgtg ataaaacgga cttgtagatt atgtttagta 4920 aaaatgatat tgaatcaaag aatatagttt ttgttaatat ttttgatgga gtgaaactta 4980 gtctatcatt ggggaatata gttataaaag ataaagaaac tgatgaggtg aaaactaagc 5040 tttctgttca taaagttctt gcattgttta tcgtaggtaa tatgacgatg acctcgcaac 5100 ttttagagac ctgtaagaaa aatgctatac agctagtttt tatgaaaaat agctttagac 5160 catatctatg ttttggtgat attgctgagg ctaatttttt agctagatat aagcaatata 5220 gtgtagttga gcaagatata agtttagcaa ggatttttat aacatcaaag atacgcaatc 5280 aacataactt agtcaaaagc ctaagagata aaactccaga gcagcaagag atagtcaaaa 5340 agaataaaca gctaatagca gagttagaaa atacaacaag cctagcggag ctaatgggta 5400 tagagggcaa tgttgccaaa aatttcttca aaggattcta tggacattta gatagttggc 5460 aagggcgcaa acctagaata aaacaggatc catataatgt tgttttagac ttgggctata 5520 gtatgttgtt taattttgta gagtgttttt tgcgactttt tggctttgat ttatacaagg 5580 gcttttgtca tcagacttgg tataagcgta aatccctagt ttgtgacttt gttgagccat 5640 ttagatgtat agtggataac caagttagaa aatcatggaa tctcgggcaa ttttctgtag 5700 aggattttgg ttgcaaaaat gagcagtttt atataaaaaa agataaaaca aaagactact 5760 caaaaatact ttttgccgag attatcagct acaagctaga gatatttgaa tatgtaagag 5820 aattttatcg tgcctttatg cgaggcaaag aaattgcaga gtatccaata ttttgttatg 5880 aaactaggag ggtgtatgtt gatagtcagt tatgatttta gtaataataa agtacgtgca 5940 aagtttgcca aatttctaga aagttatggt gtacgtttac aatattcggt atttgagctc 6000 aaatatagca agagaatgtt agacttgatt ttagctgaga tagaaaataa ctatgtacca 6060 ctatttacaa atgctgatag tgttttaatc tttaatgctc cagataaaga tgtgataaaa 6120 tatggttatg cgattcatag agaacaagag gttgttttta tagactaaaa attgcaaacc 6180 ttagtcttta tgttaaaata actactaagt tcttagagat atttaaaaat atgactgttg 6240 ttatatatca aaatgctaaa aaaatcatag attttaggtc tttttttgct gatttaggca 6300 aaaacgggtc taagaacttt aaataatttc tactgttgta gatgagaagt catttaataa 6360 ggccactgtt aaaagtctaa gaactttaaa taatttctac tgttgtagat gctactattc 6420 ctgtgccttc agataattca gtctaagaac tttaaataat ttctactgtt gtagatgtct 6480 agagcctttt gtattagtag ccggtctaag aactttaaat aatttctact gttgtagatt 6540 agcgatttat gaaggtcatt tttttgtct 6569 <210> 212 <211> 4170 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 212 tttacacttt atgcttccgg ctcgtatgtt aggaggtctt tatcatgtca atttatcaag 60 aatttgttaa taaatatagt ttaagtaaaa ctctaagatt tgagttaatc ccacagggta 120 aaacacttga aaacataaaa gcaagaggtt tgattttaga tgatgagaaa agagctaaag 180 actacaaaaa ggctaaacaa ataattgata aatatcatca gttttttata gaggagatat 240 taagttcggt ttgtattagc gaagatttat tacaaaacta ttctgatgtt tattttaaac 300 ttaaaaagag tgatgatgat aatctacaaa aagattttaa aagtgcaaaa gatacgataa 360 agaaacaaat atctgaatat ataaaggact cagagaaatt taagaatttg tttaatcaaa 420 accttatcga tgctaaaaaa gggcaagagt cagatttaat tctatggcta aagcaatcta 480 aggataatgg tatagaacta tttaaagcca atagtgatat cacagatata gatgaggcgt 540 tagaaataat caaatctttt aaaggttgga caacttattt taagggtttt catgaaaata 600 gaaaaaatgt ttatagtagc aatgatattc ctacatctat tatttatagg atagtagatg 660 ataatttgcc taaatttcta gaaaataaag ctaagtatga gagtttaaaa gacaaagctc 720 cagaagctat aaactatgaa caaattaaaa aagatttggc agaagagcta acctttgata 780 ttgactacaa aacatctgaa gttaatcaaa gagttttttc acttgatgaa gtttttgaga 840 tagcaaactt taataattat ctaaatcaaa gtggtattac taaatttaat actattattg 900 gtggtaaatt tgtaaatggt gaaaatacaa agagaaaagg tataaatgaa tatataaatc 960 tatactcaca gcaaataaat gataaaacac tcaaaaaata taaaatgagt gttttattta 1020 agcaaatttt aagtgataca gaatctaaat cttttgtaat tgataagtta gaagatgata 1080 gtgatgtagt tacaacgatg caaagttttt atgagcaaat agcagctttt aaaacagtag 1140 aagaaaaatc tattaaagaa acactatctt tattatttga tgatttaaaa gctcaaaaac 1200 ttgatttgag taaaatttat tttaaaaatg ataaatctct tactgatcta tcacaacaag 1260 tttttgatga ttatagtgtt attggtacag cggtactaga atatataact caacaaatag 1320 cacctaaaaa tcttgataac cctagtaaga aagagcaaga attaatagcc aaaaaaactg 1380 aaaaagcaaa atacttatct ctagaaacta taaagcttgc cttagaagaa tttaataagc 1440 atagagatat agataaacag tgtaggtttg aagaaatact tgcaaacttt gcggctattc 1500 cgatgatatt tgatgaaata gctcaaaaca aagacaattt ggcacagata tctatcaaat 1560 atcaaaatca aggtaaaaaa gacctacttc aagctagtgc ggaagatgat gttaaagcta 1620 tcaaggatct tttagatcaa actaataatc tcttacataa actaaaaata tttcatatta 1680 gtcagtcaga agataaggca aatattttag acaaggatga gcatttttat ctagtatttg 1740 aggagtgcta ctttgagcta gcgaatatag tgcctcttta taacaaaatt agaaactata 1800 taactcaaaa gccatatagt gatgagaaat ttaagctcaa ttttgagaac tcgactttgg 1860 ctaatggttg ggataaaaat aaagagcctg acaatacggc aattttattt atcaaagatg 1920 ataaatatta tctgggtgtg atgaataaga aaaataacaa aatatttgat gataaagcta 1980 tcaaagaaaa taaaggcgag ggttataaaa aaattgttta taaactttta cctggcgcaa 2040 ataaaatgtt acctaaggtt ttcttttctg ctaaatctat aaaattttat aatcctagtg 2100 aagatatact tagaataaga aatcattcca cacatacaaa aaatggtagt cctcaaaaag 2160 gatatgaaaa atttgagttt aatattgaag attgccgaaa atttatagat ttttataaac 2220 agtctataag taagcatccg gagtggaaag attttggatt tagattttct gatactcaaa 2280 gatataattc tatagatgaa ttttatagag aagttgaaaa tcaaggctac aaactaactt 2340 ttgaaaatat atcagagagc tatattgata gcgtagttaa tcagggtaaa ttgtacctat 2400 tccaaatcta taataaagat ttttcagctt atagcaaagg gcgaccaaat ctacatactt 2460 tatattggaa agcgctgttt gatgagagaa atcttcaaga tgtggtttat aagctaaatg 2520 gtgaggcaga gcttttttat cgtaaacaat caatacctaa aaaaatcact cacccagcta 2580 aagaggcaat agctaataaa aacaaagata atcctaaaaa agagagtgtt tttgaatatg 2640 atttaatcaa agataaacgc tttactgaag ataagttttt ctttcactgt cctattacaa 2700 tcaattttaa atctagtgga gctaataagt ttaatgatga aatcaattta ttgctaaaag 2760 aaaaagcaaa tgatgttcat atattaagta tagatagagg tgaaagacat ttagcttact 2820 atactttggt agatggtaaa ggcaatatca tcaaacaaga tactttcaac atcattggta 2880 atgatagaat gaaaacaaac taccatgata agcttgctgc aatagagaaa gatagggatt 2940 cagctaggaa agactggaaa aagataaata acatcaaaga gatgaaagag ggctatctat 3000 ctcaggtagt tcatgaaata gctaagctag ttatagagta taatgctatt gtggtttttg 3060 aggatttaaa ttttggattt aaaagagggc gtttcaaggt agagaagcag gtctatcaaa 3120 agttagaaaa aatgctaatt gagaaactaa actatctagt tttcaaagat aatgagtttg 3180 ataaaactgg gggagtgctt agagcttatc agctaacagc accttttgag acttttaaaa 3240 agatgggtaa acaaacaggt attatctact atgtaccagc tggttttact tcaaaaattt 3300 gtcctgtaac tggttttgta aatcagttat atcctaagta tgaaagtgtc agcaaatctc 3360 aagagttctt tagtaagttt gacaagattt gttataacct tgataagggc tattttgagt 3420 ttagttttga ttataaaaac tttggtgaca aggctgccaa aggcaagtgg actatagcta 3480 gctttgggag tagattgatt aactttagaa attcagataa aaatcataat tgggatactc 3540 gagaagttta tccaactaaa gagttggaga aattgctaaa agattattct atcgaatatg 3600 ggcatggcga atgtatcaaa gcagctattt gcggtgagag cgacaaaaag ttttttgcta 3660 agctaactag tgtcctaaat actatcttac aaatgcgtaa ctcaaaaaca ggtactgagt 3720 tagattatct aatttcacca gtagcagatg taaatggcaa tttctttgat tcgcgacagg 3780 cgccaaaaaa tatgcctcaa gatgctgatg ccaatggtgc ttatcatatt gggctaaaag 3840 gtctgatgct actaggtagg atcaaaaata atcaagaggg caaaaaactc aatttggtta 3900 tcaaaaatga agagtatttt gagttcgtgc agaataggaa taactaattg acagctagct 3960 cagtcctagg tataatgcta gcgctgattt aggcaaaaac gggtctaaga actttaaata 4020 atttctactg ttgtagatga gaagtcattt aataaggcca ctgttaaaag tctaagaact 4080 ttaaataatt tctactgttg tagatgctac tattcctgtg ccttcagata attcagtcta 4140 agaactttaa ataatttcta ctgttgtaga 4170 <210> 213 <211> 4613 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 213 ctgtctacta tgccgatgag tttggcaaaa ttttttagat ctacaaaatt ataaactaaa 60 taaagattct tataataact ttatatataa tcgaaatgta gagaatttta taaggagtct 120 ttatcatgtc aatttatcaa gaatttgtta ataaatatag tttaagtaaa actctaagat 180 ttgagttaat cccacagggt aaaacacttg aaaacataaa agcaagaggt ttgattttag 240 atgatgagaa aagagctaaa gactacaaaa aggctaaaca aataattgat aaatatcatc 300 agttttttat agaggagata ttaagttcgg tttgtattag cgaagattta ttacaaaact 360 attctgatgt ttattttaaa cttaaaaaga gtgatgatga taatctacaa aaagatttta 420 aaagtgcaaa agatacgata aagaaacaaa tatctgaata tataaaggac tcagagaaat 480 ttaagaattt gtttaatcaa aaccttatcg atgctaaaaa agggcaagag tcagatttaa 540 ttctatggct aaagcaatct aaggataatg gtatagaact atttaaagcc aatagtgata 600 tcacagatat agatgaggcg ttagaaataa tcaaatcttt taaaggttgg acaacttatt 660 ttaagggttt tcatgaaaat agaaaaaatg tttatagtag caatgatatt cctacatcta 720 ttatttatag gatagtagat gataatttgc ctaaatttct agaaaataaa gctaagtatg 780 agagtttaaa agacaaagct ccagaagcta taaactatga acaaattaaa aaagatttgg 840 cagaagagct aacctttgat attgactaca aaacatctga agttaatcaa agagtttttt 900 cacttgatga agtttttgag atagcaaact ttaataatta tctaaatcaa agtggtatta 960 ctaaatttaa tactattatt ggtggtaaat ttgtaaatgg tgaaaataca aagagaaaag 1020 gtataaatga atatataaat ctatactcac agcaaataaa tgataaaaca ctcaaaaaat 1080 ataaaatgag tgttttattt aagcaaattt taagtgatac agaatctaaa tcttttgtaa 1140 ttgataagtt agaagatgat agtgatgtag ttacaacgat gcaaagtttt tatgagcaaa 1200 tagcagcttt taaaacagta gaagaaaaat ctattaaaga aacactatct ttattatttg 1260 atgatttaaa agctcaaaaa cttgatttga gtaaaattta ttttaaaaat gataaatctc 1320 ttactgatct atcacaacaa gtttttgatg attatagtgt tattggtaca gcggtactag 1380 aatatataac tcaacaaata gcacctaaaa atcttgataa ccctagtaag aaagagcaag 1440 aattaatagc caaaaaaact gaaaaagcaa aatacttatc tctagaaact ataaagcttg 1500 ccttagaaga atttaataag catagagata tagataaaca gtgtaggttt gaagaaatac 1560 ttgcaaactt tgcggctatt ccgatgatat ttgatgaaat agctcaaaac aaagacaatt 1620 tggcacagat atctatcaaa tatcaaaatc aaggtaaaaa agacctactt caagctagtg 1680 cggaagatga tgttaaagct atcaaggatc ttttagatca aactaataat ctcttacata 1740 aactaaaaat atttcatatt agtcagtcag aagataaggc aaatatttta gacaaggatg 1800 agcattttta tctagtattt gaggagtgct actttgagct agcgaatata gtgcctcttt 1860 ataacaaaat tagaaactat ataactcaaa agccatatag tgatgagaaa tttaagctca 1920 attttgagaa ctcgactttg gctaatggtt gggataaaaa taaagagcct gacaatacgg 1980 caattttatt tatcaaagat gataaatatt atctgggtgt gatgaataag aaaaataaca 2040 aaatatttga tgataaagct atcaaagaaa ataaaggcga gggttataaa aaaattgttt 2100 ataaactttt acctggcgca aataaaatgt tacctaaggt tttcttttct gctaaatcta 2160 taaaatttta taatcctagt gaagatatac ttagaataag aaatcattcc acacatacaa 2220 aaaatggtag tcctcaaaaa ggatatgaaa aatttgagtt taatattgaa gattgccgaa 2280 aatttataga tttttataaa cagtctataa gtaagcatcc ggagtggaaa gattttggat 2340 ttagattttc tgatactcaa agatataatt ctatagatga attttataga gaagttgaaa 2400 atcaaggcta caaactaact tttgaaaata tatcagagag ctatattgat agcgtagtta 2460 atcagggtaa attgtaccta ttccaaatct ataataaaga tttttcagct tatagcaaag 2520 ggcgaccaaa tctacatact ttatattgga aagcgctgtt tgatgagaga aatcttcaag 2580 atgtggttta taagctaaat ggtgaggcag agctttttta tcgtaaacaa tcaataccta 2640 aaaaaatcac tcacccagct aaagaggcaa tagctaataa aaacaaagat aatcctaaaa 2700 aagagagtgt ttttgaatat gatttaatca aagataaacg ctttactgaa gataagtttt 2760 tctttcactg tcctattaca atcaatttta aatctagtgg agctaataag tttaatgatg 2820 aaatcaattt attgctaaaa gaaaaagcaa atgatgttca tatattaagt atagatagag 2880 gtgaaagaca tttagcttac tatactttgg tagatggtaa aggcaatatc atcaaacaag 2940 atactttcaa catcattggt aatgatagaa tgaaaacaaa ctaccatgat aagcttgctg 3000 caatagagaa agatagggat tcagctagga aagactggaa aaagataaat aacatcaaag 3060 agatgaaaga gggctatcta tctcaggtag ttcatgaaat agctaagcta gttatagagt 3120 ataatgctat tgtggttttt gaggatttaa attttggatt taaaagaggg cgtttcaagg 3180 tagagaagca ggtctatcaa aagttagaaa aaatgctaat tgagaaacta aactatctag 3240 ttttcaaaga taatgagttt gataaaactg ggggagtgct tagagcttat cagctaacag 3300 caccttttga gacttttaaa aagatgggta aacaaacagg tattatctac tatgtaccag 3360 ctggttttac ttcaaaaatt tgtcctgtaa ctggttttgt aaatcagtta tatcctaagt 3420 atgaaagtgt cagcaaatct caagagttct ttagtaagtt tgacaagatt tgttataacc 3480 ttgataaggg ctattttgag tttagttttg attataaaaa ctttggtgac aaggctgcca 3540 aaggcaagtg gactatagct agctttggga gtagattgat taactttaga aattcagata 3600 aaaatcataa ttgggatact cgagaagttt atccaactaa agagttggag aaattgctaa 3660 aagattattc tatcgaatat gggcatggcg aatgtatcaa agcagctatt tgcggtgaga 3720 gcgacaaaaa gttttttgct aagctaacta gtgtcctaaa tactatctta caaatgcgta 3780 actcaaaaac aggtactgag ttagattatc taatttcacc agtagcagat gtaaatggca 3840 atttctttga ttcgcgacag gcgccaaaaa atatgcctca agatgctgat gccaatggtg 3900 cttatcatat tgggctaaaa ggtctgatgc tactaggtag gatcaaaaat aatcaagagg 3960 gcaaaaaact caatttggtt atcaaaaatg aagagtattt tgagttcgtg cagaatagga 4020 ataactaatt cattcaagaa tatattaccc tgtcagttta gcgactatta cctctttaat 4080 aatttgcagg ggaattattt tagtaatagt aatatacaca agagttattg attatatgga 4140 aaattatatt tagataacat ggttaaatga ttttatattc tgtccttact cgatatattt 4200 tttatagact aaaaattgca aaccttagtc tttatgttaa aataactact aagttcttag 4260 agatatttaa aaatatgact gttgttatat atcaaaatgc taaaaaaatc atagatttta 4320 ggtctttttt tgctgattta ggcaaaaacg ggtctaagaa ctttaaataa tttctactgt 4380 tgtagatgag aagtcattta ataaggccac tgttaaaagt ctaagaactt taaataattt 4440 ctactgttgt agatgctact attcctgtgc cttcagataa ttcagtctaa gaactttaaa 4500 taatttctac tgttgtagat gtctagagcc ttttgtatta gtagccggtc taagaacttt 4560 aaataatttc tactgttgta gattagcgat ttatgaaggt catttttttg tct 4613 <210> 214 <211> 4035 <212> DNA <213> Francisella tularensis <400> 214 atgagcatct accaggagtt cgtcaacaag tattcactga gtaagacact gcggttcgag 60 ctgatcccac agggcaagac actggagaac atcaaggccc gaggcctgat tctggacgat 120 gagaagcggg caaaagacta taagaaagcc aagcagatca ttgataaata ccaccagttc 180 tttatcgagg aaattctgag ctccgtgtgc atcagtgagg atctgctgca gaattactca 240 gacgtgtact tcaagctgaa gaagagcgac gatgacaacc tgcagaagga cttcaagtcc 300 gccaaggaca ccatcaagaa acagattagc gagtacatca aggactccga aaagtttaaa 360 aatctgttca accagaatct gatcgatgct aagaaaggcc aggagtccga cctgatcctg 420 tggctgaaac agtctaagga caatgggatt gaactgttca aggctaactc cgatatcact 480 gatattgacg aggcactgga aatcatcaag agcttcaagg gatggaccac atactttaaa 540 ggcttccacg agaaccgcaa gaacgtgtac tccagcaacg acattcctac ctccatcatc 600 taccgaatcg tcgatgacaa tctgccaaag ttcctggaga acaaggccaa atatgaatct 660 ctgaaggaca aagctcccga ggcaattaat tacgaacaga tcaagaaaga tctggctgag 720 gaactgacat tcgatatcga ctataagact agcgaggtga accagagggt cttttccctg 780 gacgaggtgt ttgaaatcgc caatttcaac aattacctga accagtccgg cattactaaa 840 ttcaatacca tcattggcgg gaagtttgtg aacggggaga ataccaagcg caagggaatt 900 aacgaataca tcaatctgta tagccagcag atcaacgaca aaactctgaa gaaatacaag 960 atgtctgtgc tgttcaaaca gatcctgagt gataccgagt ccaagtcttt tgtcattgat 1020 aaactggaag atgactcaga cgtggtcact accatgcaga gcttttatga gcagatcgcc 1080 gctttcaaga cagtggagga aaaatctatt aaggaaactc tgagtctgct gttcgatgac 1140 ctgaaagccc agaagctgga cctgagtaag atctacttca aaaacgataa gagtctgaca 1200 gacctgtcac agcaggtgtt tgatgactat tccgtgattg ggaccgccgt cctggagtac 1260 attacacagc agatcgctcc aaagaacctg gataatccct ctaagaaaga gcaggaactg 1320 atcgctaaga aaaccgagaa ggcaaaatat ctgagtctgg aaacaattaa gctggcactg 1380 gaggagttca acaagcacag ggatattgac aaacagtgcc gctttgagga aatcctggcc 1440 aacttcgcag ccatccccat gatttttgat gagatcgccc agaacaaaga caatctggct 1500 cagatcagta ttaagtacca gaaccagggc aagaaagacc tgctgcaggc ttcagcagaa 1560 gatgacgtga aagccatcaa ggatctgctg gaccagacca acaatctgct gcacaagctg 1620 aaaatcttcc atattagtca gtcagaggat aaggctaata tcctggataa agacgaacac 1680 ttctacctgg tgttcgagga atgttacttc gagctggcaa acattgtccc cctgtataac 1740 aagattagga actacatcac acagaagcct tactctgacg agaagtttaa actgaacttc 1800 gaaaatagta ccctggccaa cgggtgggat aagaacaagg agcctgacaa cacagctatc 1860 ctgttcatca aggatgacaa gtactatctg ggagtgatga ataagaaaaa caataagatc 1920 ttcgatgaca aagccattaa ggagaacaaa ggggaaggat acaagaaaat cgtgtataag 1980 ctgctgcccg gcgcaaataa gatgctgcct aaggtgttct tcagcgccaa gagtatcaaa 2040 ttctacaacc catccgagga catcctgcgg attagaaatc actcaacaca tactaagaac 2100 gggagccccc agaagggata tgagaaattt gagttcaaca tcgaggattg caggaagttt 2160 attgacttct acaagcagag catctccaaa caccctgaat ggaaggattt tggcttccgg 2220 ttttccgaca cacagagata taactctatc gacgagttct accgcgaggt ggaaaatcag 2280 gggtataagc tgacttttga gaacatttct gaaagttaca tcgacagcgt ggtcaatcag 2340 ggaaagctgt acctgttcca gatctataac aaagattttt cagcatacag caagggcaga 2400 ccaaacctgc atacactgta ctggaaggcc ctgttcgatg agaggaatct gcaggacgtg 2460 gtctataaac tgaacggaga ggccgaactg ttttaccgga agcagtctat tcctaagaaa 2520 atcactcacc cagctaagga ggccatcgct aacaagaaca aggacaatcc taagaaagag 2580 agcgtgttcg aatacgatct gattaaggac aagcggttca ccgaagataa gttctttttc 2640 cattgtccaa tcaccattaa cttcaagtca agcggcgcta acaagttcaa cgacgagatc 2700 aatctgctgc tgaaggaaaa agcaaacgat gtgcacatcc tgagcattga ccgaggagag 2760 cggcatctgg cctactatac cctggtggat ggcaaaggga atatcattaa gcaggataca 2820 ttcaacatca ttggcaatga ccggatgaaa accaactacc acgataaact ggctgcaatc 2880 gagaaggata gagactcagc taggaaggac tggaagaaaa tcaacaacat taaggagatg 2940 aaggaaggct atctgagcca ggtggtccat gagattgcaa agctggtcat cgaatacaat 3000 gccattgtgg tgttcgagga tctgaacttc ggctttaaga gggggcgctt taaggtggaa 3060 aaacaggtct atcagaagct ggagaaaatg ctgatcgaaa agctgaatta cctggtgttt 3120 aaagataacg agttcgacaa gaccggaggc gtcctgagag cctaccagct gacagctccc 3180 tttgaaactt tcaagaaaat gggaaaacag acaggcatca tctactatgt gccagccgga 3240 ttcacttcca agatctgccc cgtgaccggc tttgtcaacc agctgtaccc taaatatgag 3300 tcagtgagca agtcccagga atttttcagc aagttcgata agatctgtta taatctggac 3360 aaggggtact tcgagttttc cttcgattac aagaacttcg gcgacaaggc cgctaagggg 3420 aaatggacca ttgcctcctt cggatctcgc ctgatcaact ttcgaaattc cgataaaaac 3480 cacaattggg acactaggga ggtgtaccca accaaggagc tggaaaagct gctgaaagac 3540 tactctatcg agtatggaca tggcgaatgc atcaaggcag ccatctgtgg cgagagtgat 3600 aagaaatttt tcgccaagct gacctcagtg ctgaatacaa tcctgcagat gcggaactca 3660 aagaccggga cagaactgga ctatctgatt agccccgtgg ctgatgtcaa cggaaacttc 3720 ttcgacagca gacaggcacc caaaaatatg cctcaggatg cagacgccaa cggggcctac 3780 cacatcgggc tgaagggact gatgctgctg ggccggatca agaacaatca ggaggggaag 3840 aagctgaacc tggtcattaa gaacgaggaa tacttcgagt ttgtccagaa tagaaataac 3900 aaaaggccgg cggccacgaa aaaggccggc caggcaaaaa agaaaaaggg atcctaccca 3960 tacgatgttc cagattacgc ttatccctac gacgtgcctg attatgcata cccatatgat 4020 gtccccgact atgcc 4035 <210> 215 <211> 3834 <212> DNA <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 215 atggattacg gcaacggcca gtttgagcgg agagcccccc tgaccaagac aatcaccctg 60 cgcctgaagc ctatcggcga gacacgggag acaatccgcg agcagaagct gctggagcag 120 gacgccgcct tcagaaagct ggtggagaca gtgaccccta tcgtggacga ttgtatcagg 180 aagatcgccg ataacgccct gtgccacttt ggcaccgagt atgacttcag ctgtctgggc 240 aacgccatct ctaagaatga cagcaaggcc atcaagaagg agacagagaa ggtggagaag 300 ctgctggcca aggtgctgac cgagaatctg ccagatggcc tgcgcaaggt gaacgacatc 360 aattccgccg cctttatcca ggatacactg acctctttcg tgcaggacga tgccgacaag 420 cgggtgctga tccaggagct gaagggcaag accgtgctga tgcagcggtt cctgaccaca 480 cggatcacag ccctgaccgt gtggctgccc gacagagtgt tcgagaactt taatatcttc 540 atcgagaacg ccgagaagat gagaatcctg ctggactccc ctctgaatga gaagatcatg 600 aagtttgacc cagatgccga gcagtacgcc tctctggagt tctatggcca gtgcctgtct 660 cagaaggaca tcgatagcta caacctgatc atctccggca tctatgccga cgatgaggtg 720 aagaaccctg gcatcaatga gatcgtgaag gagtacaatc agcagatccg gggcgacaag 780 gatgagtccc cactgcccaa gctgaagaag ctgcacaagc agatcctgat gccagtggag 840 aaggccttct ttgtgcgcgt gctgtctaac gacagcgatg cccggagcat cctggagaag 900 atcctgaagg acacagagat gctgccctcc aagatcatcg aggccatgaa ggaggcagat 960 gcaggcgaca tcgccgtgta cggcagccgg ctgcacgagc tgagccacgt gatctacggc 1020 gatcacggca agctgtccca gatcatctat gacaaggagt ccaagaggat ctctgagctg 1080 atggagacac tgtctccaaa ggagcgcaag gagagcaaga agcggctgga gggcctggag 1140 gagcacatca gaaagtctac atacaccttc gacgagctga acaggtatgc cgagaagaat 1200 gtgatggcag catacatcgc agcagtggag gagtcttgtg ccgagatcat gagaaaggag 1260 aaggatctga ggaccctgct gagcaaggag gacgtgaaga tccggggcaa cagacacaat 1320 acactgatcg tgaagaacta ctttaatgcc tggaccgtgt tccggaacct gatcagaatc 1380 ctgaggcgca agtccgaggc cgagatcgac tctgacttct acgatgtgct ggacgattcc 1440 gtggaggtgc tgtctctgac atacaagggc gagaatctgt gccgcagcta tatcaccaag 1500 aagatcggct ccgacctgaa gcccgagatc gccacatacg gcagcgccct gaggcctaac 1560 agccgctggt ggtccccagg agagaagttt aatgtgaagt tccacaccat cgtgcggaga 1620 gatggccggc tgtactattt catcctgccc aagggcgcca agcctgtgga gctggaggac 1680 atggatggcg acatcgagtg tctgcagatg agaaagatcc ctaacccaac aatctttctg 1740 cccaagctgg tgttcaagga ccctgaggcc ttctttaggg ataatccaga ggccgacgag 1800 ttcgtgtttc tgagcggcat gaaggccccc gtgacaatca ccagagagac atacgaggcc 1860 tacaggtata agctgtatac cgtgggcaag ctgcgcgatg gcgaggtgtc cgaagaggag 1920 tacaagcggg ccctgctgca ggtgctgacc gcctacaagg agtttctgga gaacagaatg 1980 atctatgccg acctgaattt cggctttaag gatctggagg agtataagga cagctccgag 2040 tttatcaagc aggtggagac acacaacacc ttcatgtgct gggccaaggt gtctagctcc 2100 cagctggacg atctggtgaa gtctggcaac ggcctgctgt tcgagatctg gagcgagcgc 2160 ctggagtcct actataagta cggcaatgag aaggtgctgc ggggctatga gggcgtgctg 2220 ctgagcatcc tgaaggatga gaacctggtg tccatgcgga ccctgctgaa cagccggccc 2280 atgctggtgt accggccaaa ggagtctagc aagcctatgg tggtgcaccg ggatggcagc 2340 agagtggtgg acaggtttga taaggacggc aagtacatcc cccctgaggt gcacgacgag 2400 ctgtatcgct tctttaacaa tctgctgatc aaggagaagc tgggcgagaa ggcccggaag 2460 atcctggaca acaagaaggt gaaggtgaag gtgctggaga gcgagagagt gaagtggtcc 2520 aagttctacg atgagcagtt tgccgtgacc ttcagcgtga agaagaacgc cgattgtctg 2580 gacaccacaa aggacctgaa tgccgaagtg atggagcagt atagcgagtc caacagactg 2640 atcctgatca ggaataccac agatatcctg tactatctgg tgctggacaa gaatggcaag 2700 gtgctgaagc agagatccct gaacatcatc aatgacggcg ccagggatgt ggactggaag 2760 gagaggttcc gccaggtgac aaaggataga aacgagggct acaatgagtg ggattattcc 2820 aggacctcta acgacctgaa ggaggtgtac ctgaattatg ccctgaagga gatcgccgag 2880 gccgtgatcg agtacaacgc catcctgatc atcgagaaga tgtctaatgc ctttaaggac 2940 aagtatagct tcctggacga cgtgaccttc aagggcttcg agacaaagct gctggccaag 3000 ctgagcgatc tgcactttag gggcatcaag gacggcgagc catgttcctt cacaaacccc 3060 ctgcagctgt gccagaacga ttctaataag atcctgcagg acggcgtgat ctttatggtg 3120 ccaaattcta tgacacggag cctggacccc gacaccggct tcatctttgc catcaacgac 3180 cacaatatca ggaccaagaa ggccaagctg aactttctga gcaagttcga tcagctgaag 3240 gtgtcctctg agggctgcct gatcatgaag tacagcggcg attccctgcc tacacacaac 3300 accgacaatc gcgtgtggaa ctgctgttgc aatcacccaa tcacaaacta tgaccgggag 3360 acaaagaagg tggagttcat cgaggagccc gtggaggagc tgtcccgcgt gctggaggag 3420 aatggcatcg agacagacac cgagctgaac aagctgaatg agcgggagaa cgtgcctggc 3480 aaggtggtgg atgccatcta ctctctggtg ctgaattatc tgcgcggcac agtgagcgga 3540 gtggcaggac agagggccgt gtactatagc cctgtgaccg gcaagaagta cgatatctcc 3600 tttatccagg ccatgaacct gaataggaag tgtgactact ataggatcgg ctccaaggag 3660 aggggagagt ggaccgattt cgtggcccag ctgatcaaca aaaggccggc ggccacgaaa 3720 aaggccggcc aggcaaaaaa gaaaaaggga tcctacccat acgatgttcc agattacgct 3780 tatccctacg acgtgcctga ttatgcatac ccatatgatg tccccgacta tgcc 3834 <210> 216 <211> 4035 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 216 atgagcatct accaggagtt cgtcaacaag tattcactga gtaagacact gcggttcgag 60 ctgatcccac agggcaagac actggagaac atcaaggccc gaggcctgat tctggacgat 120 gagaagcggg caaaagacta taagaaagcc aagcagatca ttgataaata ccaccagttc 180 tttatcgagg aaattctgag ctccgtgtgc atcagtgagg atctgctgca gaattactca 240 gacgtgtact tcaagctgaa gaagagcgac gatgacaacc tgcagaagga cttcaagtcc 300 gccaaggaca ccatcaagaa acagattagc gagtacatca aggactccga aaagtttaaa 360 aatctgttca accagaatct gatcgatgct aagaaaggcc aggagtccga cctgatcctg 420 tggctgaaac agtctaagga caatgggatt gaactgttca aggctaactc cgatatcact 480 gatattgacg aggcactgga aatcatcaag agcttcaagg gatggaccac atactttaaa 540 ggcttccacg agaaccgcaa gaacgtgtac tccagcaacg acattcctac ctccatcatc 600 taccgaatcg tcgatgacaa tctgccaaag ttcctggaga acaaggccaa atatgaatct 660 ctgaaggaca aagctcccga ggcaattaat tacgaacaga tcaagaaaga tctggctgag 720 gaactgacat tcgatatcga ctataagact agcgaggtga accagagggt cttttccctg 780 gacgaggtgt ttgaaatcgc caatttcaac aattacctga accagtccgg cattactaaa 840 ttcaatacca tcattggcgg gaagtttgtg aacggggaga ataccaagcg caagggaatt 900 aacgaataca tcaatctgta tagccagcag atcaacgaca aaactctgaa gaaatacaag 960 atgtctgtgc tgttcaaaca gatcctgagt gataccgagt ccaagtcttt tgtcattgat 1020 aaactggaag atgactcaga cgtggtcact accatgcaga gcttttatga gcagatcgcc 1080 gctttcaaga cagtggagga aaaatctatt aaggaaactc tgagtctgct gttcgatgac 1140 ctgaaagccc agaagctgga cctgagtaag atctacttca aaaacgataa gagtctgaca 1200 gacctgtcac agcaggtgtt tgatgactat tccgtgattg ggaccgccgt cctggagtac 1260 attacacagc agatcgctcc aaagaacctg gataatccct ctaagaaaga gcaggaactg 1320 atcgctaaga aaaccgagaa ggcaaaatat ctgagtctgg aaacaattaa gctggcactg 1380 gaggagttca acaagcacag ggatattgac aaacagtgcc gctttgagga aatcctggcc 1440 aacttcgcag ccatccccat gatttttgat gagatcgccc agaacaaaga caatctggct 1500 cagatcagta ttaagtacca gaaccagggc aagaaagacc tgctgcaggc ttcagcagaa 1560 gatgacgtga aagccatcaa ggatctgctg gaccagacca acaatctgct gcacaagctg 1620 aaaatcttcc atattagtca gtcagaggat aaggctaata tcctggataa agacgaacac 1680 ttctacctgg tgttcgagga atgttacttc gagctggcaa acattgtccc cctgtataac 1740 aagattagga actacatcac acagaagcct tactctgacg agaagtttaa actgaacttc 1800 gaaaatagta ccctggccaa cgggtgggat aagaacaagg agcctgacaa cacagctatc 1860 ctgttcatca aggatgacaa gtactatctg ggagtgatga ataagaaaaa caataagatc 1920 ttcgatgaca aagccattaa ggagaacaaa ggggaaggat acaagaaaat cgtgtataag 1980 ctgctgcccg gcgcaaataa gatgctgcct aaggtgttct tcagcgccaa gagtatcaaa 2040 ttctacaacc catccgagga catcctgcgg attagaaatc actcaacaca tactaagaac 2100 gggagccccc agaagggata tgagaaattt gagttcaaca tcgaggattg caggaagttt 2160 attgacttct acaagcagag catctccaaa caccctgaat ggaaggattt tggcttccgg 2220 ttttccgaca cacagagata taactctatc gacgagttct accgcgaggt ggaaaatcag 2280 gggtataagc tgacttttga gaacatttct gaaagttaca tcgacagcgt ggtcaatcag 2340 ggaaagctgt acctgttcca gatctataac aaagattttt cagcatacag caagggcaga 2400 ccaaacctgc atacactgta ctggaaggcc ctgttcgatg agaggaatct gcaggacgtg 2460 gtctataaac tgaacggaga ggccgaactg ttttaccgga agcagtctat tcctaagaaa 2520 atcactcacc cagctaagga ggccatcgct aacaagaaca aggacaatcc taagaaagag 2580 agcgtgttcg aatacgatct gattaaggac aagcggttca ccgaagataa gttctttttc 2640 cattgtccaa tcaccattaa cttcaagtca agcggcgcta acaagttcaa cgacgagatc 2700 aatctgctgc tgaaggaaaa agcaaacgat gtgcacatcc tgagcattga ccgaggagag 2760 cggcatctgg cctactatac cctggtggat ggcaaaggga atatcattaa gcaggataca 2820 ttcaacatca ttggcaatga ccggatgaaa accaactacc acgataaact ggctgcaatc 2880 gagaaggata gagactcagc taggaaggac tggaagaaaa tcaacaacat taaggagatg 2940 aaggaaggct atctgagcca ggtggtccat gagattgcaa agctggtcat cgaatacaat 3000 gccattgtgg tgttcgagga tctgaacttc ggctttaaga gggggcgctt taaggtggaa 3060 aaacaggtct atcagaagct ggagaaaatg ctgatcgaaa agctgaatta cctggtgttt 3120 aaagataacg agttcgacaa gaccggaggc gtcctgagag cctaccagct gacagctccc 3180 tttgaaactt tcaagaaaat gggaaaacag acaggcatca tctactatgt gccagccgga 3240 ttcacttcca agatctgccc cgtgaccggc tttgtcaacc agctgtaccc taaatatgag 3300 tcagtgagca agtcccagga atttttcagc aagttcgata agatctgtta taatctggac 3360 aaggggtact tcgagttttc cttcgattac aagaacttcg gcgacaaggc cgctaagggg 3420 aaatggacca ttgcctcctt cggatctcgc ctgatcaact ttcgaaattc cgataaaaac 3480 cacaattggg acactaggga ggtgtaccca accaaggagc tggaaaagct gctgaaagac 3540 tactctatcg agtatggaca tggcgaatgc atcaaggcag ccatctgtgg cgagagtgat 3600 aagaaatttt tcgccaagct gacctcagtg ctgaatacaa tcctgcagat gcggaactca 3660 aagaccggga cagaactgga ctatctgatt agccccgtgg ctgatgtcaa cggaaacttc 3720 ttcgacagca gacaggcacc caaaaatatg cctcaggatg cagacgccaa cggggcctac 3780 cacatcgggc tgaagggact gatgctgctg ggccggatca agaacaatca ggaggggaag 3840 aagctgaacc tggtcattaa gaacgaggaa tacttcgagt ttgtccagaa tagaaataac 3900 aaaaggccgg cggccacgaa aaaggccggc caggcaaaaa agaaaaaggg atcctaccca 3960 tacgatgttc cagattacgc ttatccctac gacgtgcctg attatgcata cccatatgat 4020 gtccccgact atgcc 4035 <210> 217 <211> 4575 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 217 atgtccaact tctttaagaa tttcaccaac ctgtatgagc tgtccaagac actgaggttt 60 gagctgaagc ccgtgggcga caccctgaca aacatgaagg accacctgga gtacgatgag 120 aagctgcaga ccttcctgaa ggatcagaat atcgacgatg cctatcaggc cctgaagcct 180 cagttcgacg agatccacga ggagtttatc acagattctc tggagagcaa gaaggccaag 240 gagatcgact tctccgagta cctggatctg tttcaggaga agaaggagct gaacgactct 300 gagaagaagc tgcgcaacaa gatcggcgag acattcaaca aggccggcga gaagtggaag 360 aaggagaagt accctcagta tgagtggaag aagggctcca agatcgccaa tggcgccgac 420 atcctgtctt gccaggatat gctgcagttt atcaagtata agaacccaga ggatgagaag 480 atcaagaatt acatcgacga tacactgaag ggcttcttta cctatttcgg cggctttaat 540 cagaacaggg ccaactacta tgagacaaag aaggaggcct ccaccgcagt ggcaacaagg 600 atcgtgcacg agaacctgcc aaagttctgt gacaatgtga tccagtttaa gcacatcatc 660 aagcggaaga aggatggcac cgtggagaaa accgagagaa agaccgagta cctgaacgcc 720 taccagtatc tgaagaacaa taacaagatc acacagatca aggacgccga gacagagaag 780 atgatcgagt ctacacccat cgccgagaag atcttcgacg tgtactactt cagcagctgc 840 ctgagccaga agcagatcga ggagtacaac cggatcatcg gccactataa tctgctgatc 900 aacctgtata accaggccaa gagatctgag ggcaagcacc tgagcgccaa cgagaagaag 960 tataaggacc tgcctaagtt caagaccctg tataagcaga tcggctgcgg caagaagaag 1020 gacctgtttt acacaatcaa gtgtgatacc gaggaggagg ccaataagtc ccggaacgag 1080 ggcaaggagt cccactctgt ggaggagatc atcaacaagg cccaggaggc catcaataag 1140 tacttcaagt ctaataacga ctgtgagaat atcaacaccg tgcccgactt catcaactat 1200 atcctgacaa aggagaatta cgagggcgtg tattggagca aggccgccat gaacaccatc 1260 tccgacaagt acttcgccaa ttatcacgac ctgcaggata gactgaagga ggccaaggtg 1320 tttcagaagg ccgataagaa gtccgaggac gatatcaaga tcccagaggc catcgagctg 1380 tctggcctgt tcggcgtgct ggacagcctg gccgattggc agaccacact gtttaagtct 1440 agcatcctga gcaacgagga caagctgaag atcatcacag attcccagac cccctctgag 1500 gccctgctga agatgatctt caatgacatc gagaagaaca tggagtcctt tctgaaggag 1560 acaaacgata tcatcaccct gaagaagtat aagggcaata aggagggcac cgagaagatc 1620 aagcagtggt tcgactatac actggccatc aaccggatgc tgaagtactt tctggtgaag 1680 gagaataaga tcaagggcaa ctccctggat accaatatct ctgaggccct gaaaaccctg 1740 atctacagcg acgatgccga gtggttcaag tggtacgacg ccctgagaaa ctatctgacc 1800 cagaagcctc aggatgaggc caaggagaat aagctgaagc tgaatttcga caacccatct 1860 ctggccggcg gctgggatgt gaacaaggag tgcagcaatt tttgcgtgat cctgaaggac 1920 aagaacgaga agaagtacct ggccatcatg aagaagggcg agaataccct gttccagaag 1980 gagtggacag agggccgggg caagaacctg acaaagaagt ctaatccact gttcgagatc 2040 aataactgcg agatcctgag caagatggag tatgactttt gggccgacgt gagcaagatg 2100 atccccaagt gtagcaccca gctgaaggcc gtggtgaacc acttcaagca gtccgacaat 2160 gagttcatct ttcctatcgg ctacaaggtg acaagcggcg agaagtttag ggaggagtgc 2220 aagatctcca agcaggactt cgagctgaat aacaaggtgt ttaataagaa cgagctgagc 2280 gtgaccgcca tgcgctacga tctgtcctct acacaggaga agcagtatat caaggccttc 2340 cagaaggagt actgggagct gctgtttaag caggagaagc gggacaccaa gctgacaaat 2400 aacgagatct tcaacgagtg gatcaatttt tgcaacaaga agtatagcga gctgctgtcc 2460 tgggagagaa agtacaagga tgccctgacc aattggatca acttctgtaa gtactttctg 2520 agcaagtatc ccaagaccac actgttcaac tactctttta aggagagcga gaattataac 2580 tccctggacg agttctaccg ggacgtggat atctgttctt acaagctgaa tatcaacacc 2640 acaatcaata agagcatcct ggatagactg gtggaggagg gcaagctgta cctgtttgag 2700 atcaagaatc aggacagcaa cgatggcaag tccatcggcc acaagaataa cctgcacacc 2760 atctactgga acgccatctt cgagaatttt gacaacaggc ctaagctgaa tggcgaggcc 2820 gagatcttct atcgcaaggc catctccaag gataagctgg gcatcgtgaa gggcaagaaa 2880 accaagaacg gcaccgagat catcaagaat tacagattca gcaaggagaa gtttatcctg 2940 cacgtgccaa tcaccctgaa cttctgctcc aataacgagt atgtgaatga catcgtgaac 3000 acaaagttct acaatttttc caacctgcac tttctgggca tcgatagggg cgagaagcac 3060 ctggcctact attctctggt gaataagaac ggcgagatcg tggaccaggg cacactgaac 3120 ctgcctttca ccgacaagga tggcaatcag cgcagcatca agaaggagaa gtacttttat 3180 aacaagcagg aggacaagtg ggaggccaag gaggtggatt gttggaatta taacgacctg 3240 ctggatgcca tggcctctaa ccgggacatg gccagaaaga attggcagag gatcggcacc 3300 atcaaggagg ccaagaacgg ctacgtgagc ctggtcatca ggaagatcgc cgatctggcc 3360 gtgaataacg agcgccccgc cttcatcgtg ctggaggacc tgaatacagg ctttaagcgg 3420 tccagacaga agatcgataa gagcgtgtac cagaagttcg agctggccct ggccaagaag 3480 ctgaactttc tggtggacaa gaatgccaag cgcgatgaga tcggctcccc tacaaaggcc 3540 ctgcagctga ccccccctgt gaataactac ggcgacattg agaacaagaa gcaggccggc 3600 atcatgctgt atacccgggc caattatacc tctcagacag atccagccac aggctggaga 3660 aagaccatct atctgaaggc cggccccgag gagacaacat acaagaagga cggcaagatc 3720 aagaacaaga gcgtgaagga ccagatcatc gagacattca ccgatatcgg ctttgacggc 3780 aaggattact atttcgagta cgacaagggc gagtttgtgg atgagaaaac cggcgagatc 3840 aagcccaaga agtggcggct gtactccggc gagaatggca agtccctgga caggttccgc 3900 ggagagaggg agaaggataa gtatgagtgg aagatcgaca agatcgatat cgtgaagatc 3960 ctggacgatc tgttcgtgaa ttttgacaag aacatcagcc tgctgaagca gctgaaggag 4020 ggcgtggagc tgacccggaa taacgagcac ggcacaggcg agtccctgag attcgccatc 4080 aacctgatcc agcagatccg gaataccggc aataacgaga gagacaacga tttcatcctg 4140 tccccagtga gggacgagaa tggcaagcac tttgactctc gcgagtactg ggataaggag 4200 acaaagggcg agaagatcag catgcccagc tccggcgatg ccaatggcgc cttcaacatc 4260 gcccggaagg gcatcatcat gaacgcccac atcctggcca atagcgactc caaggatctg 4320 tccctgttcg tgtctgacga ggagtgggat ctgcacctga ataacaagac cgagtggaag 4380 aagcagctga acatcttttc tagcaggaag gccatggcca agcgcaagaa gaaaaggccg 4440 gcggccacga aaaaggccgg ccaggcaaaa aagaaaaagg gatcctaccc atacgatgtt 4500 ccagattacg cttatcccta cgacgtgcct gattatgcat acccatatga tgtccccgac 4560 tatgcctaag aattc 4575 <210> 218 <211> 4200 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 218 atggagaaca tcttcgacca gtttatcggc aagtacagcc tgtccaagac cctgagattc 60 gagctgaagc ccgtgggcaa gacagaggac ttcctgaaga tcaacaaggt gtttgagaag 120 gatcagacca tcgacgatag ctacaatcag gccaagttct attttgattc cctgcaccag 180 aagtttatcg acgccgccct ggcctccgat aagacatccg agctgtcttt ccagaacttt 240 gccgacgtgc tggagaagca gaataagatc atcctggata agaagagaga gatgggcgcc 300 ctgaggaagc gcgacaagaa cgccgtgggc atcgataggc tgcagaagga gatcaatgac 360 gccgaggata tcatccagaa ggagaaggag aagatctaca aggacgtgcg caccctgttc 420 gataacgagg ccgagtcttg gaaaacctac tatcaggagc gggaggtgga cggcaagaag 480 atcaccttca gcaaggccga cctgaagcag aagggcgccg attttctgac agccgccggc 540 atcctgaagg tgctgaagta tgagttcccc gaggagaagg agaaggagtt tcaggccaag 600 aaccagccct ccctgttcgt ggaggagaag gagaatcctg gccagaagag gtacatcttc 660 gactcttttg ataagttcgc cggctatctg accaagtttc agcagacaaa gaagaatctg 720 tacgcagcag acggcaccag cacagcagtg gccacccgca tcgccgataa ctttatcatc 780 ttccaccaga ataccaaggt gttccgggac aagtacaaga acaatcacac agacctgggc 840 ttcgatgagg agaacatctt tgagatcgag aggtataaga attgcctgct gcagcgcgag 900 atcgagcaca tcaagaatga gaatagctac aacaagatca tcggccggat caataagaag 960 atcaaggagt atcgggacca gaaggccaag gataccaagc tgacaaagtc cgacttccct 1020 ttctttaaga acctggataa gcagatcctg ggcgaggtgg agaaggagaa gcagctgatc 1080 gagaaaaccc gggagaaaac cgaggaggac gtgctgatcg agcggttcaa ggagttcatc 1140 gagaacaatg aggagaggtt caccgccgcc aagaagctga tgaatgcctt ctgtaacggc 1200 gagtttgagt ccgagtacga gggcatctat ctgaagaata aggccatcaa cacaatctcc 1260 cggagatggt tcgtgtctga cagagatttt gagctgaagc tgcctcagca gaagtccaag 1320 aacaagtctg agaagaatga gccaaaggtg aagaagttca tctccatcgc cgagatcaag 1380 aacgccgtgg aggagctgga cggcgatatc tttaaggccg tgttctacga caagaagatc 1440 atcgcccagg gcggctctaa gctggagcag ttcctggtca tctggaagta cgagtttgag 1500 tatctgttcc gggacatcga gagagagaac ggcgagaagc tgctgggcta tgatagctgc 1560 ctgaagatcg ccaagcagct gggcatcttc ccacaggaga aggaggcccg cgagaaggca 1620 accgccgtga tcaagaatta cgccgacgcc ggcctgggca tcttccagat gatgaagtat 1680 ttttctctgg acgataagga tcggaagaac acccccggcc agctgagcac aaatttctac 1740 gccgagtatg acggctacta caaggatttc gagtttatca agtactacaa cgagtttagg 1800 aacttcatca ccaagaagcc tttcgacgag gataagatca agctgaactt tgagaatggc 1860 gccctgctga agggctggga cgagaacaag gagtacgatt tcatgggcgt gatcctgaag 1920 aaggagggcc gcctgtatct gggcatcatg cacaagaacc accggaagct gtttcagtcc 1980 atgggcaatg ccaagggcga caacgccaat agataccaga agatgatcta taagcagatc 2040 gccgacgcct ctaaggatgt gcccaggctg ctgctgacca gcaagaaggc catggagaag 2100 ttcaagcctt cccaggagat cctgagaatc aagaaggaga aaaccttcaa gcgggagagc 2160 aagaactttt ccctgagaga tctgcacgcc ctgatcgagt actataggaa ctgcatccct 2220 cagtacagca attggtcctt ttatgacttc cagtttcagg ataccggcaa gtaccagaat 2280 atcaaggagt tcacagacga tgtgcagaag tacggctata agatctcctt tcgcgacatc 2340 gacgatgagt atatcaatca ggccctgaac gagggcaaga tgtacctgtt cgaggtggtg 2400 aacaaggata tctataacac caagaatggc tccaagaatc tgcacacact gtactttgag 2460 cacatcctgt ctgccgagaa cctgaatgac ccagtgttca agctgtctgg catggccgag 2520 atctttcagc ggcagcccag cgtgaacgaa agagagaaga tcaccacaca gaagaatcag 2580 tgtatcctgg acaagggcga tagagcctac aagtataggc gctacaccga gaagaagatc 2640 atgttccaca tgagcctggt gctgaacaca ggcaagggcg agatcaagca ggtgcagttt 2700 aataagatca tcaaccagag gatcagctcc tctgacaacg agatgagggt gaatgtgatc 2760 ggcatcgatc gcggcgagaa gaacctgctg tactatagcg tggtgaagca gaatggcgag 2820 atcatcgagc aggcctccct gaacgagatc aatggcgtga actaccggga caagctgatc 2880 gagagggaga aggagcgcct gaagaaccgg cagagctgga agcctgtggt gaagatcaag 2940 gatctgaaga agggctacat ctcccacgtg atccacaaga tctgccagct gatcgagaag 3000 tattctgcca tcgtggtgct ggaggacctg aatatgagat tcaagcagat caggggagga 3060 atcgagcgga gcgtgtacca gcagttcgag aaggccctga tcgataagct gggctatctg 3120 gtgtttaagg acaacaggga tctgagggca ccaggaggcg tgctgaatgg ctaccagctg 3180 tctgccccct ttgtgagctt cgagaagatg cgcaagcaga ccggcatcct gttctacaca 3240 caggccgagt ataccagcaa gacagaccca atcaccggct ttcggaagaa cgtgtatatc 3300 tctaatagcg cctccctgga taagatcaag gaggccgtga agaagttcga cgccatcggc 3360 tgggatggca aggagcagtc ttacttcttt aagtacaacc cttacaacct ggccgacgag 3420 aagtataaga actctaccgt gagcaaggag tgggccatct ttgccagcgc cccaagaatc 3480 cggagacaga agggcgagga cggctactgg aagtatgata gggtgaaagt gaatgaggag 3540 ttcgagaagc tgctgaaggt ctggaatttt gtgaacccaa aggccacaga tatcaagcag 3600 gagatcatca agaaggagaa ggcaggcgac ctgcagggag agaaggagct ggatggccgg 3660 ctgagaaact tttggcactc tttcatctac ctgtttaacc tggtgctgga gctgcgcaat 3720 tctttcagcc tgcagatcaa gatcaaggca ggagaagtga tcgcagtgga cgagggcgtg 3780 gacttcatcg ccagcccagt gaagcccttc tttaccacac ccaaccctta catcccctcc 3840 aacctgtgct ggctggccgt ggagaatgca gacgcaaacg gagcctataa tatcgccagg 3900 aagggcgtga tgatcctgaa gaagatccgc gagcacgcca agaaggaccc cgagttcaag 3960 aagctgccaa acctgtttat cagcaatgca gagtgggacg aggcagcccg ggattggggc 4020 aagtacgcag gcaccacagc cctgaacctg gaccacaaaa ggccggcggc cacgaaaaag 4080 gccggccagg caaaaaagaa aaagggatcc tacccatacg atgttccaga ttacgcttat 4140 ccctacgacg tgcctgatta tgcataccca tatgatgtcc ccgactatgc ctaagaattc 4200 <210> 219 <211> 3894 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 219 atgcagaccc tgtttgagaa cttcacaaat cagtacccag tgtccaagac cctgcgcttt 60 gagctgatcc cccagggcaa gacaaaggac ttcatcgagc agaagggcct gctgaagaag 120 gatgaggacc gggccgagaa gtataagaag gtgaagaaca tcatcgatga gtaccacaag 180 gacttcatcg agaagtctct gaatggcctg aagctggacg gcctggagaa gtacaagacc 240 ctgtatctga agcaggagaa ggacgataag gataagaagg cctttgacaa ggagaaggag 300 aacctgcgca agcagatcgc caatgccttc cggaacaatg agaagtttaa gacactgttc 360 gccaaggagc tgatcaagaa cgatctgatg tctttcgcct gcgaggagga caagaagaat 420 gtgaaggagt ttgaggcctt caccacatac ttcaccggct tccaccagaa ccgcgccaat 480 atgtacgtgg ccgatgagaa gagaacagcc atcgccagca ggctgatcca cgagaacctg 540 ccaaagttta tcgacaatat caagatcttc gagaagatga agaaggaggc ccccgagctg 600 ctgtctcctt tcaaccagac cctgaaggat atgaaggacg tgatcaaggg caccacactg 660 gaggagatct ttagcctgga ttatttcaac aagaccctga cacagagcgg catcgacatc 720 tacaattccg tgatcggcgg cagaacccct gaggagggca agacaaagat caagggcctg 780 aacgagtaca tcaataccga cttcaaccag aagcagacag acaagaagaa gcggcagcca 840 aagttcaagc agctgtataa gcagatcctg agcgataggc agagcctgtc ctttatcgcc 900 gaggccttca agaacgacac cgagatcctg gaggccatcg agaagtttta cgtgaatgag 960 ctgctgcact tcagcaatga gggcaagtcc acaaacgtgc tggacgccat caagaatgcc 1020 gtgtctaacc tggagagctt taacctgacc aagatgtatt tccgctccgg cgcctctctg 1080 acagacgtga gccggaaggt gtttggcgag tggagcatca tcaatagagc cctggacaac 1140 tactatgcca ccacatatcc aatcaagccc agagagaagt ctgagaagta cgaggagagg 1200 aaggagaagt ggctgaagca ggacttcaac gtgagcctga tccagaccgc catcgatgag 1260 tacgacaacg agacagtgaa gggcaagaac agcggcaaag tgatcgccga ttattttgcc 1320 aagttctgcg acgataagga gacagacctg atccagaagg tgaacgaggg ctacatcgcc 1380 gtgaaggatc tgctgaatac accctgtcct gagaacgaga agctgggcag caataaggac 1440 caggtgaagc agatcaaggc ctttatggat tctatcatgg acatcatgca cttcgtgcgc 1500 cccctgagcc tgaaggatac cgacaaggag aaggatgaga cattctactc cctgttcaca 1560 cctctgtacg accacctgac ccagacaatc gccctgtata acaaggtgcg gaactatctg 1620 acccagaagc cttacagcac agagaagatc aagctgaact tcgagaacag caccctgctg 1680 ggcggctggg atctgaataa ggagacagac aacacagcca tcatcctgag gaaggataac 1740 ctgtactatc tgggcatcat ggacaagagg cacaatcgca tctttcggaa cgtgcccaag 1800 gccgataaga aggacttctg ctacgagaag atggtgtata agctgctgcc tggcgccaac 1860 aagatgctgc caaaggtgtt cttttctcag agcagaatcc aggagtttac cccttccgcc 1920 aagctgctgg agaactacgc caatgagaca cacaagaagg gcgataattt caacctgaat 1980 cactgtcaca agctgatcga tttctttaag gactctatca acaagcacga ggattggaag 2040 aatttcgact ttaggttcag cgccacctcc acctacgccg acctgagcgg cttttaccac 2100 gaggtggagc accagggcta caagatctct tttcagagcg tggccgattc cttcatcgac 2160 gatctggtga acgagggcaa gctgtacctg ttccagatct ataataagga cttttcccca 2220 ttctctaagg gcaagcccaa cctgcacacc ctgtactgga agatgctgtt tgatgagaac 2280 aatctgaagg acgtggtgta taagctgaat ggcgaggccg aggtgttcta ccgcaagaag 2340 agcattgccg agaagaacac cacaatccac aaggccaatg agtccatcat caacaagaat 2400 cctgataacc caaaggccac cagcaccttc aactatgata tcgtgaagga caagagatac 2460 accatcgaca agtttcagtt ccacatccca atcacaatga actttaaggc cgagggcatc 2520 ttcaacatga atcagagggt gaatcagttc ctgaaggcca atcccgatat caacatcatc 2580 ggcatcgaca gaggcgagag gcacctgctg tactatgccc tgatcaacca gaagggcaag 2640 atcctgaagc aggataccct gaatgtgatc gccaacgaga agcagaaggt ggactaccac 2700 aatctgctgg ataagaagga gggcgaccgc gcaaccgcaa ggcaggagtg gggcgtgatc 2760 gagacaatca aggagctgaa ggagggctat ctgtcccagg tcatccacaa gctgaccgat 2820 ctgatgatcg agaacaatgc catcatcgtg atggaggacc tgaactttgg cttcaagcgg 2880 ggcagacaga aggtggagaa gcaggtgtat cagaagtttg agaagatgct gatcgataag 2940 ctgaattacc tggtggacaa gaataagaag gcaaacgagc tgggaggcct gctgaacgca 3000 ttccagctgg ccaataagtt tgagtccttc cagaagatgg gcaagcagaa cggctttatc 3060 ttctacgtgc ccgcctggaa tacctctaag acagatcctg ccaccggctt tatcgacttc 3120 ctgaagcccc gctatgagaa cctgaatcag gccaaggatt tctttgagaa gtttgactct 3180 atccggctga acagcaaggc cgattacttt gagttcgcct ttgacttcaa gaatttcacc 3240 gagaaggccg atggcggcag aaccaagtgg acagtgtgca ccacaaacga ggacagatat 3300 gcctggaata gggccctgaa caataacagg ggcagccagg agaagtacga catcacagcc 3360 gagctgaagt ccctgttcga tggcaaggtg gactataagt ctggcaagga tctgaagcag 3420 cagatcgcca gccaggagtc cgccgacttc tttaaggccc tgatgaagaa cctgtccatc 3480 accctgtctc tgagacacaa taacggcgag aagggcgata atgagcagga ctacatcctg 3540 tcccctgtgg ccgattctaa gggccgcttc tttgactccc ggaaggccga cgatgacatg 3600 ccaaagaatg ccgacgccaa cggcgcctat cacatcgccc tgaagggcct gtggtgtctg 3660 gagcagatca gcaagaccga tgacctgaag aaggtgaagc tggccatctc caacaaggag 3720 tggctggagt tcgtgcagac actgaagggc aaaaggccgg cggccacgaa aaaggccggc 3780 caggcaaaaa agaaaaaggg atcctaccca tacgatgttc cagattacgc ttatccctac 3840 gacgtgcctg attatgcata cccatatgat gtccccgact atgcctaaga attc

    3894 <210> 220 <211> 4065 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 220 atgacacagt tcgagggctt taccaacctg tatcaggtga gcaagacact gcggtttgag 60 ctgatcccac agggcaagac cctgaagcac atccaggagc agggcttcat cgaggaggac 120 aaggcccgca atgatcacta caaggagctg aagcccatca tcgatcggat ctacaagacc 180 tatgccgacc agtgcctgca gctggtgcag ctggattggg agaacctgag cgccgccatc 240 gactcctata gaaaggagaa aaccgaggag acaaggaacg ccctgatcga ggagcaggcc 300 acatatcgca atgccatcca cgactacttc atcggccgga cagacaacct gaccgatgcc 360 atcaataaga gacacgccga gatctacaag ggcctgttca aggccgagct gtttaatggc 420 aaggtgctga agcagctggg caccgtgacc acaaccgagc acgagaacgc cctgctgcgg 480 agcttcgaca agtttacaac ctacttctcc ggcttttatg agaacaggaa gaacgtgttc 540 agcgccgagg atatcagcac agccatccca caccgcatcg tgcaggacaa cttccccaag 600 tttaaggaga attgtcacat cttcacacgc ctgatcaccg ccgtgcccag cctgcgggag 660 cactttgaga acgtgaagaa ggccatcggc atcttcgtga gcacctccat cgaggaggtg 720 ttttccttcc ctttttataa ccagctgctg acacagaccc agatcgacct gtataaccag 780 ctgctgggag gaatctctcg ggaggcaggc accgagaaga tcaagggcct gaacgaggtg 840 ctgaatctgg ccatccagaa gaatgatgag acagcccaca tcatcgcctc cctgccacac 900 agattcatcc ccctgtttaa gcagatcctg tccgatagga acaccctgtc tttcatcctg 960 gaggagttta agagcgacga ggaagtgatc cagtccttct gcaagtacaa gacactgctg 1020 agaaacgaga acgtgctgga gacagccgag gccctgttta acgagctgaa cagcatcgac 1080 ctgacacaca tcttcatcag ccacaagaag ctggagacaa tcagcagcgc cctgtgcgac 1140 cactgggata cactgaggaa tgccctgtat gagcggagaa tctccgagct gacaggcaag 1200 atcaccaagt ctgccaagga gaaggtgcag cgcagcctga agcacgagga tatcaacctg 1260 caggagatca tctctgccgc aggcaaggag ctgagcgagg ccttcaagca gaaaaccagc 1320 gagatcctgt cccacgcaca cgccgccctg gatcagccac tgcctacaac cctgaagaag 1380 caggaggaga aggagatcct gaagtctcag ctggacagcc tgctgggcct gtaccacctg 1440 ctggactggt ttgccgtgga tgagtccaac gaggtggacc ccgagttctc tgcccggctg 1500 accggcatca agctggagat ggagccttct ctgagcttct acaacaaggc cagaaattat 1560 gccaccaaga agccctactc cgtggagaag ttcaagctga actttcagat gcctacactg 1620 gcctctggct gggacgtgaa taaggagaag aacaatggcg ccatcctgtt tgtgaagaac 1680 ggcctgtact atctgggcat catgccaaag cagaagggca ggtataaggc cctgagcttc 1740 gagcccacag agaaaaccag cgagggcttt gataagatgt actatgacta cttccctgat 1800 gccgccaaga tgatcccaaa gtgcagcacc cagctgaagg ccgtgacagc ccactttcag 1860 acccacacaa cccccatcct gctgtccaac aatttcatcg agcctctgga gatcacaaag 1920 gagatctacg acctgaacaa tcctgagaag gagccaaaga agtttcagac agcctacgcc 1980 aagaaaaccg gcgaccagaa gggctacaga gaggccctgt gcaagtggat cgacttcaca 2040 agggattttc tgtccaagta taccaagaca acctctatcg atctgtctag cctgcggcca 2100 tcctctcagt ataaggacct gggcgagtac tatgccgagc tgaatcccct gctgtaccac 2160 atcagcttcc agagaatcgc cgagaaggag atcatggatg ccgtggagac aggcaagctg 2220 tacctgttcc agatctataa caaggacttt gccaagggcc accacggcaa gcctaatctg 2280 cacacactgt attggaccgg cctgttttct ccagagaacc tggccaagac aagcatcaag 2340 ctgaatggcc aggccgagct gttctaccgc cctaagtcca ggatgaagag gatggcacac 2400 cggctgggag agaagatgct gaacaagaag ctgaaggatc agaaaacccc aatccccgac 2460 accctgtacc aggagctgta cgactatgtg aatcacagac tgtcccacga cctgtctgat 2520 gaggccaggg ccctgctgcc caacgtgatc accaaggagg tgtctcacga gatcatcaag 2580 gataggcgct ttaccagcga caagttcttt ttccacgtgc ctatcacact gaactatcag 2640 gccgccaatt ccccatctaa gttcaaccag agggtgaatg cctacctgaa ggagcacccc 2700 gagacaccta tcatcggcat cgatcggggc gagagaaacc tgatctatat cacagtgatc 2760 gactccaccg gcaagatcct ggagcagcgg agcctgaaca ccatccagca gtttgattac 2820 cagaagaagc tggacaacag ggagaaggag agggtggcag caaggcaggc ctggtctgtg 2880 gtgggcacaa tcaaggatct gaagcagggc tatctgagcc aggtcatcca cgagatcgtg 2940 gacctgatga tccactacca ggccgtggtg gtgctggaga acctgaattt cggctttaag 3000 agcaagagga ccggcatcgc cgagaaggcc gtgtaccagc agttcgagaa gatgctgatc 3060 gataagctga attgcctggt gctgaaggac tatccagcag agaaagtggg aggcgtgctg 3120 aacccatacc agctgacaga ccagttcacc tcctttgcca agatgggcac ccagtctggc 3180 ttcctgtttt acgtgcctgc cccatataca tctaagatcg atcccctgac cggcttcgtg 3240 gaccccttcg tgtggaaaac catcaagaat cacgagagcc gcaagcactt cctggagggc 3300 ttcgactttc tgcactacga cgtgaaaacc ggcgacttca tcctgcactt taagatgaac 3360 agaaatctgt ccttccagag gggcctgccc ggctttatgc ctgcatggga tatcgtgttc 3420 gagaagaacg agacacagtt tgacgccaag ggcacccctt tcatcgccgg caagagaatc 3480 gtgccagtga tcgagaatca cagattcacc ggcagatacc gggacctgta tcctgccaac 3540 gagctgatcg ccctgctgga ggagaagggc atcgtgttca gggatggctc caacatcctg 3600 ccaaagctgc tggagaatga cgattctcac gccatcgaca ccatggtggc cctgatccgc 3660 agcgtgctgc agatgcggaa ctccaatgcc gccacaggcg aggactatat caacagcccc 3720 gtgcgcgatc tgaatggcgt gtgcttcgac tcccggtttc agaacccaga gtggcccatg 3780 gacgccgatg ccaatggcgc ctaccacatc gccctgaagg gccagctgct gctgaatcac 3840 ctgaaggaga gcaaggatct gaagctgcag aacggcatct ccaatcagga ctggctggcc 3900 tacatccagg agctgcgcaa caaaaggccg gcggccacga aaaaggccgg ccaggcaaaa 3960 aagaaaaagg gatcctaccc atacgatgtt ccagattacg cttatcccta cgacgtgcct 4020 gattatgcat acccatatga tgtccccgac tatgcctaag aattc 4065 <210> 221 <211> 3762 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 221 atgtactatg agtccctgac caagcagtac cccgtgtcta agacaatccg gaatgagctg 60 atccctatcg gcaagacact ggataacatc cgccagaaca atatcctgga gagcgacgtg 120 aagcggaagc agaactacga gcacgtgaag ggcatcctgg atgagtatca caagcagctg 180 atcaacgagg ccctggacaa ttgcaccctg ccatccctga agatcgccgc cgagatctac 240 ctgaagaatc agaaggaggt gtctgacaga gaggatttca acaagacaca ggacctgctg 300 aggaaggagg tggtggagaa gctgaaggcc cacgagaact ttaccaagat cggcaagaag 360 gacatcctgg atctgctgga gaagctgcct tccatctctg aggacgatta caatgccctg 420 gagagcttcc gcaactttta cacctatttc acatcctaca acaaggtgcg ggagaatctg 480 tattctgata aggagaagag ctccacagtg gcctacagac tgatcaacga gaatttccca 540 aagtttctgg acaatgtgaa gagctatagg tttgtgaaaa ccgcaggcat cctggcagat 600 ggcctgggag aggaggagca ggactccctg ttcatcgtgg agacattcaa caagaccctg 660 acacaggacg gcatcgatac ctacaattct caagtgggca agatcaactc tagcatcaat 720 ctgtataacc agaagaatca gaaggccaat ggcttcagaa agatccccaa gatgaagatg 780 ctgtataagc agatcctgtc cgatagggag gagtctttca tcgacgagtt tcagagcgat 840 gaggtgctga tcgacaacgt ggagtcttat ggcagcgtgc tgatcgagtc tctgaagtcc 900 tctaaggtga gcgccttctt tgatgccctg agagagtcta agggcaagaa cgtgtacgtg 960 aagaatgacc tggccaagac agccatgagc aacatcgtgt tcgagaattg gaggaccttt 1020 gacgatctgc tgaaccagga gtacgacctg gccaacgaga acaagaagaa ggacgataag 1080 tatttcgaga agcgccagaa ggagctgaag aagaataaga gctactccct ggagcacctg 1140 tgcaacctgt ccgaggattc ttgtaacctg atcgagaatt atatccacca gatctccgac 1200 gatatcgaga atatcatcat caacaatgag acattcctgc gcatcgtgat caatgagcac 1260 gacaggtccc gcaagctggc caagaaccgg aaggccgtga aggccatcaa ggactttctg 1320 gattctatca aggtgctgga gcgggagctg aagctgatca acagctccgg ccaggagctg 1380 gagaaggatc tgatcgtgta ctctgcccac gaggagctgc tggtggagct gaagcaggtg 1440 gacagcctgt ataacatgac cagaaattat ctgacaaaga agcctttctc taccgagaag 1500 gtgaagctga actttaatcg cagcacactg ctgaacggct gggatcggaa taaggagaca 1560 gacaacctgg gcgtgctgct gctgaaggac ggcaagtact atctgggcat catgaacaca 1620 agcgccaata aggccttcgt gaatccccct gtggccaaga ccgagaaggt gtttaagaag 1680 gtggattaca agctgctgcc agtgcccaac cagatgctgc caaaggtgtt ctttgccaag 1740 agcaatatcg acttctataa cccctctagc gagatctact ccaattataa gaagggcacc 1800 cacaagaagg gcaatatgtt ttccctggag gattgtcaca acctgatcga cttctttaag 1860 gagtctatca gcaagcacga ggactggagc aagttcggct ttaagttcag cgatacagcc 1920 tcctacaacg acatctccga gttctatcgc gaggtggaga agcagggcta caagctgacc 1980 tatacagaca tcgatgagac atacatcaat gatctgatcg agcggaacga gctgtacctg 2040 ttccagatct ataataagga ctttagcatg tactccaagg gcaagctgaa cctgcacaca 2100 ctgtatttca tgatgctgtt tgatcagcgc aatatcgacg acgtggtgta taagctgaac 2160 ggagaggcag aggtgttcta taggccagcc tccatctctg aggacgagct gatcatccac 2220 aaggccggcg aggagatcaa gaacaagaat cctaaccggg ccagaaccaa ggagacaagc 2280 accttcagct acgacatcgt gaaggataag cggtatagca aggataagtt taccctgcac 2340 atccccatca caatgaactt cggcgtggat gaggtgaagc ggttcaacga cgccgtgaac 2400 agcgccatcc ggatcgatga gaatgtgaac gtgatcggca tcgaccgggg cgagagaaat 2460 ctgctgtacg tggtggtcat cgactctaag ggcaacatcc tggagcagat ctccctgaac 2520 tctatcatca ataaggagta cgacatcgag acagattatc acgcactgct ggatgagagg 2580 gagggcggca gagataaggc ccggaaggac tggaacaccg tggagaatat cagggacctg 2640 aaggccggct acctgagcca ggtggtgaac gtggtggcca agctggtgct gaagtataat 2700 gccatcatct gcctggagga cctgaacttt ggcttcaaga ggggccgcca gaaggtggag 2760 aagcaggtgt accagaagtt cgagaagatg ctgatcgata agctgaatta cctggtcatc 2820 gacaagagcc gcgagcagac atcccctaag gagctgggag gcgccctgaa cgcactgcag 2880 ctgacctcta agttcaagag ctttaaggag ctgggcaagc agtccggcgt gatctactat 2940 gtgcctgcct acctgacctc taagatcgat ccaaccacag gcttcgccaa tctgttttat 3000 atgaagtgtg agaacgtgga gaagtccaag agattctttg acggctttga tttcatcagg 3060 ttcaacgccc tggagaacgt gttcgagttc ggctttgact accggagctt cacccagagg 3120 gcctgcggca tcaattccaa gtggaccgtg tgcaccaacg gcgagcgcat catcaagtat 3180 cggaatccag ataagaacaa tatgttcgac gagaaggtgg tggtggtgac cgatgagatg 3240 aagaacctgt ttgagcagta caagatcccc tatgaggatg gcagaaatgt gaaggacatg 3300 atcatcagca acgaggaggc cgagttctac cggagactgt ataggctgct gcagcagacc 3360 ctgcagatga gaaacagcac ctccgacggc acaagggatt acatcatctc ccctgtgaag 3420 aataagagag aggcctactt caacagcgag ctgtccgacg gctctgtgcc aaaggacgcc 3480 gatgccaacg gcgcctacaa tatcgccaga aagggcctgt gggtgctgga gcagatcagg 3540 cagaagagcg agggcgagaa gatcaatctg gccatgacca acgccgagtg gctggagtat 3600 gcccagacac acctgctgaa aaggccggcg gccacgaaaa aggccggcca ggcaaaaaag 3660 aaaaagggat cctacccata cgatgttcca gattacgctt atccctacga cgtgcctgat 3720 tatgcatacc catatgatgt ccccgactat gcctaagaat tc 3762 <210> 222 <211> 3858 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 222 atgaacaatt acgacgagtt caccaagctg tatcctatcc agaaaaccat ccggtttgag 60 ctgaagccac agggcagaac catggagcac ctggagacat tcaacttctt tgaggaggac 120 cgggatagag ccgagaagta taagatcctg aaggaggcca tcgacgagta ccacaagaag 180 tttatcgatg agcacctgac caatatgtcc ctggattgga actctctgaa gcagatcagc 240 gagaagtact ataagagcag ggaggagaag gacaagaagg tgttcctgtc cgagcagaag 300 aggatgcgcc aggagatcgt gtctgagttt aagaaggacg atcgcttcaa ggacctgttt 360 tccaagaagc tgttctctga gctgctgaag gaggagatct acaagaaggg caaccaccag 420 gagatcgacg ccctgaagag cttcgataag ttttccggct atttcatcgg cctgcacgag 480 aataggaaga acatgtactc cgacggcgat gagatcaccg ccatctccaa tcgcatcgtg 540 aatgagaact tccccaagtt tctggataac ctgcagaagt accaggaggc caggaagaag 600 tatcctgagt ggatcatcaa ggccgagagc gccctggtgg cccacaatat caagatggac 660 gaggtgttct ccctggagta ctttaataag gtgctgaacc aggagggcat ccagcggtac 720 aacctggccc tgggcggcta tgtgaccaag agcggcgaga agatgatggg cctgaatgat 780 gccctgaacc tggcccacca gtccgagaag agctccaagg gcagaatcca catgaccccc 840 ctgttcaagc agatcctgtc cgagaaggag tccttctctt acatccccga cgtgtttaca 900 gaggattctc agctgctgcc tagcatcggc ggcttctttg cccagatcga gaatgacaag 960 gatggcaaca tcttcgaccg ggccctggag ctgatctcta gctacgccga gtatgatacc 1020 gagcggatct atatcagaca ggccgacatc aatagagtgt ccaacgtgat ctttggagag 1080 tggggcaccc tgggaggcct gatgagggag tacaaggccg actctatcaa tgatatcaac 1140 ctggagcgca catgcaagaa ggtggacaag tggctggatt ctaaggagtt tgccctgagc 1200 gatgtgctgg aggccatcaa gaggaccggc aacaatgacg ccttcaacga gtatatctcc 1260 aagatgcgga cagccagaga gaagatcgat gccgcccgca aggagatgaa gttcatcagc 1320 gagaagatct ccggcgatga ggagtctatc cacatcatca agaccctgct ggacagcgtg 1380 cagcagttcc tgcacttctt taatctgttt aaggcaaggc aggacatccc actggatgga 1440 gccttctacg ccgagtttga cgaggtgcac agcaagctgt ttgccatcgt gcccctgtat 1500 aacaaggtgc ggaactatct gaccaagaac aatctgaaca caaagaagat caagctgaat 1560 ttcaagaacc ctacactggc caatggctgg gaccagaaca aggtgtacga ttatgcctcc 1620 ctgatctttc tgcgggacgg caattactat ctgggcatca tcaatcctaa gagaaagaag 1680 aacatcaagt tcgagcaggg ctctggcaac ggccccttct accggaagat ggtgtataag 1740 cagatccccg gccctaataa gaacctgcca agagtgttcc tgacctccac aaagggcaag 1800 aaggagtata agccctctaa ggagatcatc gagggctacg aggccgacaa gcacatcagg 1860 ggcgataagt tcgacctgga tttttgtcac aagctgatcg atttctttaa ggagtccatc 1920 gagaagcaca aggactggtc taagttcaac ttctacttca gcccaaccga gagctatggc 1980 gacatctctg agttctacct ggatgtggag aagcagggct atcgcatgca ctttgagaat 2040 atcagcgccg agacaatcga cgagtatgtg gagaagggcg atctgtttct gttccagatc 2100 tacaacaagg attttgtgaa ggccgccacc ggcaagaagg acatgcacac aatctactgg 2160 aatgccgcct tcagccccga gaacctgcag gacgtggtgg tgaagctgaa cggcgaggcc 2220 gagctgtttt atagggacaa gtccgatatc aaggagatcg tgcaccgcga gggcgagatc 2280 ctggtgaata ggacctacaa cggccgcaca ccagtgcccg acaagatcca caagaagctg 2340 accgattatc acaatggccg gacaaaggac ctgggcgagg ccaaggagta cctggataag 2400 gtgagatact tcaaggccca ctatgacatc accaaggatc ggagatacct gaacgacaag 2460 atctatttcc acgtgcctct gaccctgaac ttcaaggcca acggcaagaa gaatctgaac 2520 aagatggtca tcgagaagtt cctgtccgat gagaaggccc acatcatcgg catcgacagg 2580 ggcgagcgca atctgctgta ctattccatc atcgacaggt ctggcaagat catcgatcag 2640 cagagcctga atgtgatcga cggctttgat tatcgggaga agctgaacca gagagagatc 2700 gagatgaagg atgcccgcca gtcttggaac gccatcggca agatcaagga cctgaaggag 2760 ggctacctga gcaaggccgt gcacgagatc accaagatgg ccatccagta taatgccatc 2820 gtggtcatgg aggagctgaa ctacggcttc aagcggggcc ggttcaaggt ggagaagcag 2880 atctatcaga agttcgagaa tatgctgatc gataagatga actacctggt gtttaaggac 2940 gcacctgatg agtccccagg aggcgtgctg aatgcctacc agctgacaaa cccactggag 3000 tctttcgcca agctgggcaa gcagaccggc atcctgtttt acgtgccagc cgcctataca 3060 tccaagatcg accccaccac aggcttcgtg aatctgttta acacctcctc taagacaaac 3120 gcccaggagc ggaaggagtt cctgcagaag tttgagagca tctcctattc tgccaaggat 3180 ggcggcatct ttgccttcgc ctttgactac agaaagttcg gcaccagcaa gacagatcac 3240 aagaacgtgt ggaccgccta tacaaacggc gagaggatgc gctacatcaa ggagaagaag 3300 cggaatgagc tgtttgaccc ttctaaggag atcaaggagg ccctgaccag ctccggcatc 3360 aagtacgatg gcggccagaa catcctgcca gacatcctga ggagcaacaa taacggcctg 3420 atctacacaa tgtattctag cttcatcgcc gccatccaga tgcgcgtgta cgacggcaag 3480 gaggattata tcatcagccc catcaagaac tccaagggcg agttctttag gaccgacccc 3540 aagaggcgcg agctgcctat cgacgccgat gccaatggcg cctacaacat cgccctgagg 3600 ggagagctga caatgagggc aatcgcagag aagttcgacc ctgatagcga gaagatggcc 3660 aagctggagc tgaagcacaa ggattggttc gagtttatgc agaccagagg cgacaaaagg 3720 ccggcggcca cgaaaaaggc cggccaggca aaaaagaaaa agggatccta cccatacgat 3780 gttccagatt acgcttatcc ctacgacgtg cctgattatg catacccata tgatgtcccc 3840 gactatgcct aagaattc 3858 <210> 223 <211> 3990 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 223 atgaacggca ataggtccat cgtgtaccgc gagttcgtgg gcgtgatccc cgtggccaag 60 accctgagga atgagctgcg ccctgtgggc cacacacagg agcacatcat ccagaacggc 120 ctgatccagg aggacgagct gcggcaggag aagagcaccg agctgaagaa catcatggac 180 gattactata gagagtacat cgataagtct ctgagcggcg tgaccgacct ggacttcacc 240 ctgctgttcg agctgatgaa cctggtgcag agctccccct ccaaggacaa taagaaggcc 300 ctggagaagg agcagtctaa gatgagggag cagatctgca cccacctgca gtccgactct 360 aactacaaga atatctttaa cgccaagctg ctgaaggaga tcctgcctga tttcatcaag 420 aactacaatc agtatgacgt gaaggataag gccggcaagc tggagacact ggccctgttt 480 aatggcttca gcacatactt taccgacttc tttgagaaga ggaagaacgt gttcaccaag 540 gaggccgtga gcacatccat cgcctaccgc atcgtgcacg agaactccct gatcttcctg 600 gccaatatga cctcttataa gaagatcagc gagaaggccc tggatgagat cgaagtgatc 660 gagaagaaca atcaggacaa gatgggcgat tgggagctga atcagatctt taaccctgac 720 ttctacaata tggtgctgat ccagtccggc atcgacttct acaacgagat ctgcggcgtg 780 gtgaatgccc acatgaacct gtactgtcag cagaccaaga acaattataa cctgttcaag 840 atgcggaagc tgcacaagca gatcctggcc tacaccagca ccagcttcga ggtgcccaag 900 atgttcgagg acgatatgag cgtgtataac gccgtgaacg ccttcatcga cgagacagag 960 aagggcaaca tcatcggcaa gctgaaggat atcgtgaata agtacgacga gctggatgag 1020 aagagaatct atatcagcaa ggacttttac gagacactga gctgcttcat gtccggcaac 1080 tggaatctga tcacaggctg cgtggagaac ttctacgatg agaacatcca cgccaagggc 1140 aagtccaagg aggagaaggt gaagaaggcc gtgaaggagg acaagtacaa gtctatcaat 1200 gacgtgaacg atctggtgga gaagtatatc gatgagaagg agaggaatga gttcaagaac 1260 agcaatgcca agcagtacat ccgcgagatc tccaacatca tcaccgacac agagacagcc 1320 cacctggagt atgacgatca catctctctg atcgagagcg aggagaaggc cgacgagatg 1380 aagaagcggc tggatatgta tatgaacatg taccactggg ccaaggcctt tatcgtggac 1440 gaggtgctgg acagagatga gatgttctac agcgatatcg acgatatcta taatatcctg 1500 gagaacatcg tgccactgta taatcgggtg agaaactacg tgacccagaa gccctacaac 1560 tctaagaaga tcaagctgaa tttccagagc cctacactgg ccaatggctg gtcccagtct 1620 aaggagttcg acaacaatgc catcatcctg atcagagata acaagtacta tctggccatc 1680 ttcaatgcca agaacaagcc agacaagaag atcatccagg gcaactccga taagaagaac 1740 gacaacgatt acaagaagat ggtgtataac ctgctgccag gcgccaacaa gatgctgccc 1800 aaggtgtttc tgtctaagaa gggcatcgag acattcaagc cctccgacta tatcatctct 1860 ggctacaacg cccacaagca catcaagaca agcgagaatt ttgatatctc cttctgtcgg 1920 gacctgatcg attacttcaa gaacagcatc gagaagcacg ccgagtggag aaagtatgag 1980 ttcaagtttt ccgccaccga cagctactcc gatatctctg agttctatcg ggaggtggag 2040 atgcagggct acagaatcga ctggacatat atcagcgagg ccgacatcaa caagctggat 2100 gaggagggca agatctatct gtttcagatc tacaataagg atttcgccga gaacagcacc 2160 ggcaaggaga atctgcacac aatgtacttt aagaacatct tctccgagga gaatctgaag 2220 gacatcatca tcaagctgaa cggccaggcc gagctgtttt atcggagagc ctctgtgaag 2280 aatcccgtga agcacaagaa ggatagcgtg ctggtgaaca agacctacaa gaatcagctg 2340 gacaacggcg acgtggtgag aatccccatc cctgacgata tctataacga gatctacaag 2400 atgtataatg gctacatcaa ggagtccgac ctgtctgagg ccgccaagga gtacctggat 2460 aaggtggagg tgaggaccgc ccagaaggac atcgtgaagg attaccgcta tacagtggac 2520 aagtacttca tccacacacc tatcaccatc aactataagg tgaccgcccg caacaatgtg 2580 aatgatatgg tggtgaagta catcgcccag aacgacgata tccacgtgat cggcatcgac 2640 cggggcgaga gaaacctgat ctacatctcc gtgatcgatt ctcacggcaa catcgtgaag 2700 cagaaatcct acaacatcct gaacaactac gactacaaga agaagctggt ggagaaggag 2760 aaaacccggg agtacgccag aaagaactgg aagagcatcg gcaatatcaa ggagctgaag 2820 gagggctata tctccggcgt ggtgcacgag atcgccatgc tgatcgtgga gtacaacgcc 2880 atcatcgcca tggaggacct gaattatggc tttaagaggg gccgcttcaa ggtggagcgg 2940 caggtgtacc agaagtttga gagcatgctg atcaataagc tgaactattt cgccagcaag 3000 gagaagtccg tggacgagcc aggaggcctg ctgaagggct atcagctgac ctacgtgccc 3060 gataatatca agaacctggg caagcagtgc ggcgtgatct tttacgtgcc tgccgccttc 3120 accagcaaga tcgacccatc cacaggcttt atctctgcct tcaactttaa gtctatcagc 3180 acaaatgcct ctcggaagca gttctttatg cagtttgacg agatcagata ctgtgccgag 3240 aaggatatgt tcagctttgg cttcgactac aacaacttcg atacctacaa catcacaatg 3300 ggcaagacac agtggaccgt gtatacaaac ggcgagagac tgcagtctga gttcaacaat 3360 gccaggcgca ccggcaagac aaagagcatc aatctgacag agacaatcaa gctgctgctg 3420 gaggacaatg agatcaacta cgccgacggc cacgatatca ggatcgatat ggagaagatg 3480 gacgaggata agaagagcga gttctttgcc cagctgctga gcctgtataa gctgaccgtg 3540 cagatgcgca attcctatac agaggccgag gagcaggaga acggcatctc ttacgacaag 3600 atcatcagcc ctgtgatcaa tgatgagggc gagttctttg actccgataa ctataaggag 3660 tctgacgata aggagtgcaa gatgccaaag gacgccgatg ccaacggcgc ctactgtatc 3720 gccctgaagg gcctgtatga ggtgctgaag atcaagagcg agtggaccga ggacggcttt 3780 gataggaatt gcctgaagct gccacacgca gagtggctgg acttcatcca gaacaagcgg 3840 tacgagaaaa ggccggcggc cacgaaaaag gccggccagg caaaaaagaa aaagggatcc 3900 tacccatacg atgttccaga ttacgcttat ccctacgacg tgcctgatta tgcataccca 3960 tatgatgtcc ccgactatgc ctaagaattc 3990 <210> 224 <211> 4263 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 224 atgctgttcc aggactttac ccacctgtat ccactgtcca agacagtgag atttgagctg 60 aagcccatcg ataggaccct ggagcacatc cacgccaaga acttcctgtc tcaggacgag 120 acaatggccg atatgcacca gaaggtgaaa gtgatcctgg acgattacca ccgcgacttc 180 atcgccgata tgatgggcga ggtgaagctg accaagctgg ccgagttcta tgacgtgtac 240 ctgaagtttc ggaagaaccc aaaggacgat gagctgcaga agcagctgaa ggatctgcag 300 gccgtgctga gaaaggagat cgtgaagccc atcggcaatg gcggcaagta taaggccggc 360 tacgacaggc tgttcggcgc caagctgttt aaggacggca aggagctggg cgatctggcc 420 aagttcgtga tcgcacagga gggagagagc tccccaaagc tggcccacct ggcccacttc 480 gagaagtttt ccacctattt cacaggcttt cacgataacc ggaagaatat gtattctgac 540 gaggataagc acaccgccat cgcctaccgc ctgatccacg agaacctgcc ccggtttatc 600 gacaatctgc agatcctgac cacaatcaag cagaagcact ctgccctgta cgatcagatc 660 atcaacgagc tgaccgccag cggcctggac gtgtctctgg ccagccacct ggatggctat 720 cacaagctgc tgacacagga gggcatcacc gcctacaata cactgctggg aggaatctcc 780 ggagaggcag gctctcctaa gatccagggc atcaacgagc tgatcaattc tcaccacaac 840 cagcactgcc acaagagcga gagaatcgcc aagctgaggc cactgcacaa gcagatcctg 900 tccgacggca tgagcgtgtc cttcctgccc tctaagtttg ccgacgatag cgagatgtgc 960 caggccgtga acgagttcta tcgccactac gccgacgtgt tcgccaaggt gcagagcctg 1020 ttcgacggct ttgacgatca ccagaaggat ggcatctacg tggagcacaa gaacctgaat 1080 gagctgtcca agcaggcctt cggcgacttt gcactgctgg gacgcgtgct ggacggatac 1140 tatgtggatg tggtgaatcc agagttcaac gagcggtttg ccaaggccaa gaccgacaat 1200 gccaaggcca agctgacaaa ggagaaggat aagttcatca agggcgtgca ctccctggcc 1260 tctctggagc aggccatcga gcactatacc gcaaggcacg acgatgagag cgtgcaggca 1320 ggcaagctgg gacagtactt caagcacggc ctggccggag tggacaaccc catccagaag 1380 atccacaaca atcacagcac catcaagggc tttctggaga gggagcgccc tgcaggagag 1440 agagccctgc caaagatcaa gtccggcaag aatcctgaga tgacacagct gaggcagctg 1500 aaggagctgc tggataacgc cctgaatgtg gcccacttcg ccaagctgct gaccacaaag 1560 accacactgg acaatcagga tggcaacttc tatggcgagt ttggcgtgct gtacgacgag 1620 ctggccaaga tccccaccct gtataacaag gtgagagatt acctgagcca gaagcctttc 1680 tccaccgaga agtacaagct gaactttggc aatccaacac tgctgaatgg ctgggacctg 1740 aacaaggaga aggataattt cggcgtgatc ctgcagaagg acggctgcta ctatctggcc 1800 ctgctggaca aggcccacaa gaaggtgttt gataacgccc ctaatacagg caagagcatc 1860 tatcagaaga tgatctataa gtacctggag gtgaggaagc agttccccaa ggtgttcttt 1920 tccaaggagg ccatcgccat caactaccac ccttctaagg agctggtgga gatcaaggac 1980 aagggccggc agagatccga cgatgagcgc ctgaagctgt atcggtttat cctggagtgt 2040 ctgaagatcc accctaagta cgataagaag ttcgagggcg ccatcggcga catccagctg 2100 tttaagaagg ataagaaggg cagagaggtg ccaatcagcg agaaggacct gttcgataag 2160 atcaacggca tcttttctag caagcctaag ctggagatgg aggacttctt tatcggcgag 2220 ttcaagaggt ataacccaag ccaggacctg gtggatcagt ataatatcta caagaagatc 2280 gactccaacg ataatcgcaa gaaggagaat ttctacaaca atcaccccaa gtttaagaag 2340 gatctggtgc ggtactatta cgagtctatg tgcaagcacg aggagtggga ggagagcttc 2400 gagttttcca agaagctgca ggacatcggc tgttacgtgg atgtgaacga gctgtttacc 2460 gagatcgaga cacggagact gaattataag atctccttct gcaacatcaa tgccgactac 2520 atcgatgagc tggtggagca gggccagctg tatctgttcc agatctacaa caaggacttt 2580 tccccaaagg cccacggcaa gcccaatctg cacaccctgt acttcaaggc cctgttttct 2640 gaggacaacc tggccgatcc tatctataag ctgaatggcg aggcccagat cttctacaga 2700 aaggcctccc tggacatgaa cgagacaaca atccacaggg ccggcgaggt gctggagaac 2760 aagaatcccg ataatcctaa gaagagacag ttcgtgtacg acatcatcaa ggataagagg 2820 tacacacagg acaagttcat gctgcacgtg ccaatcacca tgaactttgg cgtgcagggc 2880 atgacaatca aggagttcaa taagaaggtg aaccagtcta tccagcagta tgacgaggtg 2940 aacgtgatcg gcatcgatcg gggcgagaga cacctgctgt acctgaccgt gatcaatagc 3000 aagggcgaga tcctggagca gtgttccctg aacgacatca ccacagcctc tgccaatggc 3060 acacagatga ccacacctta ccacaagatc ctggataaga gggagatcga gcgcctgaac 3120 gcccgggtgg gatggggcga gatcgagaca atcaaggagc tgaagtctgg ctatctgagc 3180 cacgtggtgc accagatcag ccagctgatg ctgaagtaca acgccatcgt ggtgctggag 3240 gacctgaatt tcggctttaa gaggggccgc tttaaggtgg agaagcagat ctatcagaac 3300 ttcgagaatg ccctgatcaa gaagctgaac cacctggtgc tgaaggacaa ggccgacgat 3360 gagatcggct cttacaagaa tgccctgcag ctgaccaaca atttcacaga tctgaagagc 3420 atcggcaagc agaccggctt cctgttttat gtgcccgcct ggaacacctc taagatcgac 3480 cctgagacag gctttgtgga tctgctgaag ccaagatacg agaacatcgc ccagagccag 3540 gccttctttg gcaagttcga caagatctgc tataatgccg acaaggatta cttcgagttt 3600 cacatcgact acgccaagtt taccgataag gccaagaata gccgccagat ctggacaatc 3660 tgttcccacg gcgacaagcg gtacgtgtac gataagacag ccaaccagaa taagggcgcc 3720 gccaagggca tcaacgtgaa tgatgagctg aagtccctgt tcgcccgcca ccacatcaac 3780 gagaagcagc ccaacctggt catggacatc tgccagaaca atgataagga gtttcacaag 3840 tctctgatgt acctgctgaa aaccctgctg gccctgcggt acagcaacgc ctcctctgac 3900 gaggatttca tcctgtcccc cgtggcaaac gacgagggcg tgttctttaa tagcgccctg 3960 gccgacgata cacagcctca gaatgccgat gccaacggcg cctaccacat cgccctgaag 4020 ggcctgtggc tgctgaatga gctgaagaac tccgacgatc tgaacaaggt gaagctggcc 4080 atcgacaatc agacctggct gaatttcgcc cagaacagga aaaggccggc ggccacgaaa 4140 aaggccggcc aggcaaaaaa gaaaaaggga tcctacccat acgatgttcc agattacgct 4200 tatccctacg acgtgcctga ttatgcatac ccatatgatg tccccgacta tgcctaagaa 4260 ttc 4263 <210> 225 <211> 3933 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 225 atggaggact attccggctt tgtgaacatc tactctatcc agaaaaccct gaggttcgag 60 ctgaagccag tgggcaagac actggagcac atcgagaaga agggcttcct gaagaaggac 120 aagatccggg ccgaggatta caaggccgtg aagaagatca tcgataagta ccacagagcc 180 tatatcgagg aggtgtttga ttccgtgctg caccagaaga agaagaagga caagacccgc 240 ttttctacac agttcatcaa ggagatcaag gagttcagcg agctgtacta taagaccgag 300 aagaacatcc ccgacaagga gaggctggag gccctgagcg agaagctgcg caagatgctg 360 gtgggcgcct ttaagggcga gttctccgag gaggtggccg agaagtataa gaacctgttt 420 tctaaggagc tgatcaggaa tgagatcgag aagttctgcg agacagacga ggagcgcaag 480 caggtgtcta acttcaagag cttcaccaca tactttaccg gcttccactc caacaggcag 540 aatatctatt ccgacgagaa gaagtctaca gccatcggct accgcatcat ccaccagaac 600 ctgcctaagt tcctggataa tctgaagatc atcgagtcca tccagcggcg gttcaaggac 660 ttcccatggt ctgatctgaa gaagaacctg aagaagatcg ataagaatat caagctgacc 720 gagtacttca gcatcgacgg cttcgtgaac gtgctgaatc agaagggcat cgatgcctac 780 aacacaatcc tgggcggcaa gtccgaggag tctggcgaga agatccaggg cctgaacgag 840 tacatcaatc tgtatcggca gaagaacaat atcgacagaa agaacctgcc caatgtgaag 900 atcctgttta agcagatcct gggcgatagg gagacaaaga gctttatccc tgaggccttc 960 ccagacgatc agtccgtgct gaactctatc acagagttcg ccaagtacct gaagctggat 1020 aagaagaaga agagcatcat cgccgagctg aagaagtttc tgagctcctt caatcgctac 1080 gagctggacg gcatctatct ggccaacgat aatagcctgg cctctatcag caccttcctg 1140 tttgacgatt ggtcctttat caagaagtcc gtgtctttca agtatgacga gtccgtgggc 1200 gaccccaaga agaagatcaa gtctcccctg aagtacgaga aggagaagga gaagtggctg 1260 aagcagaagt actatacaat ctctttcctg aacgatgcca tcgagagcta ttccaagtct 1320 caggacgaga agagggtgaa gatccgcctg gaggcctact ttgccgagtt caagagcaag 1380 gacgatgcca agaagcagtt cgacctgctg gagaggatcg aggaggccta tgccatcgtg 1440 gagcctctgc tgggagcaga gtacccaagg gaccgcaacc tgaaggccga taagaaggaa 1500 gtgggcaaga tcaaggactt cctggatagc atcaagtccc tgcagttctt tctgaagcct 1560 ctgctgtccg ccgagatctt tgacgagaag gatctgggct tctacaatca gctggagggc 1620 tactatgagg agatcgattc tatcggccac ctgtataaca aggtgcggaa ttatctgacc 1680 ggcaagatct acagcaagga gaagtttaag ctgaacttcg agaacagcac cctgctgaag 1740 ggctgggacg agaaccggga ggtggccaat ctgtgcgtga tcttcagaga ggaccagaag 1800 tactatctgg gcgtgatgga taaggagaac aataccatcc tgtccgacat ccccaaggtg 1860 aagcctaacg agctgtttta cgagaagatg gtgtataagc tgatccccac acctcacatg 1920 cagctgcccc ggatcatctt ctctagcgac aacctgtcta tctataatcc tagcaagtcc 1980 atcctgaaga tcagagaggc caagagcttt aaggagggca agaacttcaa gctgaaggac 2040 tgtcacaagt ttatcgattt ctacaaggag tctatcagca agaatgagga ctggagcaga 2100 ttcgacttca agttcagcaa gaccagcagc tacgagaaca tcagcgagtt ttaccgggag 2160 gtggagagac agggctataa cctggacttc aagaaggtgt ctaagttcta catcgacagc 2220 ctggtggagg atggcaagct gtacctgttc cagatctata acaaggactt ttctatcttc 2280 agcaagggca agcccaatct gcacaccatc tattttcggt ccctgttctc taaggagaac 2340 ctgaaggacg tgtgcctgaa gctgaatggc gaggccgaga tgttctttcg gaagaagtcc 2400 atcaactacg atgagaagaa gaagcgggag ggccaccacc ccgagctgtt tgagaagctg 2460 aagtatccta tcctgaagga caagagatac agcgaggata agtttcagtt ccacctgccc 2520 atcagcctga acttcaagtc caaggagcgg ctgaacttta atctgaaagt gaatgagttc 2580 ctgaagagaa acaaggacat caatatcatc ggcatcgatc ggggcgagag aaacctgctg 2640 tacctggtca tgatcaatca gaagggcgag atcctgaagc agaccctgct ggacagcatg 2700 cagtccggca agggccggcc tgagatcaac tacaaggaga agctgcagga gaaggagatc 2760 gagagggata aggcccgcaa gagctggggc acagtggaga atatcaagga gctgaaggag 2820 ggctatctgt ctatcgtgat ccaccagatc agcaagctga tggtggagaa caatgccatc 2880 gtggtgctgg aggacctgaa catcggcttt aagcggggca gacagaaggt ggagcggcag 2940 gtgtaccaga agttcgagaa gatgctgatc gataagctga actttctggt gttcaaggag 3000 aataagccaa ccgagccagg aggcgtgctg aaggcctatc agctgacaga cgagtttcag 3060 tctttcgaga agctgagcaa gcagaccggc tttctgttct acgtgccaag ctggaacacc 3120 tccaagatcg accccagaac aggctttatc gatttcctgc accctgccta cgagaatatc 3180 gagaaggcca agcagtggat caacaagttt gattccatca ggttcaattc taagatggac 3240 tggtttgagt tcaccgccga tacacgcaag ttttccgaga acctgatgct gggcaagaat 3300 cgggtgtggg tcatctgcac cacaaatgtg gagcggtact tcaccagcaa gaccgccaac 3360 agctccatcc agtacaatag catccagatc accgagaagc tgaaggagct gtttgtggac 3420 atccctttca gcaacggcca ggatctgaag ccagagatcc tgaggaagaa tgacgccgtg 3480 ttctttaaga gcctgctgtt ttacatcaag accacactgt ccctgcgcca gaacaatggc 3540 aagaagggcg aggaggagaa ggacttcatc ctgagcccag tggtggattc caagggccgg 3600 ttctttaact ctctggaggc cagcgacgat gagcccaagg acgccgatgc caatggcgcc 3660 taccacatcg ccctgaaggg cctgatgaac ctgctggtgc tgaatgagac aaaggaggag 3720 aacctgagca gaccaaagtg gaagatcaag aataaggact ggctggagtt cgtgtgggag 3780 aggaaccgca aaaggccggc ggccacgaaa aaggccggcc aggcaaaaaa gaaaaaggga 3840 tcctacccat acgatgttcc agattacgct tatccctacg acgtgcctga ttatgcatac 3900 ccatatgatg tccccgacta tgcctaagaa ttc 3933 <210> 226 <211> 3828 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 226 atgagcaagc tggagaagtt tacaaactgc tactccctgt ctaagaccct gaggttcaag 60 gccatccctg tgggcaagac ccaggagaac atcgacaata agcggctgct ggtggaggac 120 gagaagagag ccgaggatta taagggcgtg aagaagctgc tggatcgcta ctatctgtct 180 tttatcaacg acgtgctgca cagcatcaag ctgaagaatc tgaacaatta catcagcctg 240 ttccggaaga aaaccagaac cgagaaggag aataaggagc tggagaacct ggagatcaat 300 ctgcggaagg agatcgccaa ggccttcaag ggcaacgagg gctacaagtc cctgtttaag 360 aaggatatca tcgagacaat cctgccagag ttcctggacg ataaggacga gatcgccctg 420 gtgaacagct tcaatggctt taccacagcc ttcaccggct tctttgataa cagagagaat 480 atgttttccg aggaggccaa gagcacatcc atcgccttca ggtgtatcaa cgagaatctg 540 acccgctaca tctctaatat ggacatcttc gagaaggtgg acgccatctt tgataagcac 600 gaggtgcagg agatcaagga gaagatcctg aacagcgact atgatgtgga ggatttcttt 660 gagggcgagt tctttaactt tgtgctgaca caggagggca tcgacgtgta taacgccatc 720 atcggcggct tcgtgaccga gagcggcgag aagatcaagg gcctgaacga gtacatcaac 780 ctgtataatc agaaaaccaa gcagaagctg cctaagttta agccactgta taagcaggtg 840 ctgagcgatc gggagtctct gagcttctac ggcgagggct atacatccga tgaggaggtg 900 ctggaggtgt ttagaaacac cctgaacaag aacagcgaga tcttcagctc catcaagaag 960 ctggagaagc tgttcaagaa ttttgacgag tactctagcg ccggcatctt tgtgaagaac 1020 ggccccgcca tcagcacaat ctccaaggat atcttcggcg agtggaacgt gatccgggac 1080 aagtggaatg ccgagtatga cgatatccac ctgaagaaga aggccgtggt gaccgagaag 1140 tacgaggacg atcggagaaa gtccttcaag aagatcggct ccttttctct ggagcagctg 1200 caggagtacg ccgacgccga tctgtctgtg gtggagaagc tgaaggagat catcatccag 1260 aaggtggatg agatctacaa ggtgtatggc tcctctgaga agctgttcga cgccgatttt 1320 gtgctggaga agagcctgaa gaagaacgac gccgtggtgg ccatcatgaa ggacctgctg 1380 gattctgtga agagcttcga gaattacatc aaggccttct ttggcgaggg caaggagaca 1440 aacagggacg agtccttcta tggcgatttt gtgctggcct acgacatcct gctgaaggtg 1500 gaccacatct acgatgccat ccgcaattat gtgacccaga agccctactc taaggataag 1560 ttcaagctgt attttcagaa ccctcagttc atgggcggct gggacaagga taaggagaca 1620 gactatcggg ccaccatcct gagatacggc tccaagtact atctggccat catggataag 1680 aagtacgcca agtgcctgca gaagatcgac aaggacgatg tgaacggcaa ttacgagaag 1740 atcaactata agctgctgcc cggccctaat aagatgctgc caaaggtgtt cttttctaag 1800 aagtggatgg cctactataa ccccagcgag gacatccaga agatctacaa gaatggcaca 1860 ttcaagaagg gcgatatgtt taacctgaat gactgtcaca agctgatcga cttctttaag 1920 gatagcatct cccggtatcc aaagtggtcc aatgcctacg atttcaactt ttctgagaca 1980 gagaagtata aggacatcgc cggcttttac agagaggtgg aggagcaggg ctataaggtg 2040 agcttcgagt ctgccagcaa gaaggaggtg gataagctgg tggaggaggg caagctgtat 2100 atgttccaga tctataacaa ggacttttcc gataagtctc acggcacacc caatctgcac 2160 accatgtact tcaagctgct gtttgacgag aacaatcacg gacagatcag gctgagcgga 2220 ggagcagagc tgttcatgag gcgcgcctcc ctgaagaagg aggagctggt ggtgcaccca 2280 gccaactccc ctatcgccaa caagaatcca gataatccca agaaaaccac aaccctgtcc 2340 tacgacgtgt ataaggataa gaggttttct gaggaccagt acgagctgca catcccaatc 2400 gccatcaata agtgccccaa gaacatcttc aagatcaata cagaggtgcg cgtgctgctg 2460 aagcacgacg ataaccccta tgtgatcggc atcgataggg gcgagcgcaa tctgctgtat 2520 atcgtggtgg tggacggcaa gggcaacatc gtggagcagt attccctgaa cgagatcatc 2580 aacaacttca acggcatcag gatcaagaca gattaccact ctctgctgga caagaaggag 2640 aaggagaggt tcgaggcccg ccagaactgg acctccatcg agaatatcaa ggagctgaag 2700 gccggctata tctctcaggt ggtgcacaag atctgcgagc tggtggagaa gtacgatgcc 2760 gtgatcgccc tggaggacct gaactctggc tttaagaata gccgcgtgaa ggtggagaag 2820 caggtgtatc agaagttcga gaagatgctg atcgataagc tgaactacat ggtggacaag 2880 aagtctaatc cttgtgcaac aggcggcgcc ctgaagggct atcagatcac caataagttc 2940 gagagcttta agtccatgtc tacccagaac ggcttcatct tttacatccc tgcctggctg 3000 acatccaaga tcgatccatc taccggcttt gtgaacctgc tgaaaaccaa gtataccagc 3060 atcgccgatt ccaagaagtt catcagctcc tttgacagga tcatgtacgt gcccgaggag 3120 gatctgttcg agtttgccct ggactataag aacttctctc gcacagacgc cgattacatc 3180 aagaagtgga agctgtactc ctacggcaac cggatcagaa tcttccggaa tcctaagaag 3240 aacaacgtgt tcgactggga ggaggtgtgc ctgaccagcg cctataagga gctgttcaac 3300 aagtacggca tcaattatca gcagggcgat atcagagccc tgctgtgcga gcagtccgac 3360 aaggccttct actctagctt tatggccctg atgagcctga tgctgcagat gcggaacagc 3420 atcacaggcc gcaccgacgt ggattttctg atcagccctg tgaagaactc cgacggcatc 3480 ttctacgata gccggaacta tgaggcccag gagaatgcca tcctgccaaa gaacgccgac 3540 gccaatggcg cctataacat cgccagaaag gtgctgtggg ccatcggcca gttcaagaag 3600 gccgaggacg agaagctgga taaggtgaag atcgccatct ctaacaagga gtggctggag 3660 tacgcccaga ccagcgtgaa gcacaaaagg ccggcggcca cgaaaaaggc cggccaggca 3720 aaaaagaaaa agggatccta cccatacgat gttccagatt acgcttatcc ctacgacgtg 3780 cctgattatg catacccata tgatgtcccc gactatgcct aagaattc 3828 <210> 227 <211> 3924 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 227 atggacagcc tgaaggattt caccaacctg taccccgtgt ccaagacact gcggtttgag 60 ctgaagcctg tgggcaagac cctggagaat atcgagaagg ccggcatcct gaaggaggat 120 gagcacagag ccgagagcta ccggagagtg aagaagatca tcgatacata tcacaaggtg 180 ttcatcgaca gctccctgga gaacatggcc aagatgggca tcgagaatga gatcaaggcc 240 atgctgcagt ccttttgcga gctgtataag aaggaccaca ggaccgaggg agaggacaag 300 gccctggata agatcagggc cgtgctgagg ggcctgatcg tgggagcctt caccggcgtg 360 tgcggccggc gggagaacac agtgcagaat gagaagtatg agagcctgtt taaggagaag 420 ctgatcaagg agatcctgcc agatttcgtg ctgtctacag aggccgagtc cctgcccttt 480 tctgtggagg aggccaccag aagcctgaag gagttcgact cctttacatc ttacttcgcc 540 ggcttttatg agaaccggaa gaatatctac tctaccaagc cccagagcac agccatcgcc 600 tatagactga tccacgagaa cctgcctaag ttcatcgata atatcctggt gtttcagaag 660 atcaaggagc caatcgccaa ggagctggag cacatcaggg cagacttcag cgccggcggc 720 tacatcaaga aggatgagcg cctggaggac atcttttccc tgaactacta tatccacgtg 780 ctgtctcagg ccggcatcga gaagtacaat gccctgatcg gcaagatcgt gaccgagggc 840 gatggcgaga tgaagggcct gaacgagcac atcaacctgt ataatcagca gaggggccgc 900 gaggaccggc tgccactgtt cagacccctg tataagcaga tcctgtctga tagggagcag 960 ctgtcctatc tgccagagtc tttcgagaag gacgaggagc tgctgagggc cctgaaggag 1020 ttttacgatc acatcgcaga ggacatcctg ggaaggaccc agcagctgat gacaagcatc 1080 tccgagtacg atctgtcccg gatctatgtg agaaacgata gccagctgac cgacatctcc 1140 aagaagatgc tgggcgattg gaatgccatc tacatggccc gggagagagc ctatgaccac 1200 gagcaggccc ccaagcgcat cacagccaag tacgagaggg accgcatcaa ggccctgaag 1260 ggcgaggagt ctatcagcct ggccaacctg aacagctgca tcgccttcct ggacaacgtg 1320 agggattgtc gcgtggacac ctatctgtct acactgggac agaaggaggg acctcacggc 1380 ctgagcaacc tggtggagaa cgtgttcgcc tcctaccacg aggccgagca gctgctgtct 1440 tttccctatc ctgaggagaa caatctgatc caggacaagg ataacgtggt gctgatcaag 1500 aacctgctgg ataatatcag cgacctgcag aggttcctga agccactgtg gggcatgggc 1560 gatgagcccg acaaggatga gaggttttac ggcgagtaca attatatcag gggcgccctg 1620 gaccaggtca tccctctgta taacaaggtg cggaattatc tgacccgcaa gccatactcc 1680 acacgcaagg tgaagctgaa cttcggcaat agccagctgc tgtccggctg ggataggaac 1740 aaggagaagg acaattcttg cgtgatcctg cgcaagggcc agaacttcta cctggccatc 1800 atgaacaatc ggcacaagcg gagcttcgag aataagatgc tgcccgagta taaggagggc 1860 gagccttact tcgagaagat ggattataag tttctgccag accccaacaa gatgctgccc 1920 aaggtgttcc tgtctaagaa gggcatcgag atctacaagc ctagcccaaa gctgctggag 1980 cagtatggcc acggcaccca caagaagggc gataccttca gcatggacga tctgcacgag 2040 ctgatcgact tctttaagca ctccatcgag gcccacgagg attggaagca gttcggcttt 2100 aagttcagcg acaccgccac atacgagaac gtgagcagct tctaccggga ggtggaggac 2160 cagggctaca agctgtcttt tagaaaggtg tccgagtctt acgtgtatag cctgatcgat 2220 cagggcaagc tgtacctgtt ccagatctat aacaaggact ttagcccttg ttccaagggc 2280 accccaaatc tgcacacact gtactggcgg atgctgttcg atgagagaaa cctggccgac 2340 gtgatctata agctggatgg caaggccgag atcttctttc gggagaagtc cctgaagaat 2400 gaccacccaa cccaccctgc aggcaagccc atcaagaaga agagccggca gaagaagggc 2460 gaggagagcc tgttcgagta cgatctggtg aaggaccgga gatataccat ggataagttt 2520 cagttccacg tgccaatcac aatgaacttt aagtgctctg ccggcagcaa ggtgaacgac 2580 atggtgaatg cccacatcag ggaggccaag gacatgcacg tgatcggcat cgataggggc 2640 gagcgcaatc tgctgtatat ctgcgtgatc gacagccgcg gcaccatcct ggatcagatc 2700 tccctgaaca caatcaatga catcgattat cacgatctgc tggagtccag ggacaaggat 2760 cgccagcagg agcacaggaa ctggcagacc atcgagggca tcaaggagct gaagcagggc 2820 tacctgtctc aggccgtgca ccgcatcgcc gagctgatgg tggcctataa ggccgtggtg 2880 gccctggagg acctgaacat gggcttcaag cggggcagac agaaggtgga gagcagcgtg 2940 taccagcagt ttgagaagca gctgatcgac aagctgaatt atctggtgga taagaagaag 3000 cggcccgagg acatcggagg cctgctgaga gcctaccagt tcaccgcccc tttcaagagc 3060 tttaaggaga tgggcaagca gaacggcttt ctgttctata tccctgcctg gaacacatcc 3120 aatatcgacc caaccacagg cttcgtgaac ctgtttcacg tgcagtacga gaatgtggat 3180 aaggccaaga gcttctttca gaagttcgac agcatctcct acaaccctaa gaaggattgg 3240 tttgagttcg cctttgacta taagaacttc accaagaagg ccgagggctc taggagcatg 3300 tggattctgt gcacccacgg ctcccggatc aagaacttca gaaattctca gaagaatggc 3360 cagtgggata gcgaggagtt tgccctgacc gaggccttca agtccctgtt tgtgcggtac 3420 gagatcgatt ataccgccga cctgaaaacc gccatcgtgg acgagaagca gaaggatttc 3480 tttgtggacc tgctgaagct gttcaagctg accgtgcaga tgagaaactc ctggaaggag 3540 aaggacctgg attacctgat ctctccagtg gccggcgccg atggcaggtt ctttgacaca 3600 cgcgagggca ataagagcct gcccaaggac gcagatgcaa acggagccta taatatcgcc 3660 ctgaagggcc tgtgggcact gaggcagatc agacagacct ccgagggcgg caagctgaag 3720 ctggccatct ctaacaagga gtggctgcag tttgtgcagg agagatccta cgagaaggac 3780 aaaaggccgg cggccacgaa aaaggccggc caggcaaaaa agaaaaaggg atcctaccca 3840 tacgatgttc cagattacgc ttatccctac gacgtgcctg attatgcata cccatatgat 3900 gtccccgact atgcctaaga attc 3924 <210> 228 <211> 4113 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 228 atggagaact atcaggagtt caccaacctg tttcagctga ataagacact gagattcgag 60 ctgaagccca tcggcaagac ctgcgagctg ctggaggagg gcaagatctt cgccagcggc 120 tcctttctgg agaaggacaa ggtgagggcc gataacgtga gctacgtgaa gaaggagatc 180 gacaagaagc acaagatctt tatcgaggag acactgagct ccttctctat cagcaacgat 240 ctgctgaagc agtactttga ctgctataat gagctgaagg ccttcaagaa ggactgtaag 300 agcgatgagg aggaggtgaa gaaaaccgcc ctgcgcaaca agtgtacctc catccagagg 360 gccatgcgcg aggccatctc tcaggccttt ctgaagagcc cccagaagaa gctgctggcc 420 atcaagaacc tgatcgagaa cgtgttcaag gccgacgaga atgtgcagca cttctccgag 480 tttaccagct atttctccgg ctttgagaca aacagagaga atttctactc tgacgaggag 540 aagtccacat ctatcgccta taggctggtg cacgataacc tgcctatctt catcaagaac 600 atctacatct tcgagaagct gaaggagcag ttcgacgcca agaccctgag cgagatcttc 660 gagaactaca agctgtatgt ggccggctct agcctggatg aggtgttctc cctggagtac 720 tttaacaata ccctgacaca gaagggcatc gacaactata atgccgtgat cggcaagatc 780 gtgaaggagg ataagcagga gatccagggc ctgaacgagc acatcaacct gtataatcag 840 aagcacaagg accggagact gcccttcttt atctccctga agaagcagat cctgtccgat 900 cgggaggccc tgtcttggct gcctgacatg ttcaagaatg attctgaagt gatcaaggcc 960 ctgaagggct tctacatcga ggacggcttt gagaacaatg tgctgacacc tctggccacc 1020 ctgctgtcct ctctggataa gtacaacctg aatggcatct ttatccgcaa caatgaggcc 1080 ctgagctccc tgtcccagaa cgtgtatcgg aatttttcta tcgacgaggc catcgatgcc 1140 aacgccgagc tgcagacctt caacaattac gagctgatcg ccaatgccct gcgcgccaag 1200 atcaagaagg agacaaagca gggccggaag tctttcgaga agtacgagga gtatatcgat 1260 aagaaggtga aggccatcga cagcctgtcc atccaggaga tcaacgagct ggtggagaat 1320 tacgtgagcg agtttaactc taatagcggc aacatgccaa gaaaggtgga ggactacttc 1380 agcctgatga ggaagggcga cttcggctcc aacgatctga tcgaaaatat caagaccaag 1440 ctgagcgccg cagagaagct gctgggcaca aagtaccagg agacagccaa ggacatcttc 1500 aagaaggatg agaactccaa gctgatcaag gagctgctgg acgccaccaa gcagttccag 1560 cactttatca agccactgct gggcacaggc gaggaggcag atcgggacct ggtgttctac 1620 ggcgattttc tgcccctgta tgagaagttt gaggagctga ccctgctgta taacaaggtg 1680 cggaatagac tgacacagaa gccctattcc aaggacaaga tccgcctgtg cttcaacaag 1740 cctaagctga tgacaggctg ggtggattcc aagaccgaga agtctgacaa cggcacacag 1800 tacggcggct atctgtttcg gaagaagaat gagatcggcg agtacgatta ttttctgggc 1860 atctctagca aggcccagct gttcagaaag aacgaggccg tgatcggcga ctacgagagg 1920 ctggattact atcagccaaa ggccaatacc atctacggct ctgcctatga gggcgagaac 1980 agctacaagg aggacaagaa gcggctgaac aaagtgatca tcgcctatat cgagcagatc 2040 aagcagacaa acatcaagaa gtctatcatc gagtccatct ctaagtatcc taatatcagc 2100 gacgatgaca aggtgacccc atcctctctg ctggagaaga tcaagaaggt gtctatcgac 2160 agctacaacg gcatcctgtc cttcaagtct tttcagagcg tgaacaagga agtgatcgat 2220 aacctgctga aaaccatcag ccccctgaag aacaaggccg agtttctgga cctgatcaat 2280 aaggattatc agatcttcac cgaggtgcag gccgtgatcg acgagatctg caagcagaaa 2340 accttcatct actttccaat ctccaacgtg gagctggaga aggagatggg cgataaggac 2400 aagcccctgt gcctgttcca gatcagcaat aaggatctgt ccttcgccaa gacctttagc 2460 gccaacctgc ggaagaagag aggcgccgag aatctgcaca caatgctgtt taaggccctg 2520 atggagggca accaggataa tctggacctg ggctctggcg ccatcttcta cagagccaag 2580 agcctggacg gcaacaagcc cacacaccct gccaatgagg ccatcaagtg taggaacgtg 2640 gccaataagg ataaggtgtc cctgttcacc tacgacatct ataagaacag gcgctacatg 2700 gagaataagt tcctgtttca cctgagcatc gtgcagaact ataaggccgc caatgactcc 2760 gcccagctga acagctccgc caccgagtat atcagaaagg ccgatgacct gcacatcatc 2820 ggcatcgata ggggcgagcg caatctgctg tactattccg tgatcgatat gaagggcaac 2880 atcgtggagc aggactctct gaatatcatc aggaacaatg acctggagac agattaccac 2940 gacctgctgg ataagaggga gaaggagcgc aaggccaacc ggcagaattg ggaggccgtg 3000 gagggcatca aggacctgaa gaagggctac ctgagccagg ccgtgcacca gatcgcccag 3060 ctgatgctga agtataacgc catcatcgcc ctggaggatc tgggccagat gtttgtgacc 3120 cgcggccaga agatcgagaa ggccgtgtac cagcagttcg agaagagcct ggtggataag 3180 ctgtcctacc tggtggacaa gaagcggcct tataatgagc tgggcggcat cctgaaggcc 3240 taccagctgg cctctagcat caccaagaac aattctgaca agcagaacgg cttcctgttt 3300 tatgtgccag cctggaatac aagcaagatc gatcccgtga ccggctttac agacctgctg 3360 cggcccaagg ccatgaccat caaggaggcc caggacttct ttggcgcctt cgataacatc 3420 tcttacaatg acaagggcta tttcgagttt gagacaaact acgacaagtt taagatcaga 3480 atgaagagcg cccagaccag gtggacaatc tgcaccttcg gcaatcggat caagagaaag 3540 aaggataaga actactggaa ttatgaggag gtggagctga ccgaggagtt caagaagctg 3600 tttaaggaca gcaacatcga ttacgagaac tgtaatctga aggaggagat ccagaacaag 3660 gacaatcgca agttctttga tgacctgatc aagctgctgc agctgacact gcagatgcgg 3720 aactccgatg acaagggcaa tgattatatc atctctcctg tggccaacgc cgagggccag 3780 ttctttgact cccgcaatgg cgataagaag ctgccactgg atgcagacgc aaacggagcc 3840 tacaatatcg cccgcaaggg cctgtggaac atccggcaga tcaagcagac caagaacgac 3900 aagaagctga atctgagcat ctcctctaca gagtggctgg atttcgtgcg ggagaagcct 3960 tacctgaaga aaaggccggc ggccacgaaa aaggccggcc aggcaaaaaa gaaaaaggga 4020 tcctacccat acgatgttcc agattacgct tatccctacg acgtgcctga ttatgcatac 4080 ccatatgatg tccccgacta tgcctaagaa ttc 4113 <210> 229 <211> 3882 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 229 atgaaaaccc agcacttctt tgaggacttc acaagcctgt actctctgag caagaccatc 60 cggtttgagc tgaagccaat cggcaagacc ctggagaaca tcaagaagaa tggcctgatc 120 cggagagatg agcagagact ggacgattac gagaagctga agaaagtgat cgacgagtat 180 cacgaggatt tcatcgccaa catcctgagc tccttttcct tctctgagga gatcctgcag 240 tcctacatcc agaatctgag cgagtccgag gccagggcca agatcgagaa aaccatgcgc 300 gacacactgg ccaaggcctt ctctgaggat gagaggtaca agagcatctt taagaaggag 360 ctggtgaaga aggacatccc cgtgtggtgc cctgcctata agagcctgtg caagaagttc 420 gataacttta ccacatctct ggtgcccttc cacgagaaca ggaagaacct gtataccagc 480 aatgagatca cagcctctat cccttatcgc atcgtgcacg tgaacctgcc aaagtttatc 540 cagaatatcg aggccctgtg cgagctgcag aagaagatgg gcgccgacct gtacctggag 600 atgatggaga acctgcgcaa cgtgtggccc agcttcgtga aaaccccaga cgacctgtgc 660 aacctgaaaa cctataatca cctgatggtg cagtctagca tcagcgagta caacaggttt 720 gtgggcggct attccaccga ggacggcaca aagcaccagg gcatcaacga gtggatcaat 780 atctacagac agaggaataa ggagatgcgc ctgcctggcc tggtgttcct gcacaagcag 840 atcctggcca aggtggactc ctctagcttc atcagcgata cactggagaa cgacgatcag 900 gtgttttgcg tgctgagaca gttcaggaag ctgttttgga ataccgtgtc ctctaaggag 960 gacgatgccg cctccctgaa ggacctgttc tgtggcctgt ctggctatga ccctgaggcc 1020 atctacgtga gcgatgccca cctggccaca atctccaaga acatctttga cagatggaat 1080 tacatctccg atgccatcag gcgcaagacc gaggtgctga tgccacggaa gaaggagagc 1140 gtggagagat atgccgagaa gatctccaag cagatcaaga agagacagtc ttacagcctg 1200 gccgagctgg acgatctgct ggcccactat agcgaggagt ccctgcccgc aggcttctct 1260 ctgctgagct actttacatc tctgggcggc cagaagtatc tggtgagcga cggcgaagtg 1320 atcctgtacg aggagggcag caacatctgg gacgaggtgc tgatcgcctt cagggatctg 1380 caggtcatcc tggacaagga cttcaccgag aagaagctgg gcaaggatga ggaggccgtg 1440 tctgtgatca agaaggccct ggacagcgcc ctgcgcctgc ggaagttctt tgatctgctg 1500 tccggcacag gcgcagagat caggagagac agctccttct atgccctgta taccgaccgg 1560 atggataagc tgaagggcct gctgaagatg tatgataagg tgagaaacta cctgaccaag 1620 aagccttatt ccatcgagaa gttcaagctg cactttgaca acccatccct gctgtctggc 1680 tgggataaga ataaggagct gaacaatctg tctgtgatct tccggcagaa cggctactat 1740 tacctgggca tcatgacacc caagggcaag aatctgttca agaccctgcc taagctgggc 1800 gccgaggaga tgttttatga gaagatggag tacaagcaga tcgccgagcc tatgctgatg 1860 ctgccaaagg tgttctttcc caagaaaacc aagccagcct tcgccccaga ccagagcgtg 1920 gtggatatct acaacaagaa aaccttcaag acaggccaga agggctttaa taagaaggac 1980 ctgtaccggc tgatcgactt ctacaaggag gccctgacag tgcacgagtg gaagctgttt 2040 aacttctcct tttctccaac cgagcagtat cggaatatcg gcgagttctt tgacgaggtg 2100 agagagcagg cctacaaggt gtccatggtg aacgtgcccg cctcttatat cgacgaggcc 2160 gtggagaacg gcaagctgta tctgttccag atctacaata aggacttcag cccctactcc 2220 aagggcatcc ctaacctgca cacactgtat tggaaggccc tgttcagcga gcagaatcag 2280 agccgggtgt ataagctgtg cggaggagga gagctgtttt atagaaaggc cagcctgcac 2340 atgcaggaca ccacagtgca ccccaagggc atctctatcc acaagaagaa cctgaataag 2400 aagggcgaga caagcctgtt caactacgac ctggtgaagg ataagaggtt taccgaggac 2460 aagttctttt tccacgtgcc tatctctatc aactacaaga ataagaagat caccaacgtg 2520 aatcagatgg tgcgcgatta tatcgcccag aacgacgatc tgcagatcat cggcatcgac 2580 cgcggcgagc ggaatctgct gtatatcagc cggatcgata caaggggcaa cctgctggag 2640 cagttcagcc tgaatgtgat cgagtccgac aagggcgatc tgagaaccga ctatcagaag 2700 atcctgggcg atcgcgagca ggagcggctg aggcgccggc aggagtggaa gtctatcgag 2760 agcatcaagg acctgaagga tggctacatg agccaggtgg tgcacaagat ctgtaacatg 2820 gtggtggagc acaaggccat cgtggtgctg gagaacctga atctgagctt catgaagggc 2880 aggaagaagg tggagaagtc cgtgtacgag aagtttgagc gcatgctggt ggacaagctg 2940 aactatctgg tggtggataa gaagaacctg tccaatgagc caggaggcct gtatgcagca 3000 taccagctga ccaatccact gttctctttt gaggagctgc acagataccc ccagagcggc 3060 atcctgtttt tcgtggaccc atggaacacc tctctgacag atcccagcac aggcttcgtg 3120 aatctgctgg gcagaatcaa ctacaccaat gtgggcgacg cccgcaagtt tttcgatcgg 3180 tttaacgcca tcagatatga cggcaagggc aatatcctgt tcgacctgga tctgtccaga 3240 tttgatgtga gggtggagac acagaggaag ctgtggacac tgaccacatt cggctctcgc 3300 atcgccaaat ccaagaagtc tggcaagtgg atggtggagc ggatcgagaa cctgagcctg 3360 tgctttctgg agctgttcga gcagtttaat atcggctaca gagtggagaa ggacctgaag 3420 aaggccatcc tgagccagga taggaaggag ttctatgtgc gcctgatcta cctgtttaac 3480 ctgatgatgc agatccggaa cagcgacggc gaggaggatt atatcctgtc tcccgccctg 3540 aacgagaaga atctgcagtt cgacagcagg ctgatcgagg ccaaggatct gcctgtggac 3600 gcagatgcaa acggagcata caatgtggcc cgcaagggcc tgatggtggt gcagagaatc 3660 aagaggggcg accacgagtc catccacagg atcggaaggg cacagtggct gagatatgtg 3720 caggagggca tcgtggagaa aaggccggcg gccacgaaaa aggccggcca ggcaaaaaag 3780 aaaaagggat cctacccata cgatgttcca gattacgctt atccctacga cgtgcctgat 3840 tatgcatacc catatgatgt ccccgactat gcctaagaat tc

    3882 <210> 230 <211> 1345 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 230

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr

    100 105 110

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys

    305

    310

    315

    320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu

    1025

    1030

    1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn Lys Arg Pro Ala Ala Thr Lys Lys 1295 1300 1305

    Ala Gly Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val 1310 1315 1320

    Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro 1325 1330 1335

    Tyr Asp Val Pro Asp Tyr Ala 1340 1345 <210> 231 <211> 1278 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 231

    Met Asp Tyr Gly Asn Gly Gln Phe Glu Arg Arg Ala Pro Leu Thr Lys 1 5 10 15

    Thr Ile Thr Leu Arg Leu Lys Pro Ile Gly Glu Thr Arg Glu Thr Ile 20 25 30

    Arg Glu Gln Lys Leu Leu Glu Gln Asp Ala Ala Phe Arg Lys Leu Val 35 40 45

    Glu Thr Val Thr Pro Ile Val Asp Asp Cys Ile Arg Lys Ile Ala Asp 50 55 60

    Asn Ala Leu Cys His Phe Gly Thr Glu Tyr Asp Phe Ser Cys Leu Gly 65 70 75 80

    Asn Ala Ile Ser Lys Asn Asp Ser Lys Ala Ile Lys Lys Glu Thr Glu 85 90 95

    Lys Val Glu Lys Leu Leu Ala Lys Val Leu Thr Glu Asn Leu Pro Asp 100 105 110

    Gly Leu Arg Lys Val Asn Asp Ile Asn Ser Ala Ala Phe Ile Gln Asp 115 120 125

    Thr Leu Thr Ser Phe Val Gln Asp Asp Ala Asp Lys Arg Val Leu Ile 130 135 140

    Gln Glu Leu Lys Gly Lys Thr Val Leu Met Gln Arg Phe Leu Thr Thr 145 150 155 160

    Arg Ile Thr Ala Leu Thr Val Trp Leu Pro Asp Arg Val Phe Glu Asn 165 170 175

    Phe Asn Ile Phe Ile Glu Asn Ala Glu Lys Met Arg Ile Leu Leu Asp 180 185 190

    Ser Pro Leu Asn Glu Lys Ile Met Lys Phe Asp Pro Asp Ala Glu Gln 195 200 205

    Tyr Ala Ser Leu Glu Phe Tyr Gly Gln Cys Leu Ser Gln Lys Asp Ile 210 215 220

    Asp Ser Tyr Asn Leu Ile Ile Ser Gly Ile Tyr Ala Asp Asp Glu Val 225 230 235 240

    Lys Asn Pro Gly Ile Asn Glu Ile Val Lys Glu Tyr Asn Gln Gln Ile 245 250 255

    Arg Gly Asp Lys Asp Glu Ser Pro Leu Pro Lys Leu Lys Lys Leu His 260 265 270

    Lys Gln Ile Leu Met Pro Val Glu Lys Ala Phe Phe Val Arg Val Leu 275 280 285

    Ser Asn Asp Ser Asp Ala Arg Ser Ile Leu Glu Lys Ile Leu Lys Asp 290 295 300

    Thr Glu Met Leu Pro Ser Lys Ile Ile Glu Ala Met Lys Glu Ala Asp 305 310 315 320

    Ala Gly Asp Ile Ala Val Tyr Gly Ser Arg Leu His Glu Leu Ser His 325 330 335

    Val Ile Tyr Gly Asp His Gly Lys Leu Ser Gln Ile Ile Tyr Asp Lys 340 345 350

    Glu Ser Lys Arg Ile Ser Glu Leu Met Glu Thr Leu Ser Pro Lys Glu 355 360 365

    Arg Lys Glu Ser Lys Lys Arg Leu Glu Gly Leu Glu Glu His Ile Arg 370 375 380

    Lys Ser Thr Tyr Thr Phe Asp Glu Leu Asn Arg Tyr Ala Glu Lys Asn 385 390 395 400

    Val Met Ala Ala Tyr Ile Ala Ala Val Glu Glu Ser Cys Ala Glu Ile 405 410 415

    Met Arg Lys Glu Lys Asp Leu Arg Thr Leu Leu Ser Lys Glu Asp Val 420 425 430

    Lys Ile Arg Gly Asn Arg His Asn Thr Leu Ile Val Lys Asn Tyr Phe 435 440 445

    Asn Ala Trp Thr Val Phe Arg Asn Leu Ile Arg Ile Leu Arg Arg Lys 450 455 460

    Ser Glu Ala Glu Ile Asp Ser Asp Phe Tyr Asp Val Leu Asp Asp Ser 465 470 475 480

    Val Glu Val Leu Ser Leu Thr Tyr Lys Gly Glu Asn Leu Cys Arg Ser 485 490 495

    Tyr Ile Thr Lys Lys Ile Gly Ser Asp Leu Lys Pro Glu Ile Ala Thr 500 505 510

    Tyr Gly Ser Ala Leu Arg Pro Asn Ser Arg Trp Trp Ser Pro Gly Glu 515 520 525

    Lys Phe Asn Val Lys Phe His Thr Ile Val Arg Arg Asp Gly Arg Leu 530 535 540

    Tyr Tyr Phe Ile Leu Pro Lys Gly Ala Lys Pro Val Glu Leu Glu Asp 545 550 555 560

    Met Asp Gly Asp Ile Glu Cys Leu Gln Met Arg Lys Ile Pro Asn Pro 565 570 575

    Thr Ile Phe Leu Pro Lys Leu Val Phe Lys Asp Pro Glu Ala Phe Phe 580 585 590

    Arg Asp Asn Pro Glu Ala Asp Glu Phe Val Phe Leu Ser Gly Met Lys 595 600 605

    Ala Pro Val Thr Ile Thr Arg Glu Thr Tyr Glu Ala Tyr Arg Tyr Lys 610 615 620

    Leu Tyr Thr Val Gly Lys Leu Arg Asp Gly Glu Val Ser Glu Glu Glu 625 630 635 640

    Tyr Lys Arg Ala Leu Leu Gln Val Leu Thr Ala Tyr Lys Glu Phe Leu 645 650 655

    Glu Asn Arg Met Ile Tyr Ala Asp Leu Asn Phe Gly Phe Lys Asp Leu 660 665 670

    Glu Glu Tyr Lys Asp Ser Ser Glu Phe Ile Lys Gln Val Glu Thr His 675 680 685

    Asn Thr Phe Met Cys Trp Ala Lys Val Ser Ser Ser Gln Leu Asp Asp

    690

    695

    700

    Leu Val Lys Ser Gly Asn Gly Leu Leu Phe Glu Ile Trp Ser Glu Arg 705 710 715 720

    Leu Glu Ser Tyr Tyr Lys Tyr Gly Asn Glu Lys Val Leu Arg Gly Tyr 725 730 735

    Glu Gly Val Leu Leu Ser Ile Leu Lys Asp Glu Asn Leu Val Ser Met 740 745 750

    Arg Thr Leu Leu Asn Ser Arg Pro Met Leu Val Tyr Arg Pro Lys Glu 755 760 765

    Ser Ser Lys Pro Met Val Val His Arg Asp Gly Ser Arg Val Val Asp 770 775 780

    Arg Phe Asp Lys Asp Gly Lys Tyr Ile Pro Pro Glu Val His Asp Glu 785 790 795 800

    Leu Tyr Arg Phe Phe Asn Asn Leu Leu Ile Lys Glu Lys Leu Gly Glu 805 810 815

    Lys Ala Arg Lys Ile Leu Asp Asn Lys Lys Val Lys Val Lys Val Leu 820 825 830

    Glu Ser Glu Arg Val Lys Trp Ser Lys Phe Tyr Asp Glu Gln Phe Ala 835 840 845

    Val Thr Phe Ser Val Lys Lys Asn Ala Asp Cys Leu Asp Thr Thr Lys 850 855 860

    Asp Leu Asn Ala Glu Val Met Glu Gln Tyr Ser Glu Ser Asn Arg Leu 865 870 875 880

    Ile Leu Ile Arg Asn Thr Thr Asp Ile Leu Tyr Tyr Leu Val Leu Asp 885 890 895

    Lys Asn Gly Lys Val Leu Lys Gln Arg Ser Leu Asn Ile Ile Asn Asp 900 905 910

    Gly Ala Arg Asp Val Asp Trp Lys Glu Arg Phe Arg Gln Val Thr Lys 915 920 925

    Asp Arg Asn Glu Gly Tyr Asn Glu Trp Asp Tyr Ser Arg Thr Ser Asn 930 935 940

    Asp Leu Lys Glu Val Tyr Leu Asn Tyr Ala Leu Lys Glu Ile Ala Glu 945 950 955 960

    Ala Val Ile Glu Tyr Asn Ala Ile Leu Ile Ile Glu Lys Met Ser Asn 965 970 975

    Ala Phe Lys Asp Lys Tyr Ser Phe Leu Asp Asp Val Thr Phe Lys Gly 980 985 990

    Phe Glu Thr Lys Leu Leu Ala Lys Leu Ser Asp Leu His Phe Arg Gly 995 1000 1005

    Ile Lys Asp Gly Glu Pro Cys Ser Phe Thr Asn Pro Leu Gln Leu 1010 1015 1020

    Cys Gln Asn Asp Ser Asn Lys Ile Leu Gln Asp Gly Val Ile Phe 1025 1030 1035

    Met Val Pro Asn Ser Met Thr Arg Ser Leu Asp Pro Asp Thr Gly 1040 1045 1050

    Phe Ile Phe Ala Ile Asn Asp His Asn Ile Arg Thr Lys Lys Ala 1055 1060 1065

    Lys Leu Asn Phe Leu Ser Lys Phe Asp Gln Leu Lys Val Ser Ser 1070 1075 1080

    Glu Gly Cys Leu Ile Met Lys Tyr Ser Gly Asp Ser Leu Pro Thr 1085 1090 1095

    His Asn Thr Asp Asn Arg Val Trp Asn Cys Cys Cys Asn His Pro 1100 1105 1110

    Ile Thr Asn Tyr Asp Arg Glu Thr Lys Lys Val Glu Phe Ile Glu 1115 1120 1125

    Glu Pro Val Glu Glu Leu Ser Arg Val Leu Glu Glu Asn Gly Ile 1130 1135 1140

    Glu Thr Asp Thr Glu Leu Asn Lys Leu Asn Glu Arg Glu Asn Val 1145 1150 1155

    Pro Gly Lys Val Val Asp Ala Ile Tyr Ser Leu Val Leu Asn Tyr 1160 1165 1170

    Leu Arg Gly Thr Val Ser Gly Val Ala Gly Gln Arg Ala Val Tyr 1175 1180 1185

    Tyr Ser Pro Val Thr Gly Lys Lys Tyr Asp Ile Ser Phe Ile Gln 1190 1195 1200

    Ala Met Asn Leu Asn Arg Lys Cys Asp Tyr Tyr Arg Ile Gly Ser 1205 1210 1215

    Lys Glu Arg Gly Glu Trp Thr Asp Phe Val Ala Gln Leu Ile Asn 1220 1225 1230

    Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys 1235 1240 1245

    Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr 1250 1255 1260

    Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1265 1270 1275 <210> 232 <211> 1286 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 232

    Met Leu Leu Tyr Glu Asn Tyr Thr Lys Arg Asn Gln Ile Thr Lys Ser 1 5 10 15

    Leu Arg Leu Glu Leu Arg Pro Gln Gly Lys Thr Leu Arg Asn Ile Lys 20 25 30

    Glu Leu Asn Leu Leu Glu Gln Asp Lys Ala Ile Tyr Ala Leu Leu Glu 35 40 45

    Arg Leu Lys Pro Val Ile Asp Glu Gly Ile Lys Asp Ile Ala Arg Asp 50 55 60

    Thr Leu Lys Asn Cys Glu Leu Ser Phe Glu Lys Leu Tyr Glu His Phe 65 70 75 80

    Leu Ser Gly Asp Lys Lys Ala Tyr Ala Lys Glu Ser Glu Arg Leu Lys 85 90 95

    Lys Glu Ile Val Lys Thr Leu Ile Lys Asn Leu Pro Glu Gly Ile Gly 100 105 110

    Lys Ile Ser Glu Ile Asn Ser Ala Lys Tyr Leu Asn Gly Val Leu Tyr 115 120 125

    Asp Phe Ile Asp Lys Thr His Lys Asp Ser Glu Glu Lys Gln Asn Ile 130 135 140

    Leu Ser Asp Ile Leu Glu Thr Lys Gly Tyr Leu Ala Leu Phe Ser Lys 145 150 155 160

    Phe Leu Thr Ser Arg Ile Thr Thr Leu Glu Gln Ser Met Pro Lys Arg 165 170 175

    Val Ile Glu Asn Phe Glu Ile Tyr Ala Ala Asn Ile Pro Lys Met Gln 180 185 190

    Asp Ala Leu Glu Arg Gly Ala Val Ser Phe Ala Ile Glu Tyr Glu Ser 195 200 205

    Ile Cys Ser Val Asp Tyr Tyr Asn Gln Ile Leu Ser Gln Glu Asp Ile 210 215 220

    Asp Ser Tyr Asn Arg Leu Ile Ser Gly Ile Met Asp Glu Asp Gly Ala 225 230 235 240

    Lys Glu Lys Gly Ile Asn Gln Thr Ile Ser Glu Lys Asn Ile Lys Ile 245 250 255

    Lys Ser Glu His Leu Glu Glu Lys Pro Phe Arg Ile Leu Lys Gln Leu 260 265 270

    His Lys Gln Ile Leu Glu Glu Arg Glu Lys Ala Phe Thr Ile Asp His 275 280 285

    Ile Asp Ser Asp Glu Glu Val Val Gln Val Thr Lys Glu Ala Phe Glu 290 295 300

    Gln Thr Lys Glu Gln Trp Glu Asn Ile Lys Lys Ile Asn Gly Phe Tyr 305 310 315 320

    Ala Lys Asp Pro Gly Asp Ile Thr Leu Phe Ile Val Val Gly Pro Asn 325 330 335

    Gln Thr His Val Leu Ser Gln Leu Ile Tyr Gly Glu His Asp Arg Ile 340 345 350

    Arg Leu Leu Leu Glu Glu Tyr Glu Lys Asn Thr Leu Glu Val Leu Pro 355 360 365

    Arg Arg Thr Lys Ser Glu Lys Ala Arg Tyr Asp Lys Phe Val Asn Ala 370 375 380

    Val Pro Lys Lys Val Ala Lys Glu Ser His Thr Phe Asp Gly Leu Gln 385 390 395 400

    Lys Met Thr Gly Asp Asp Arg Leu Phe Ile Leu Tyr Arg Asp Glu Leu 405 410 415

    Ala Arg Asn Tyr Met Arg Ile Lys Glu Ala Tyr Gly Thr Phe Glu Arg 420 425 430

    Asp Ile Leu Lys Ser Arg Arg Gly Ile Lys Gly Asn Arg Asp Val Gln

    435

    440

    445

    Glu Ser Leu Val Ser Phe Tyr Asp Glu Leu Thr Lys Phe Arg Ser Ala 450 455 460

    Leu Arg Ile Ile Asn Ser Gly Asn Asp Glu Lys Ala Asp Pro Ile Phe 465 470 475 480

    Tyr Asn Thr Phe Asp Gly Ile Phe Glu Lys Ala Asn Arg Thr Tyr Lys 485 490 495

    Ala Glu Asn Leu Cys Arg Asn Tyr Val Thr Lys Ser Pro Ala Asp Asp 500 505 510

    Ala Arg Ile Met Ala Ser Cys Leu Gly Thr Pro Ala Arg Leu Arg Thr 515 520 525

    His Trp Trp Asn Gly Glu Glu Asn Phe Ala Ile Asn Asp Val Ala Met 530 535 540

    Ile Arg Arg Gly Asp Glu Tyr Tyr Tyr Phe Val Leu Thr Pro Asp Val 545 550 555 560

    Lys Pro Val Asp Leu Lys Thr Lys Asp Glu Thr Asp Ala Gln Ile Phe 565 570 575

    Val Gln Arg Lys Gly Ala Lys Ser Phe Leu Gly Leu Pro Lys Ala Leu 580 585 590

    Phe Lys Cys Ile Leu Glu Pro Tyr Phe Glu Ser Pro Glu His Lys Asn 595 600 605

    Asp Lys Asn Cys Val Ile Glu Glu Tyr Val Ser Lys Pro Leu Thr Ile 610 615 620

    Asp Arg Arg Ala Tyr Asp Ile Phe Lys Asn Gly Thr Phe Lys Lys Thr 625 630 635 640

    Asn Ile Gly Ile Asp Gly Leu Thr Glu Glu Lys Phe Lys Asp Asp Cys 645 650 655

    Arg Tyr Leu Ile Asp Val Tyr Lys Glu Phe Ile Ala Val Tyr Thr Arg 660 665 670

    Tyr Ser Cys Phe Asn Met Ser Gly Leu Lys Arg Ala Asp Glu Tyr Asn 675 680 685

    Asp Ile Gly Glu Phe Phe Ser Asp Val Asp Thr Arg Leu Cys Thr Met 690 695 700

    Glu Trp Ile Pro Val Ser Phe Glu Arg Ile Asn Asp Met Val Asp Lys 705 710 715 720

    Lys Glu Gly Leu Leu Phe Leu Val Arg Ser Met Phe Leu Tyr Asn Arg 725 730 735

    Pro Arg Lys Pro Tyr Glu Arg Thr Phe Ile Gln Leu Phe Ser Asp Ser 740 745 750

    Asn Met Glu His Thr Ser Met Leu Leu Asn Ser Arg Ala Met Ile Gln 755 760 765

    Tyr Arg Ala Ala Ser Leu Pro Arg Arg Val Thr His Lys Lys Gly Ser 770 775 780

    Ile Leu Val Ala Leu Arg Asp Ser Asn Gly Glu His Ile Pro Met His 785 790 795 800

    Ile Arg Glu Ala Ile Tyr Lys Met Lys Asn Asn Phe Asp Ile Ser Ser 805 810 815

    Glu Asp Phe Ile Met Ala Lys Ala Tyr Leu Ala Glu His Asp Val Ala 820 825 830

    Ile Lys Lys Ala Asn Glu Asp Ile Ile Arg Asn Arg Arg Tyr Thr Glu 835 840 845

    Asp Lys Phe Phe Leu Ser Leu Ser Tyr Thr Lys Asn Ala Asp Ile Ser 850 855 860

    Ala Arg Thr Leu Asp Tyr Ile Asn Asp Lys Val Glu Glu Asp Thr Gln 865 870 875 880

    Asp Ser Arg Met Ala Val Ile Val Thr Arg Asn Leu Lys Asp Leu Thr 885 890 895

    Tyr Val Ala Val Val Asp Glu Lys Asn Asn Val Leu Glu Glu Lys Ser 900 905 910

    Leu Asn Glu Ile Asp Gly Val Asn Tyr Arg Glu Leu Leu Lys Glu Arg 915 920 925

    Thr Lys Ile Lys Tyr His Asp Lys Thr Arg Leu Trp Gln Tyr Asp Val 930 935 940

    Ser Ser Lys Gly Leu Lys Glu Ala Tyr Val Glu Leu Ala Val Thr Gln 945 950 955 960

    Ile Ser Lys Leu Ala Thr Lys Tyr Asn Ala Val Val Val Val Glu Ser 965 970 975

    Met Ser Ser Thr Phe Lys Asp Lys Phe Ser Phe Leu Asp Glu Gln Ile 980 985 990

    Phe Lys Ala Phe Glu Ala Arg Leu Cys Ala Arg Met Ser Asp Leu Ser 995 1000 1005

    Phe Asn Thr Ile Lys Glu Gly Glu Ala Gly Ser Ile Ser Asn Pro 1010 1015 1020

    Ile Gln Val Ser Asn Asn Asn Gly Asn Ser Tyr Gln Asp Gly Val 1025 1030 1035

    Ile Tyr Phe Leu Asn Asn Ala Tyr Thr Arg Thr Leu Cys Pro Asp 1040 1045 1050

    Thr Gly Phe Val Asp Val Phe Asp Lys Thr Arg Leu Ile Thr Met 1055 1060 1065

    Gln Ser Lys Arg Gln Phe Phe Ala Lys Met Lys Asp Ile Arg Ile 1070 1075 1080

    Asp Asp Gly Glu Met Leu Phe Thr Phe Asn Leu Glu Glu Tyr Pro 1085 1090 1095

    Thr Lys Arg Leu Leu Asp Arg Lys Glu Trp Thr Val Lys Ile Ala 1100 1105 1110

    Gly Asp Gly Ser Tyr Phe Asp Lys Asp Lys Gly Glu Tyr Val Tyr 1115 1120 1125

    Val Asn Asp Ile Val Arg Glu Gln Ile Ile Pro Ala Leu Leu Glu 1130 1135 1140

    Asp Lys Ala Val Phe Asp Gly Asn Met Ala Glu Lys Phe Leu Asp

    1145

    1150

    1155

    Lys Thr Ala Ile Ser Gly Lys Ser Val Glu Leu Ile Tyr Lys Trp 1160 1165 1170

    Phe Ala Asn Ala Leu Tyr Gly Ile Ile Thr Lys Lys Asp Gly Glu 1175 1180 1185

    Lys Ile Tyr Arg Ser Pro Ile Thr Gly Thr Glu Ile Asp Val Ser 1190 1195 1200

    Lys Asn Thr Thr Tyr Asn Phe Gly Lys Lys Phe Met Phe Lys Gln 1205 1210 1215

    Glu Tyr Arg Gly Asp Gly Asp Phe Leu Asp Ala Phe Leu Asn Tyr 1220 1225 1230

    Met Gln Ala Gln Asp Ile Ala Val Lys Arg Pro Ala Ala Thr Lys 1235 1240 1245

    Lys Ala Gly Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp 1250 1255 1260

    Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr 1265 1270 1275

    Pro Tyr Asp Val Pro Asp Tyr Ala 1280 1285 <210> 233 <211> 1522 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 233

    Met Ser Asn Phe Phe Lys Asn Phe Thr Asn Leu Tyr Glu Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Asp Thr Leu Thr Asn Met 20 25 30

    Lys Asp His Leu Glu Tyr Asp Glu Lys Leu Gln Thr Phe Leu Lys Asp 35 40 45

    Gln Asn Ile Asp Asp Ala Tyr Gln Ala Leu Lys Pro Gln Phe Asp Glu 50 55 60

    Ile His Glu Glu Phe Ile Thr Asp Ser Leu Glu Ser Lys Lys Ala Lys 65 70 75 80

    Glu Ile Asp Phe Ser Glu Tyr Leu Asp Leu Phe Gln Glu Lys Lys Glu 85 90 95

    Leu Asn Asp Ser Glu Lys Lys Leu Arg Asn Lys Ile Gly Glu Thr Phe 100 105 110

    Asn Lys Ala Gly Glu Lys Trp Lys Lys Glu Lys Tyr Pro Gln Tyr Glu 115 120 125

    Trp Lys Lys Gly Ser Lys Ile Ala Asn Gly Ala Asp Ile Leu Ser Cys 130 135 140

    Gln Asp Met Leu Gln Phe Ile Lys Tyr Lys Asn Pro Glu Asp Glu Lys 145 150 155 160

    Ile Lys Asn Tyr Ile Asp Asp Thr Leu Lys Gly Phe Phe Thr Tyr Phe

    165

    170

    175

    Gly Gly Phe Asn Gln Asn Arg Ala Asn Tyr Tyr Glu Thr Lys Lys Glu 180 185 190

    Ala Ser Thr Ala Val Ala Thr Arg Ile Val His Glu Asn Leu Pro Lys 195 200 205

    Phe Cys Asp Asn Val Ile Gln Phe Lys His Ile Ile Lys Arg Lys Lys 210 215 220

    Asp Gly Thr Val Glu Lys Thr Glu Arg Lys Thr Glu Tyr Leu Asn Ala 225 230 235 240

    Tyr Gln Tyr Leu Lys Asn Asn Asn Lys Ile Thr Gln Ile Lys Asp Ala 245 250 255

    Glu Thr Glu Lys Met Ile Glu Ser Thr Pro Ile Ala Glu Lys Ile Phe 260 265 270

    Asp Val Tyr Tyr Phe Ser Ser Cys Leu Ser Gln Lys Gln Ile Glu Glu 275 280 285

    Tyr Asn Arg Ile Ile Gly His Tyr Asn Leu Leu Ile Asn Leu Tyr Asn 290 295 300

    Gln Ala Lys Arg Ser Glu Gly Lys His Leu Ser Ala Asn Glu Lys Lys 305 310 315 320

    Tyr Lys Asp Leu Pro Lys Phe Lys Thr Leu Tyr Lys Gln Ile Gly Cys 325 330 335

    Gly Lys Lys Lys Asp Leu Phe Tyr Thr Ile Lys Cys Asp Thr Glu Glu 340 345 350

    Glu Ala Asn Lys Ser Arg Asn Glu Gly Lys Glu Ser His Ser Val Glu 355 360 365

    Glu Ile Ile Asn Lys Ala Gln Glu Ala Ile Asn Lys Tyr Phe Lys Ser 370 375 380

    Asn Asn Asp Cys Glu Asn Ile Asn Thr Val Pro Asp Phe Ile Asn Tyr 385 390 395 400

    Ile Leu Thr Lys Glu Asn Tyr Glu Gly Val Tyr Trp Ser Lys Ala Ala 405 410 415

    Met Asn Thr Ile Ser Asp Lys Tyr Phe Ala Asn Tyr His Asp Leu Gln 420 425 430

    Asp Arg Leu Lys Glu Ala Lys Val Phe Gln Lys Ala Asp Lys Lys Ser 435 440 445

    Glu Asp Asp Ile Lys Ile Pro Glu Ala Ile Glu Leu Ser Gly Leu Phe 450 455 460

    Gly Val Leu Asp Ser Leu Ala Asp Trp Gln Thr Thr Leu Phe Lys Ser 465 470 475 480

    Ser Ile Leu Ser Asn Glu Asp Lys Leu Lys Ile Ile Thr Asp Ser Gln 485 490 495

    Thr Pro Ser Glu Ala Leu Leu Lys Met Ile Phe Asn Asp Ile Glu Lys 500 505 510

    Asn Met Glu Ser Phe Leu Lys Glu Thr Asn Asp Ile Ile Thr Leu Lys 515 520 525

    Lys Tyr Lys Gly Asn Lys Glu Gly Thr Glu Lys Ile Lys Gln Trp Phe 530 535 540

    Asp Tyr Thr Leu Ala Ile Asn Arg Met Leu Lys Tyr Phe Leu Val Lys 545 550 555 560

    Glu Asn Lys Ile Lys Gly Asn Ser Leu Asp Thr Asn Ile Ser Glu Ala 565 570 575

    Leu Lys Thr Leu Ile Tyr Ser Asp Asp Ala Glu Trp Phe Lys Trp Tyr 580 585 590

    Asp Ala Leu Arg Asn Tyr Leu Thr Gln Lys Pro Gln Asp Glu Ala Lys 595 600 605

    Glu Asn Lys Leu Lys Leu Asn Phe Asp Asn Pro Ser Leu Ala Gly Gly 610 615 620

    Trp Asp Val Asn Lys Glu Cys Ser Asn Phe Cys Val Ile Leu Lys Asp 625 630 635 640

    Lys Asn Glu Lys Lys Tyr Leu Ala Ile Met Lys Lys Gly Glu Asn Thr 645 650 655

    Leu Phe Gln Lys Glu Trp Thr Glu Gly Arg Gly Lys Asn Leu Thr Lys 660 665 670

    Lys Ser Asn Pro Leu Phe Glu Ile Asn Asn Cys Glu Ile Leu Ser Lys 675 680 685

    Met Glu Tyr Asp Phe Trp Ala Asp Val Ser Lys Met Ile Pro Lys Cys 690 695 700

    Ser Thr Gln Leu Lys Ala Val Val Asn His Phe Lys Gln Ser Asp Asn 705 710 715 720

    Glu Phe Ile Phe Pro Ile Gly Tyr Lys Val Thr Ser Gly Glu Lys Phe 725 730 735

    Arg Glu Glu Cys Lys Ile Ser Lys Gln Asp Phe Glu Leu Asn Asn Lys 740 745 750

    Val Phe Asn Lys Asn Glu Leu Ser Val Thr Ala Met Arg Tyr Asp Leu 755 760 765

    Ser Ser Thr Gln Glu Lys Gln Tyr Ile Lys Ala Phe Gln Lys Glu Tyr 770 775 780

    Trp Glu Leu Leu Phe Lys Gln Glu Lys Arg Asp Thr Lys Leu Thr Asn 785 790 795 800

    Asn Glu Ile Phe Asn Glu Trp Ile Asn Phe Cys Asn Lys Lys Tyr Ser 805 810 815

    Glu Leu Leu Ser Trp Glu Arg Lys Tyr Lys Asp Ala Leu Thr Asn Trp 820 825 830

    Ile Asn Phe Cys Lys Tyr Phe Leu Ser Lys Tyr Pro Lys Thr Thr Leu 835 840 845

    Phe Asn Tyr Ser Phe Lys Glu Ser Glu Asn Tyr Asn Ser Leu Asp Glu 850 855 860

    Phe Tyr Arg Asp Val Asp Ile Cys Ser Tyr Lys Leu Asn Ile Asn Thr 865 870 875 880

    Thr Ile Asn Lys Ser Ile Leu Asp Arg Leu Val Glu Glu Gly Lys Leu

    885

    890

    895

    Tyr Leu Phe Glu Ile Lys Asn Gln Asp Ser Asn Asp Gly Lys Ser Ile 900 905 910

    Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp Asn Ala Ile Phe Glu 915 920 925

    Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr 930 935 940

    Arg Lys Ala Ile Ser Lys Asp Lys Leu Gly Ile Val Lys Gly Lys Lys 945 950 955 960

    Thr Lys Asn Gly Thr Glu Ile Ile Lys Asn Tyr Arg Phe Ser Lys Glu 965 970 975

    Lys Phe Ile Leu His Val Pro Ile Thr Leu Asn Phe Cys Ser Asn Asn 980 985 990

    Glu Tyr Val Asn Asp Ile Val Asn Thr Lys Phe Tyr Asn Phe Ser Asn 995 1000 1005

    Leu His Phe Leu Gly Ile Asp Arg Gly Glu Lys His Leu Ala Tyr 1010 1015 1020

    Tyr Ser Leu Val Asn Lys Asn Gly Glu Ile Val Asp Gln Gly Thr 1025 1030 1035

    Leu Asn Leu Pro Phe Thr Asp Lys Asp Gly Asn Gln Arg Ser Ile 1040 1045 1050

    Lys Lys Glu Lys Tyr Phe Tyr Asn Lys Gln Glu Asp Lys Trp Glu 1055 1060 1065

    Ala Lys Glu Val Asp Cys Trp Asn Tyr Asn Asp Leu Leu Asp Ala 1070 1075 1080

    Met Ala Ser Asn Arg Asp Met Ala Arg Lys Asn Trp Gln Arg Ile 1085 1090 1095

    Gly Thr Ile Lys Glu Ala Lys Asn Gly Tyr Val Ser Leu Val Ile 1100 1105 1110

    Arg Lys Ile Ala Asp Leu Ala Val Asn Asn Glu Arg Pro Ala Phe 1115 1120 1125

    Ile Val Leu Glu Asp Leu Asn Thr Gly Phe Lys Arg Ser Arg Gln 1130 1135 1140

    Lys Ile Asp Lys Ser Val Tyr Gln Lys Phe Glu Leu Ala Leu Ala 1145 1150 1155

    Lys Lys Leu Asn Phe Leu Val Asp Lys Asn Ala Lys Arg Asp Glu 1160 1165 1170

    Ile Gly Ser Pro Thr Lys Ala Leu Gln Leu Thr Pro Pro Val Asn 1175 1180 1185

    Asn Tyr Gly Asp Ile Glu Asn Lys Lys Gln Ala Gly Ile Met Leu 1190 1195 1200

    Tyr Thr Arg Ala Asn Tyr Thr Ser Gln Thr Asp Pro Ala Thr Gly 1205 1210 1215

    Trp Arg Lys Thr Ile Tyr Leu Lys Ala Gly Pro Glu Glu Thr Thr 1220 1225 1230

    Tyr Lys Lys Asp Gly Lys Ile Lys Asn Lys Ser Val Lys Asp Gln 1235 1240 1245

    Ile Ile Glu Thr Phe Thr Asp Ile Gly Phe Asp Gly Lys Asp Tyr 1250 1255 1260

    Tyr Phe Glu Tyr Asp Lys Gly Glu Phe Val Asp Glu Lys Thr Gly 1265 1270 1275

    Glu Ile Lys Pro Lys Lys Trp Arg Leu Tyr Ser Gly Glu Asn Gly 1280 1285 1290

    Lys Ser Leu Asp Arg Phe Arg Gly Glu Arg Glu Lys Asp Lys Tyr 1295 1300 1305

    Glu Trp Lys Ile Asp Lys Ile Asp Ile Val Lys Ile Leu Asp Asp 1310 1315 1320

    Leu Phe Val Asn Phe Asp Lys Asn Ile Ser Leu Leu Lys Gln Leu 1325 1330 1335

    Lys Glu Gly Val Glu Leu Thr Arg Asn Asn Glu His Gly Thr Gly 1340 1345 1350

    Glu Ser Leu Arg Phe Ala Ile Asn Leu Ile Gln Gln Ile Arg Asn 1355 1360 1365

    Thr Gly Asn Asn Glu Arg Asp Asn Asp Phe Ile Leu Ser Pro Val 1370 1375 1380

    Arg Asp Glu Asn Gly Lys His Phe Asp Ser Arg Glu Tyr Trp Asp 1385 1390 1395

    Lys Glu Thr Lys Gly Glu Lys Ile Ser Met Pro Ser Ser Gly Asp 1400 1405 1410

    Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Ile Ile Met Asn 1415 1420 1425

    Ala His Ile Leu Ala Asn Ser Asp Ser Lys Asp Leu Ser Leu Phe 1430 1435 1440

    Val Ser Asp Glu Glu Trp Asp Leu His Leu Asn Asn Lys Thr Glu 1445 1450 1455

    Trp Lys Lys Gln Leu Asn Ile Phe Ser Ser Arg Lys Ala Met Ala 1460 1465 1470

    Lys Arg Lys Lys Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln 1475 1480 1485

    Ala Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr 1490 1495 1500

    Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val 1505 1510 1515

    Pro Asp Tyr Ala 1520 <210> 234 <211> 1397 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 234

    Met Glu Asn Ile Phe Asp Gln Phe Ile Gly Lys Tyr Ser Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Glu Asp Phe Leu 20 25 30

    Lys Ile Asn Lys Val Phe Glu Lys Asp Gln Thr Ile Asp Asp Ser Tyr 35 40 45

    Asn Gln Ala Lys Phe Tyr Phe Asp Ser Leu His Gln Lys Phe Ile Asp 50 55 60

    Ala Ala Leu Ala Ser Asp Lys Thr Ser Glu Leu Ser Phe Gln Asn Phe 65 70 75 80

    Ala Asp Val Leu Glu Lys Gln Asn Lys Ile Ile Leu Asp Lys Lys Arg 85 90 95

    Glu Met Gly Ala Leu Arg Lys Arg Asp Lys Asn Ala Val Gly Ile Asp 100 105 110

    Arg Leu Gln Lys Glu Ile Asn Asp Ala Glu Asp Ile Ile Gln Lys Glu 115 120 125

    Lys Glu Lys Ile Tyr Lys Asp Val Arg Thr Leu Phe Asp Asn Glu Ala 130 135 140

    Glu Ser Trp Lys Thr Tyr Tyr Gln Glu Arg Glu Val Asp Gly Lys Lys 145 150 155 160

    Ile Thr Phe Ser Lys Ala Asp Leu Lys Gln Lys Gly Ala Asp Phe Leu 165 170 175

    Thr Ala Ala Gly Ile Leu Lys Val Leu Lys Tyr Glu Phe Pro Glu Glu 180 185 190

    Lys Glu Lys Glu Phe Gln Ala Lys Asn Gln Pro Ser Leu Phe Val Glu 195 200 205

    Glu Lys Glu Asn Pro Gly Gln Lys Arg Tyr Ile Phe Asp Ser Phe Asp 210 215 220

    Lys Phe Ala Gly Tyr Leu Thr Lys Phe Gln Gln Thr Lys Lys Asn Leu 225 230 235 240

    Tyr Ala Ala Asp Gly Thr Ser Thr Ala Val Ala Thr Arg Ile Ala Asp 245 250 255

    Asn Phe Ile Ile Phe His Gln Asn Thr Lys Val Phe Arg Asp Lys Tyr 260 265 270

    Lys Asn Asn His Thr Asp Leu Gly Phe Asp Glu Glu Asn Ile Phe Glu 275 280 285

    Ile Glu Arg Tyr Lys Asn Cys Leu Leu Gln Arg Glu Ile Glu His Ile 290 295 300

    Lys Asn Glu Asn Ser Tyr Asn Lys Ile Ile Gly Arg Ile Asn Lys Lys 305 310 315 320

    Ile Lys Glu Tyr Arg Asp Gln Lys Ala Lys Asp Thr Lys Leu Thr Lys 325 330 335

    Ser Asp Phe Pro Phe Phe Lys Asn Leu Asp Lys Gln Ile Leu Gly Glu 340 345 350

    Val Glu Lys Glu Lys Gln Leu Ile Glu Lys Thr Arg Glu Lys Thr Glu

    355

    360

    365

    Glu Asp Val Leu Ile Glu Arg Phe Lys Glu Phe Ile Glu Asn Asn Glu 370 375 380

    Glu Arg Phe Thr Ala Ala Lys Lys Leu Met Asn Ala Phe Cys Asn Gly 385 390 395 400

    Glu Phe Glu Ser Glu Tyr Glu Gly Ile Tyr Leu Lys Asn Lys Ala Ile 405 410 415

    Asn Thr Ile Ser Arg Arg Trp Phe Val Ser Asp Arg Asp Phe Glu Leu 420 425 430

    Lys Leu Pro Gln Gln Lys Ser Lys Asn Lys Ser Glu Lys Asn Glu Pro 435 440 445

    Lys Val Lys Lys Phe Ile Ser Ile Ala Glu Ile Lys Asn Ala Val Glu 450 455 460

    Glu Leu Asp Gly Asp Ile Phe Lys Ala Val Phe Tyr Asp Lys Lys Ile 465 470 475 480

    Ile Ala Gln Gly Gly Ser Lys Leu Glu Gln Phe Leu Val Ile Trp Lys 485 490 495

    Tyr Glu Phe Glu Tyr Leu Phe Arg Asp Ile Glu Arg Glu Asn Gly Glu 500 505 510

    Lys Leu Leu Gly Tyr Asp Ser Cys Leu Lys Ile Ala Lys Gln Leu Gly 515 520 525

    Ile Phe Pro Gln Glu Lys Glu Ala Arg Glu Lys Ala Thr Ala Val Ile 530 535 540

    Lys Asn Tyr Ala Asp Ala Gly Leu Gly Ile Phe Gln Met Met Lys Tyr 545 550 555 560

    Phe Ser Leu Asp Asp Lys Asp Arg Lys Asn Thr Pro Gly Gln Leu Ser 565 570 575

    Thr Asn Phe Tyr Ala Glu Tyr Asp Gly Tyr Tyr Lys Asp Phe Glu Phe 580 585 590

    Ile Lys Tyr Tyr Asn Glu Phe Arg Asn Phe Ile Thr Lys Lys Pro Phe 595 600 605

    Asp Glu Asp Lys Ile Lys Leu Asn Phe Glu Asn Gly Ala Leu Leu Lys 610 615 620

    Gly Trp Asp Glu Asn Lys Glu Tyr Asp Phe Met Gly Val Ile Leu Lys 625 630 635 640

    Lys Glu Gly Arg Leu Tyr Leu Gly Ile Met His Lys Asn His Arg Lys 645 650 655

    Leu Phe Gln Ser Met Gly Asn Ala Lys Gly Asp Asn Ala Asn Arg Tyr 660 665 670

    Gln Lys Met Ile Tyr Lys Gln Ile Ala Asp Ala Ser Lys Asp Val Pro 675 680 685

    Arg Leu Leu Leu Thr Ser Lys Lys Ala Met Glu Lys Phe Lys Pro Ser 690 695 700

    Gln Glu Ile Leu Arg Ile Lys Lys Glu Lys Thr Phe Lys Arg Glu Ser 705 710 715 720

    Lys Asn Phe Ser Leu Arg Asp Leu His Ala Leu Ile Glu Tyr Tyr Arg 725 730 735

    Asn Cys Ile Pro Gln Tyr Ser Asn Trp Ser Phe Tyr Asp Phe Gln Phe 740 745 750

    Gln Asp Thr Gly Lys Tyr Gln Asn Ile Lys Glu Phe Thr Asp Asp Val 755 760 765

    Gln Lys Tyr Gly Tyr Lys Ile Ser Phe Arg Asp Ile Asp Asp Glu Tyr 770 775 780

    Ile Asn Gln Ala Leu Asn Glu Gly Lys Met Tyr Leu Phe Glu Val Val 785 790 795 800

    Asn Lys Asp Ile Tyr Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr 805 810 815

    Leu Tyr Phe Glu His Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val 820 825 830

    Phe Lys Leu Ser Gly Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val 835 840 845

    Asn Glu Arg Glu Lys Ile Thr Thr Gln Lys Asn Gln Cys Ile Leu Asp 850 855 860

    Lys Gly Asp Arg Ala Tyr Lys Tyr Arg Arg Tyr Thr Glu Lys Lys Ile 865 870 875 880

    Met Phe His Met Ser Leu Val Leu Asn Thr Gly Lys Gly Glu Ile Lys 885 890 895

    Gln Val Gln Phe Asn Lys Ile Ile Asn Gln Arg Ile Ser Ser Ser Asp 900 905 910

    Asn Glu Met Arg Val Asn Val Ile Gly Ile Asp Arg Gly Glu Lys Asn 915 920 925

    Leu Leu Tyr Tyr Ser Val Val Lys Gln Asn Gly Glu Ile Ile Glu Gln 930 935 940

    Ala Ser Leu Asn Glu Ile Asn Gly Val Asn Tyr Arg Asp Lys Leu Ile 945 950 955 960

    Glu Arg Glu Lys Glu Arg Leu Lys Asn Arg Gln Ser Trp Lys Pro Val 965 970 975

    Val Lys Ile Lys Asp Leu Lys Lys Gly Tyr Ile Ser His Val Ile His 980 985 990

    Lys Ile Cys Gln Leu Ile Glu Lys Tyr Ser Ala Ile Val Val Leu Glu 995 1000 1005

    Asp Leu Asn Met Arg Phe Lys Gln Ile Arg Gly Gly Ile Glu Arg 1010 1015 1020

    Ser Val Tyr Gln Gln Phe Glu Lys Ala Leu Ile Asp Lys Leu Gly 1025 1030 1035

    Tyr Leu Val Phe Lys Asp Asn Arg Asp Leu Arg Ala Pro Gly Gly 1040 1045 1050

    Val Leu Asn Gly Tyr Gln Leu Ser Ala Pro Phe Val Ser Phe Glu 1055 1060 1065

    Lys Met Arg Lys Gln Thr Gly Ile Leu Phe Tyr Thr Gln Ala Glu

    1070

    1075

    1080

    Tyr Thr Ser Lys Thr Asp Pro Ile Thr Gly Phe Arg Lys Asn Val 1085 1090 1095

    Tyr Ile Ser Asn Ser Ala Ser Leu Asp Lys Ile Lys Glu Ala Val 1100 1105 1110

    Lys Lys Phe Asp Ala Ile Gly Trp Asp Gly Lys Glu Gln Ser Tyr 1115 1120 1125

    Phe Phe Lys Tyr Asn Pro Tyr Asn Leu Ala Asp Glu Lys Tyr Lys 1130 1135 1140

    Asn Ser Thr Val Ser Lys Glu Trp Ala Ile Phe Ala Ser Ala Pro 1145 1150 1155

    Arg Ile Arg Arg Gln Lys Gly Glu Asp Gly Tyr Trp Lys Tyr Asp 1160 1165 1170

    Arg Val Lys Val Asn Glu Glu Phe Glu Lys Leu Leu Lys Val Trp 1175 1180 1185

    Asn Phe Val Asn Pro Lys Ala Thr Asp Ile Lys Gln Glu Ile Ile 1190 1195 1200

    Lys Lys Glu Lys Ala Gly Asp Leu Gln Gly Glu Lys Glu Leu Asp 1205 1210 1215

    Gly Arg Leu Arg Asn Phe Trp His Ser Phe Ile Tyr Leu Phe Asn 1220 1225 1230

    Leu Val Leu Glu Leu Arg Asn Ser Phe Ser Leu Gln Ile Lys Ile 1235 1240 1245

    Lys Ala Gly Glu Val Ile Ala Val Asp Glu Gly Val Asp Phe Ile 1250 1255 1260

    Ala Ser Pro Val Lys Pro Phe Phe Thr Thr Pro Asn Pro Tyr Ile 1265 1270 1275

    Pro Ser Asn Leu Cys Trp Leu Ala Val Glu Asn Ala Asp Ala Asn 1280 1285 1290

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Val Met Ile Leu Lys Lys 1295 1300 1305

    Ile Arg Glu His Ala Lys Lys Asp Pro Glu Phe Lys Lys Leu Pro 1310 1315 1320

    Asn Leu Phe Ile Ser Asn Ala Glu Trp Asp Glu Ala Ala Arg Asp 1325 1330 1335

    Trp Gly Lys Tyr Ala Gly Thr Thr Ala Leu Asn Leu Asp His Lys 1340 1345 1350

    Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys 1355 1360 1365

    Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp 1370 1375 1380

    Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala

    1385 1390 1395 <210> 235 <211> 1295 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 235

    Met Gln Thr Leu Phe Glu Asn Phe Thr Asn Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Lys Asp Phe Ile 20 25 30

    Glu Gln Lys Gly Leu Leu Lys Lys Asp Glu Asp Arg Ala Glu Lys Tyr 35 40 45

    Lys Lys Val Lys Asn Ile Ile Asp Glu Tyr His Lys Asp Phe Ile Glu 50 55 60

    Lys Ser Leu Asn Gly Leu Lys Leu Asp Gly Leu Glu Lys Tyr Lys Thr 65 70 75 80

    Leu Tyr Leu Lys Gln Glu Lys Asp Asp Lys Asp Lys Lys Ala Phe Asp 85 90 95

    Lys Glu Lys Glu Asn Leu Arg Lys Gln Ile Ala Asn Ala Phe Arg Asn 100 105 110

    Asn Glu Lys Phe Lys Thr Leu Phe Ala Lys Glu Leu Ile Lys Asn Asp 115 120 125

    Leu Met Ser Phe Ala Cys Glu Glu Asp Lys Lys Asn Val Lys Glu Phe 130 135 140

    Glu Ala Phe Thr Thr Tyr Phe Thr Gly Phe His Gln Asn Arg Ala Asn 145 150 155 160

    Met Tyr Val Ala Asp Glu Lys Arg Thr Ala Ile Ala Ser Arg Leu Ile 165 170 175

    His Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe Glu Lys 180 185 190

    Met Lys Lys Glu Ala Pro Glu Leu Leu Ser Pro Phe Asn Gln Thr Leu 195 200 205

    Lys Asp Met Lys Asp Val Ile Lys Gly Thr Thr Leu Glu Glu Ile Phe 210 215 220

    Ser Leu Asp Tyr Phe Asn Lys Thr Leu Thr Gln Ser Gly Ile Asp Ile 225 230 235 240

    Tyr Asn Ser Val Ile Gly Gly Arg Thr Pro Glu Glu Gly Lys Thr Lys 245 250 255

    Ile Lys Gly Leu Asn Glu Tyr Ile Asn Thr Asp Phe Asn Gln Lys Gln 260 265 270

    Thr Asp Lys Lys Lys Arg Gln Pro Lys Phe Lys Gln Leu Tyr Lys Gln 275 280 285

    Ile Leu Ser Asp Arg Gln Ser Leu Ser Phe Ile Ala Glu Ala Phe Lys 290 295 300

    Asn Asp Thr Glu Ile Leu Glu Ala Ile Glu Lys Phe Tyr Val Asn Glu 305 310 315 320

    Leu Leu His Phe Ser Asn Glu Gly Lys Ser Thr Asn Val Leu Asp Ala 325 330 335

    Ile Lys Asn Ala Val Ser Asn Leu Glu Ser Phe Asn Leu Thr Lys Met 340 345 350

    Tyr Phe Arg Ser Gly Ala Ser Leu Thr Asp Val Ser Arg Lys Val Phe 355 360 365

    Gly Glu Trp Ser Ile Ile Asn Arg Ala Leu Asp Asn Tyr Tyr Ala Thr 370 375 380

    Thr Tyr Pro Ile Lys Pro Arg Glu Lys Ser Glu Lys Tyr Glu Glu Arg 385 390 395 400

    Lys Glu Lys Trp Leu Lys Gln Asp Phe Asn Val Ser Leu Ile Gln Thr 405 410 415

    Ala Ile Asp Glu Tyr Asp Asn Glu Thr Val Lys Gly Lys Asn Ser Gly 420 425 430

    Lys Val Ile Ala Asp Tyr Phe Ala Lys Phe Cys Asp Asp Lys Glu Thr 435 440 445

    Asp Leu Ile Gln Lys Val Asn Glu Gly Tyr Ile Ala Val Lys Asp Leu 450 455 460

    Leu Asn Thr Pro Cys Pro Glu Asn Glu Lys Leu Gly Ser Asn Lys Asp 465 470 475 480

    Gln Val Lys Gln Ile Lys Ala Phe Met Asp Ser Ile Met Asp Ile Met 485 490 495

    His Phe Val Arg Pro Leu Ser Leu Lys Asp Thr Asp Lys Glu Lys Asp 500 505 510

    Glu Thr Phe Tyr Ser Leu Phe Thr Pro Leu Tyr Asp His Leu Thr Gln 515 520 525

    Thr Ile Ala Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu 545 550 555 560

    Gly Gly Trp Asp Leu Asn Lys Glu Thr Asp Asn Thr Ala Ile Ile Leu 565 570 575

    Arg Lys Asp Asn Leu Tyr Tyr Leu Gly Ile Met Asp Lys Arg His Asn 580 585 590

    Arg Ile Phe Arg Asn Val Pro Lys Ala Asp Lys Lys Asp Phe Cys Tyr 595 600 605

    Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro 610 615 620

    Lys Val Phe Phe Ser Gln Ser Arg Ile Gln Glu Phe Thr Pro Ser Ala 625 630 635 640

    Lys Leu Leu Glu Asn Tyr Ala Asn Glu Thr His Lys Lys Gly Asp Asn 645 650 655

    Phe Asn Leu Asn His Cys His Lys Leu Ile Asp Phe Phe Lys Asp Ser 660 665 670

    Ile Asn Lys His Glu Asp Trp Lys Asn Phe Asp Phe Arg Phe Ser Ala 675 680 685

    Thr Ser Thr Tyr Ala Asp Leu Ser Gly Phe Tyr His Glu Val Glu His

    690

    695

    700

    Gln Gly Tyr Lys Ile Ser Phe Gln Ser Val Ala Asp Ser Phe Ile Asp 705 710 715 720

    Asp Leu Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 725 730 735

    Asp Phe Ser Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr 740 745 750

    Trp Lys Met Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys 755 760 765

    Leu Asn Gly Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala Glu 770 775 780

    Lys Asn Thr Thr Ile His Lys Ala Asn Glu Ser Ile Ile Asn Lys Asn 785 790 795 800

    Pro Asp Asn Pro Lys Ala Thr Ser Thr Phe Asn Tyr Asp Ile Val Lys 805 810 815

    Asp Lys Arg Tyr Thr Ile Asp Lys Phe Gln Phe His Ile Pro Ile Thr 820 825 830

    Met Asn Phe Lys Ala Glu Gly Ile Phe Asn Met Asn Gln Arg Val Asn 835 840 845

    Gln Phe Leu Lys Ala Asn Pro Asp Ile Asn Ile Ile Gly Ile Asp Arg 850 855 860

    Gly Glu Arg His Leu Leu Tyr Tyr Ala Leu Ile Asn Gln Lys Gly Lys 865 870 875 880

    Ile Leu Lys Gln Asp Thr Leu Asn Val Ile Ala Asn Glu Lys Gln Lys 885 890 895

    Val Asp Tyr His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr 900 905 910

    Ala Arg Gln Glu Trp Gly Val Ile Glu Thr Ile Lys Glu Leu Lys Glu 915 920 925

    Gly Tyr Leu Ser Gln Val Ile His Lys Leu Thr Asp Leu Met Ile Glu 930 935 940

    Asn Asn Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe Lys Arg 945 950 955 960

    Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met 965 970 975

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Lys Ala Asn 980 985 990

    Glu Leu Gly Gly Leu Leu Asn Ala Phe Gln Leu Ala Asn Lys Phe Glu 995 1000 1005

    Ser Phe Gln Lys Met Gly Lys Gln Asn Gly Phe Ile Phe Tyr Val 1010 1015 1020

    Pro Ala Trp Asn Thr Ser Lys Thr Asp Pro Ala Thr Gly Phe Ile 1025 1030 1035

    Asp Phe Leu Lys Pro Arg Tyr Glu Asn Leu Asn Gln Ala Lys Asp 1040 1045 1050

    Phe Phe Glu Lys Phe Asp Ser Ile Arg Leu Asn Ser Lys Ala Asp 1055 1060 1065

    Tyr Phe Glu Phe Ala Phe Asp Phe Lys Asn Phe Thr Glu Lys Ala 1070 1075 1080

    Asp Gly Gly Arg Thr Lys Trp Thr Val Cys Thr Thr Asn Glu Asp 1085 1090 1095

    Arg Tyr Ala Trp Asn Arg Ala Leu Asn Asn Asn Arg Gly Ser Gln 1100 1105 1110

    Glu Lys Tyr Asp Ile Thr Ala Glu Leu Lys Ser Leu Phe Asp Gly 1115 1120 1125

    Lys Val Asp Tyr Lys Ser Gly Lys Asp Leu Lys Gln Gln Ile Ala 1130 1135 1140

    Ser Gln Glu Ser Ala Asp Phe Phe Lys Ala Leu Met Lys Asn Leu 1145 1150 1155

    Ser Ile Thr Leu Ser Leu Arg His Asn Asn Gly Glu Lys Gly Asp 1160 1165 1170

    Asn Glu Gln Asp Tyr Ile Leu Ser Pro Val Ala Asp Ser Lys Gly 1175 1180 1185

    Arg Phe Phe Asp Ser Arg Lys Ala Asp Asp Asp Met Pro Lys Asn 1190 1195 1200

    Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Trp 1205 1210 1215

    Cys Leu Glu Gln Ile Ser Lys Thr Asp Asp Leu Lys Lys Val Lys 1220 1225 1230

    Leu Ala Ile Ser Asn Lys Glu Trp Leu Glu Phe Val Gln Thr Leu 1235 1240 1245

    Lys Gly Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys 1250 1255 1260

    Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr 1265 1270 1275

    Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp 1280 1285 1290

    Tyr Ala 1295 <210> 236 <211> 1352 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 236

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu

    405

    410

    415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln 865 870 875 880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu 930 935 940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly 1025 1030 1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly

    1115

    1120

    1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn 1130 1135 1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu 1205 1210 1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn Lys 1295 1300 1305

    Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys 1310 1315 1320

    Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp 1325 1330 1335

    Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1340 1345 1350 <210> 237 <211> 1251 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 237

    Met Tyr Tyr Glu Ser Leu Thr Lys Gln Tyr Pro Val Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Ile Pro Ile Gly Lys Thr Leu Asp Asn Ile Arg Gln 20 25 30

    Asn Asn Ile Leu Glu Ser Asp Val Lys Arg Lys Gln Asn Tyr Glu His 35 40 45

    Val Lys Gly Ile Leu Asp Glu Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Cys Thr Leu Pro Ser Leu Lys Ile Ala Ala Glu Ile Tyr

    Leu Lys Asn Gln Lys Glu Val Ser Asp Arg Glu Asp Phe Asn Lys Thr 85 90 95

    Gln Asp Leu Leu Arg Lys Glu Val Val Glu Lys Leu Lys Ala His Glu 100 105 110

    Asn Phe Thr Lys Ile Gly Lys Lys Asp Ile Leu Asp Leu Leu Glu Lys 115 120 125

    Leu Pro Ser Ile Ser Glu Asp Asp Tyr Asn Ala Leu Glu Ser Phe Arg 130 135 140

    Asn Phe Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Glu Asn Leu 145 150 155 160

    Tyr Ser Asp Lys Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn 165 170 175

    Glu Asn Phe Pro Lys Phe Leu Asp Asn Val Lys Ser Tyr Arg Phe Val 180 185 190

    Lys Thr Ala Gly Ile Leu Ala Asp Gly Leu Gly Glu Glu Glu Gln Asp 195 200 205

    Ser Leu Phe Ile Val Glu Thr Phe Asn Lys Thr Leu Thr Gln Asp Gly 210 215 220

    Ile Asp Thr Tyr Asn Ser Gln Val Gly Lys Ile Asn Ser Ser Ile Asn 225 230 235 240

    Leu Tyr Asn Gln Lys Asn Gln Lys Ala Asn Gly Phe Arg Lys Ile Pro 245 250 255

    Lys Met Lys Met Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ser 260 265 270

    Phe Ile Asp Glu Phe Gln Ser Asp Glu Val Leu Ile Asp Asn Val Glu 275 280 285

    Ser Tyr Gly Ser Val Leu Ile Glu Ser Leu Lys Ser Ser Lys Val Ser 290 295 300

    Ala Phe Phe Asp Ala Leu Arg Glu Ser Lys Gly Lys Asn Val Tyr Val 305 310 315 320

    Lys Asn Asp Leu Ala Lys Thr Ala Met Ser Asn Ile Val Phe Glu Asn 325 330 335

    Trp Arg Thr Phe Asp Asp Leu Leu Asn Gln Glu Tyr Asp Leu Ala Asn 340 345 350

    Glu Asn Lys Lys Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Glu 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Ser Leu Glu His Leu Cys Asn Leu Ser 370 375 380

    Glu Asp Ser Cys Asn Leu Ile Glu Asn Tyr Ile His Gln Ile Ser Asp 385 390 395 400

    Asp Ile Glu Asn Ile Ile Ile Asn Asn Glu Thr Phe Leu Arg Ile Val 405 410 415

    Ile Asn Glu His Asp Arg Ser Arg Lys Leu Ala Lys Asn Arg Lys Ala 420 425 430

    Val Lys Ala Ile Lys Asp Phe Leu Asp Ser Ile Lys Val Leu Glu Arg 435 440 445

    Glu Leu Lys Leu Ile Asn Ser Ser Gly Gln Glu Leu Glu Lys Asp Leu 450 455 460

    Ile Val Tyr Ser Ala His Glu Glu Leu Leu Val Glu Leu Lys Gln Val 465 470 475 480

    Asp Ser Leu Tyr Asn Met Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe 485 490 495

    Ser Thr Glu Lys Val Lys Leu Asn Phe Asn Arg Ser Thr Leu Leu Asn 500 505 510

    Gly Trp Asp Arg Asn Lys Glu Thr Asp Asn Leu Gly Val Leu Leu Leu 515 520 525

    Lys Asp Gly Lys Tyr Tyr Leu Gly Ile Met Asn Thr Ser Ala Asn Lys 530 535 540

    Ala Phe Val Asn Pro Pro Val Ala Lys Thr Glu Lys Val Phe Lys Lys 545 550 555 560

    Val Asp Tyr Lys Leu Leu Pro Val Pro Asn Gln Met Leu Pro Lys Val 565 570 575

    Phe Phe Ala Lys Ser Asn Ile Asp Phe Tyr Asn Pro Ser Ser Glu Ile 580 585 590

    Tyr Ser Asn Tyr Lys Lys Gly Thr His Lys Lys Gly Asn Met Phe Ser 595 600 605

    Leu Glu Asp Cys His Asn Leu Ile Asp Phe Phe Lys Glu Ser Ile Ser 610 615 620

    Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser Asp Thr Ala 625 630 635 640

    Ser Tyr Asn Asp Ile Ser Glu Phe Tyr Arg Glu Val Glu Lys Gln Gly 645 650 655

    Tyr Lys Leu Thr Tyr Thr Asp Ile Asp Glu Thr Tyr Ile Asn Asp Leu 660 665 670

    Ile Glu Arg Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 675 680 685

    Ser Met Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met 690 695 700

    Met Leu Phe Asp Gln Arg Asn Ile Asp Asp Val Val Tyr Lys Leu Asn 705 710 715 720

    Gly Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ser Glu Asp Glu 725 730 735

    Leu Ile Ile His Lys Ala Gly Glu Glu Ile Lys Asn Lys Asn Pro Asn 740 745 750

    Arg Ala Arg Thr Lys Glu Thr Ser Thr Phe Ser Tyr Asp Ile Val Lys 755 760 765

    Asp Lys Arg Tyr Ser Lys Asp Lys Phe Thr Leu His Ile Pro Ile Thr 770 775 780

    Met Asn Phe Gly Val Asp Glu Val Lys Arg Phe Asn Asp Ala Val Asn

    785

    790

    795

    800

    Ser Ala Ile Arg Ile Asp Glu Asn Val Asn Val Ile Gly Ile Asp Arg 805 810 815

    Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asp Ser Lys Gly Asn 820 825 830

    Ile Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Lys Glu Tyr Asp 835 840 845

    Ile Glu Thr Asp Tyr His Ala Leu Leu Asp Glu Arg Glu Gly Gly Arg 850 855 860

    Asp Lys Ala Arg Lys Asp Trp Asn Thr Val Glu Asn Ile Arg Asp Leu 865 870 875 880

    Lys Ala Gly Tyr Leu Ser Gln Val Val Asn Val Val Ala Lys Leu Val 885 890 895

    Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe 900 905 910

    Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 915 920 925

    Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg 930 935 940

    Glu Gln Thr Ser Pro Lys Glu Leu Gly Gly Ala Leu Asn Ala Leu Gln 945 950 955 960

    Leu Thr Ser Lys Phe Lys Ser Phe Lys Glu Leu Gly Lys Gln Ser Gly 965 970 975

    Val Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr 980 985 990

    Thr Gly Phe Ala Asn Leu Phe Tyr Met Lys Cys Glu Asn Val Glu Lys 995 1000 1005

    Ser Lys Arg Phe Phe Asp Gly Phe Asp Phe Ile Arg Phe Asn Ala 1010 1015 1020

    Leu Glu Asn Val Phe Glu Phe Gly Phe Asp Tyr Arg Ser Phe Thr 1025 1030 1035

    Gln Arg Ala Cys Gly Ile Asn Ser Lys Trp Thr Val Cys Thr Asn 1040 1045 1050

    Gly Glu Arg Ile Ile Lys Tyr Arg Asn Pro Asp Lys Asn Asn Met 1055 1060 1065

    Phe Asp Glu Lys Val Val Val Val Thr Asp Glu Met Lys Asn Leu 1070 1075 1080

    Phe Glu Gln Tyr Lys Ile Pro Tyr Glu Asp Gly Arg Asn Val Lys 1085 1090 1095

    Asp Met Ile Ile Ser Asn Glu Glu Ala Glu Phe Tyr Arg Arg Leu 1100 1105 1110

    Tyr Arg Leu Leu Gln Gln Thr Leu Gln Met Arg Asn Ser Thr Ser 1115 1120 1125

    Asp Gly Thr Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Lys Arg 1130 1135 1140

    Glu Ala Tyr Phe Asn Ser Glu Leu Ser Asp Gly Ser Val Pro Lys 1145 1150 1155

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1160 1165 1170

    Trp Val Leu Glu Gln Ile Arg Gln Lys Ser Glu Gly Glu Lys Ile 1175 1180 1185

    Asn Leu Ala Met Thr Asn Ala Glu Trp Leu Glu Tyr Ala Gln Thr 1190 1195 1200

    His Leu Leu Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala 1205 1210 1215

    Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1220 1225 1230

    Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro 1235 1240 1245

    Asp Tyr Ala 1250 <210> 238 <211> 1283 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 238

    Met Asn Asn Tyr Asp Glu Phe Thr Lys Leu Tyr Pro Ile Gln Lys Thr

    1 5 10 15

    Ile Arg Phe Glu Leu Lys Pro Gln Gly Arg Thr Met Glu His Leu Glu 20 25 30

    Thr Phe Asn Phe Phe Glu Glu Asp Arg Asp Arg Ala Glu Lys Tyr Lys 35 40 45

    Ile Leu Lys Glu Ala Ile Asp Glu Tyr His Lys Lys Phe Ile Asp Glu 50 55 60

    His Leu Thr Asn Met Ser Leu Asp Trp Asn Ser Leu Lys Gln Ile Ser 65 70 75 80

    Glu Lys Tyr Tyr Lys Ser Arg Glu Glu Lys Asp Lys Lys Val Phe Leu 85 90 95

    Ser Glu Gln Lys Arg Met Arg Gln Glu Ile Val Ser Glu Phe Lys Lys 100 105 110

    Asp Asp Arg Phe Lys Asp Leu Phe Ser Lys Lys Leu Phe Ser Glu Leu 115 120 125

    Leu Lys Glu Glu Ile Tyr Lys Lys Gly Asn His Gln Glu Ile Asp Ala 130 135 140

    Leu Lys Ser Phe Asp Lys Phe Ser Gly Tyr Phe Ile Gly Leu His Glu 145 150 155 160

    Asn Arg Lys Asn Met Tyr Ser Asp Gly Asp Glu Ile Thr Ala Ile Ser 165 170 175

    Asn Arg Ile Val Asn Glu Asn Phe Pro Lys Phe Leu Asp Asn Leu Gln 180 185 190

    Lys Tyr Gln Glu Ala Arg Lys Lys Tyr Pro Glu Trp Ile Ile Lys Ala 195 200 205

    Glu Ser Ala Leu Val Ala His Asn Ile Lys Met Asp Glu Val Phe Ser 210 215 220

    Leu Glu Tyr Phe Asn Lys Val Leu Asn Gln Glu Gly Ile Gln Arg Tyr 225 230 235 240

    Asn Leu Ala Leu Gly Gly Tyr Val Thr Lys Ser Gly Glu Lys Met Met 245 250 255

    Gly Leu Asn Asp Ala Leu Asn Leu Ala His Gln Ser Glu Lys Ser Ser 260 265 270

    Lys Gly Arg Ile His Met Thr Pro Leu Phe Lys Gln Ile Leu Ser Glu 275 280 285

    Lys Glu Ser Phe Ser Tyr Ile Pro Asp Val Phe Thr Glu Asp Ser Gln 290 295 300

    Leu Leu Pro Ser Ile Gly Gly Phe Phe Ala Gln Ile Glu Asn Asp Lys 305 310 315 320

    Asp Gly Asn Ile Phe Asp Arg Ala Leu Glu Leu Ile Ser Ser Tyr Ala 325 330 335

    Glu Tyr Asp Thr Glu Arg Ile Tyr Ile Arg Gln Ala Asp Ile Asn Arg 340 345 350

    Val Ser Asn Val Ile Phe Gly Glu Trp Gly Thr Leu Gly Gly Leu Met 355 360 365

    Arg Glu Tyr Lys Ala Asp Ser Ile Asn Asp Ile Asn Leu Glu Arg Thr 370 375 380

    Cys Lys Lys Val Asp Lys Trp Leu Asp Ser Lys Glu Phe Ala Leu Ser 385 390 395 400

    Asp Val Leu Glu Ala Ile Lys Arg Thr Gly Asn Asn Asp Ala Phe Asn 405 410 415

    Glu Tyr Ile Ser Lys Met Arg Thr Ala Arg Glu Lys Ile Asp Ala Ala 420 425 430

    Arg Lys Glu Met Lys Phe Ile Ser Glu Lys Ile Ser Gly Asp Glu Glu 435 440 445

    Ser Ile His Ile Ile Lys Thr Leu Leu Asp Ser Val Gln Gln Phe Leu 450 455 460

    His Phe Phe Asn Leu Phe Lys Ala Arg Gln Asp Ile Pro Leu Asp Gly 465 470 475 480

    Ala Phe Tyr Ala Glu Phe Asp Glu Val His Ser Lys Leu Phe Ala Ile 485 490 495

    Val Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Lys Asn Asn Leu 500 505 510

    Asn Thr Lys Lys Ile Lys Leu Asn Phe Lys Asn Pro Thr Leu Ala Asn 515 520 525

    Gly Trp Asp Gln Asn Lys Val Tyr Asp Tyr Ala Ser Leu Ile Phe Leu 530 535 540

    Arg Asp Gly Asn Tyr Tyr Leu Gly Ile Ile Asn Pro Lys Arg Lys Lys

    545

    550

    555

    560

    Asn Ile Lys Phe Glu Gln Gly Ser Gly Asn Gly Pro Phe Tyr Arg Lys 565 570 575

    Met Val Tyr Lys Gln Ile Pro Gly Pro Asn Lys Asn Leu Pro Arg Val 580 585 590

    Phe Leu Thr Ser Thr Lys Gly Lys Lys Glu Tyr Lys Pro Ser Lys Glu 595 600 605

    Ile Ile Glu Gly Tyr Glu Ala Asp Lys His Ile Arg Gly Asp Lys Phe 610 615 620

    Asp Leu Asp Phe Cys His Lys Leu Ile Asp Phe Phe Lys Glu Ser Ile 625 630 635 640

    Glu Lys His Lys Asp Trp Ser Lys Phe Asn Phe Tyr Phe Ser Pro Thr 645 650 655

    Glu Ser Tyr Gly Asp Ile Ser Glu Phe Tyr Leu Asp Val Glu Lys Gln 660 665 670

    Gly Tyr Arg Met His Phe Glu Asn Ile Ser Ala Glu Thr Ile Asp Glu 675 680 685

    Tyr Val Glu Lys Gly Asp Leu Phe Leu Phe Gln Ile Tyr Asn Lys Asp 690 695 700

    Phe Val Lys Ala Ala Thr Gly Lys Lys Asp Met His Thr Ile Tyr Trp 705 710 715 720

    Asn Ala Ala Phe Ser Pro Glu Asn Leu Gln Asp Val Val Val Lys Leu 725 730 735

    Asn Gly Glu Ala Glu Leu Phe Tyr Arg Asp Lys Ser Asp Ile Lys Glu 740 745 750

    Ile Val His Arg Glu Gly Glu Ile Leu Val Asn Arg Thr Tyr Asn Gly 755 760 765

    Arg Thr Pro Val Pro Asp Lys Ile His Lys Lys Leu Thr Asp Tyr His 770 775 780

    Asn Gly Arg Thr Lys Asp Leu Gly Glu Ala Lys Glu Tyr Leu Asp Lys 785 790 795 800

    Val Arg Tyr Phe Lys Ala His Tyr Asp Ile Thr Lys Asp Arg Arg Tyr 805 810 815

    Leu Asn Asp Lys Ile Tyr Phe His Val Pro Leu Thr Leu Asn Phe Lys 820 825 830

    Ala Asn Gly Lys Lys Asn Leu Asn Lys Met Val Ile Glu Lys Phe Leu 835 840 845

    Ser Asp Glu Lys Ala His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn 850 855 860

    Leu Leu Tyr Tyr Ser Ile Ile Asp Arg Ser Gly Lys Ile Ile Asp Gln 865 870 875 880

    Gln Ser Leu Asn Val Ile Asp Gly Phe Asp Tyr Arg Glu Lys Leu Asn 885 890 895

    Gln Arg Glu Ile Glu Met Lys Asp Ala Arg Gln Ser Trp Asn Ala Ile 900 905 910

    Gly Lys Ile Lys Asp Leu Lys Glu Gly Tyr Leu Ser Lys Ala Val His 915 920 925

    Glu Ile Thr Lys Met Ala Ile Gln Tyr Asn Ala Ile Val Val Met Glu 930 935 940

    Glu Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln 945 950 955 960

    Ile Tyr Gln Lys Phe Glu Asn Met Leu Ile Asp Lys Met Asn Tyr Leu 965 970 975

    Val Phe Lys Asp Ala Pro Asp Glu Ser Pro Gly Gly Val Leu Asn Ala 980 985 990

    Tyr Gln Leu Thr Asn Pro Leu Glu Ser Phe Ala Lys Leu Gly Lys Gln 995 1000 1005

    Thr Gly Ile Leu Phe Tyr Val Pro Ala Ala Tyr Thr Ser Lys Ile 1010 1015 1020

    Asp Pro Thr Thr Gly Phe Val Asn Leu Phe Asn Thr Ser Ser Lys 1025 1030 1035

    Thr Asn Ala Gln Glu Arg Lys Glu Phe Leu Gln Lys Phe Glu Ser 1040 1045 1050

    Ile Ser Tyr Ser Ala Lys Asp Gly Gly Ile Phe Ala Phe Ala Phe 1055 1060 1065

    Asp Tyr Arg Lys Phe Gly Thr Ser Lys Thr Asp His Lys Asn Val 1070 1075 1080

    Trp Thr Ala Tyr Thr Asn Gly Glu Arg Met Arg Tyr Ile Lys Glu 1085 1090 1095

    Lys Lys Arg Asn Glu Leu Phe Asp Pro Ser Lys Glu Ile Lys Glu 1100 1105 1110

    Ala Leu Thr Ser Ser Gly Ile Lys Tyr Asp Gly Gly Gln Asn Ile 1115 1120 1125

    Leu Pro Asp Ile Leu Arg Ser Asn Asn Asn Gly Leu Ile Tyr Thr 1130 1135 1140

    Met Tyr Ser Ser Phe Ile Ala Ala Ile Gln Met Arg Val Tyr Asp 1145 1150 1155

    Gly Lys Glu Asp Tyr Ile Ile Ser Pro Ile Lys Asn Ser Lys Gly 1160 1165 1170

    Glu Phe Phe Arg Thr Asp Pro Lys Arg Arg Glu Leu Pro Ile Asp 1175 1180 1185

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Arg Gly Glu Leu 1190 1195 1200

    Thr Met Arg Ala Ile Ala Glu Lys Phe Asp Pro Asp Ser Glu Lys 1205 1210 1215

    Met Ala Lys Leu Glu Leu Lys His Lys Asp Trp Phe Glu Phe Met 1220 1225 1230

    Gln Thr Arg Gly Asp Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly 1235 1240 1245

    Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp

    1250

    1255

    1260

    Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp 1265 1270 1275

    Val Pro Asp Tyr Ala 1280 <210> 239 <211> 1327 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 239

    Met Asn Gly Asn Arg Ser Ile Val Tyr Arg Glu Phe Val Gly Val Ile 1 5 10 15

    Pro Val Ala Lys Thr Leu Arg Asn Glu Leu Arg Pro Val Gly His Thr 20 25 30

    Gln Glu His Ile Ile Gln Asn Gly Leu Ile Gln Glu Asp Glu Leu Arg 35 40 45

    Gln Glu Lys Ser Thr Glu Leu Lys Asn Ile Met Asp Asp Tyr Tyr Arg 50 55 60

    Glu Tyr Ile Asp Lys Ser Leu Ser Gly Val Thr Asp Leu Asp Phe Thr 65 70 75 80

    Leu Leu Phe Glu Leu Met Asn Leu Val Gln Ser Ser Pro Ser Lys Asp 85 90 95

    Asn Lys Lys Ala Leu Glu Lys Glu Gln Ser Lys Met Arg Glu Gln Ile 100 105 110

    Cys Thr His Leu Gln Ser Asp Ser Asn Tyr Lys Asn Ile Phe Asn Ala 115 120 125

    Lys Leu Leu Lys Glu Ile Leu Pro Asp Phe Ile Lys Asn Tyr Asn Gln 130 135 140

    Tyr Asp Val Lys Asp Lys Ala Gly Lys Leu Glu Thr Leu Ala Leu Phe 145 150 155 160

    Asn Gly Phe Ser Thr Tyr Phe Thr Asp Phe Phe Glu Lys Arg Lys Asn 165 170 175

    Val Phe Thr Lys Glu Ala Val Ser Thr Ser Ile Ala Tyr Arg Ile Val 180 185 190

    His Glu Asn Ser Leu Ile Phe Leu Ala Asn Met Thr Ser Tyr Lys Lys 195 200 205

    Ile Ser Glu Lys Ala Leu Asp Glu Ile Glu Val Ile Glu Lys Asn Asn 210 215 220

    Gln Asp Lys Met Gly Asp Trp Glu Leu Asn Gln Ile Phe Asn Pro Asp 225 230 235 240

    Phe Tyr Asn Met Val Leu Ile Gln Ser Gly Ile Asp Phe Tyr Asn Glu 245 250 255

    Ile Cys Gly Val Val Asn Ala His Met Asn Leu Tyr Cys Gln Gln Thr 260 265 270

    Lys Asn Asn Tyr Asn Leu Phe Lys Met Arg Lys Leu His Lys Gln Ile

    275

    280

    285

    Leu Ala Tyr Thr Ser Thr Ser Phe Glu Val Pro Lys Met Phe Glu Asp 290 295 300

    Asp Met Ser Val Tyr Asn Ala Val Asn Ala Phe Ile Asp Glu Thr Glu 305 310 315 320

    Lys Gly Asn Ile Ile Gly Lys Leu Lys Asp Ile Val Asn Lys Tyr Asp 325 330 335

    Glu Leu Asp Glu Lys Arg Ile Tyr Ile Ser Lys Asp Phe Tyr Glu Thr 340 345 350

    Leu Ser Cys Phe Met Ser Gly Asn Trp Asn Leu Ile Thr Gly Cys Val 355 360 365

    Glu Asn Phe Tyr Asp Glu Asn Ile His Ala Lys Gly Lys Ser Lys Glu 370 375 380

    Glu Lys Val Lys Lys Ala Val Lys Glu Asp Lys Tyr Lys Ser Ile Asn 385 390 395 400

    Asp Val Asn Asp Leu Val Glu Lys Tyr Ile Asp Glu Lys Glu Arg Asn 405 410 415

    Glu Phe Lys Asn Ser Asn Ala Lys Gln Tyr Ile Arg Glu Ile Ser Asn 420 425 430

    Ile Ile Thr Asp Thr Glu Thr Ala His Leu Glu Tyr Asp Asp His Ile 435 440 445

    Ser Leu Ile Glu Ser Glu Glu Lys Ala Asp Glu Met Lys Lys Arg Leu 450 455 460

    Asp Met Tyr Met Asn Met Tyr His Trp Ala Lys Ala Phe Ile Val Asp 465 470 475 480

    Glu Val Leu Asp Arg Asp Glu Met Phe Tyr Ser Asp Ile Asp Asp Ile 485 490 495

    Tyr Asn Ile Leu Glu Asn Ile Val Pro Leu Tyr Asn Arg Val Arg Asn 500 505 510

    Tyr Val Thr Gln Lys Pro Tyr Asn Ser Lys Lys Ile Lys Leu Asn Phe 515 520 525

    Gln Ser Pro Thr Leu Ala Asn Gly Trp Ser Gln Ser Lys Glu Phe Asp 530 535 540

    Asn Asn Ala Ile Ile Leu Ile Arg Asp Asn Lys Tyr Tyr Leu Ala Ile 545 550 555 560

    Phe Asn Ala Lys Asn Lys Pro Asp Lys Lys Ile Ile Gln Gly Asn Ser 565 570 575

    Asp Lys Lys Asn Asp Asn Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu 580 585 590

    Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Leu Ser Lys Lys Gly 595 600 605

    Ile Glu Thr Phe Lys Pro Ser Asp Tyr Ile Ile Ser Gly Tyr Asn Ala 610 615 620

    His Lys His Ile Lys Thr Ser Glu Asn Phe Asp Ile Ser Phe Cys Arg 625 630 635 640

    Asp Leu Ile Asp Tyr Phe Lys Asn Ser Ile Glu Lys His Ala Glu Trp 645 650 655

    Arg Lys Tyr Glu Phe Lys Phe Ser Ala Thr Asp Ser Tyr Ser Asp Ile 660 665 670

    Ser Glu Phe Tyr Arg Glu Val Glu Met Gln Gly Tyr Arg Ile Asp Trp 675 680 685

    Thr Tyr Ile Ser Glu Ala Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys 690 695 700

    Ile Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Glu Asn Ser Thr 705 710 715 720

    Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asp Ile Ile Ile Lys Leu Asn Gly Gln Ala Glu Leu 740 745 750

    Phe Tyr Arg Arg Ala Ser Val Lys Asn Pro Val Lys His Lys Lys Asp 755 760 765

    Ser Val Leu Val Asn Lys Thr Tyr Lys Asn Gln Leu Asp Asn Gly Asp 770 775 780

    Val Val Arg Ile Pro Ile Pro Asp Asp Ile Tyr Asn Glu Ile Tyr Lys 785 790 795 800

    Met Tyr Asn Gly Tyr Ile Lys Glu Ser Asp Leu Ser Glu Ala Ala Lys 805 810 815

    Glu Tyr Leu Asp Lys Val Glu Val Arg Thr Ala Gln Lys Asp Ile Val 820 825 830

    Lys Asp Tyr Arg Tyr Thr Val Asp Lys Tyr Phe Ile His Thr Pro Ile 835 840 845

    Thr Ile Asn Tyr Lys Val Thr Ala Arg Asn Asn Val Asn Asp Met Val 850 855 860

    Val Lys Tyr Ile Ala Gln Asn Asp Asp Ile His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Ile Tyr Ile Ser Val Ile Asp Ser His Gly 885 890 895

    Asn Ile Val Lys Gln Lys Ser Tyr Asn Ile Leu Asn Asn Tyr Asp Tyr 900 905 910

    Lys Lys Lys Leu Val Glu Lys Glu Lys Thr Arg Glu Tyr Ala Arg Lys 915 920 925

    Asn Trp Lys Ser Ile Gly Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 930 935 940

    Ser Gly Val Val His Glu Ile Ala Met Leu Ile Val Glu Tyr Asn Ala 945 950 955 960

    Ile Ile Ala Met Glu Asp Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe 965 970 975

    Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 980 985 990

    Lys Leu Asn Tyr Phe Ala Ser Lys Glu Lys Ser Val Asp Glu Pro Gly

    995 1000 1005

    Gly Leu Leu Lys Gly Tyr Gln Leu Thr Tyr Val Pro Asp Asn Ile 1010 1015 1020

    Lys Asn Leu Gly Lys Gln Cys Gly Val Ile Phe Tyr Val Pro Ala 1025 1030 1035

    Ala Phe Thr Ser Lys Ile Asp Pro Ser Thr Gly Phe Ile Ser Ala 1040 1045 1050

    Phe Asn Phe Lys Ser Ile Ser Thr Asn Ala Ser Arg Lys Gln Phe 1055 1060 1065

    Phe Met Gln Phe Asp Glu Ile Arg Tyr Cys Ala Glu Lys Asp Met 1070 1075 1080

    Phe Ser Phe Gly Phe Asp Tyr Asn Asn Phe Asp Thr Tyr Asn Ile 1085 1090 1095

    Thr Met Gly Lys Thr Gln Trp Thr Val Tyr Thr Asn Gly Glu Arg 1100 1105 1110

    Leu Gln Ser Glu Phe Asn Asn Ala Arg Arg Thr Gly Lys Thr Lys 1115 1120 1125

    Ser Ile Asn Leu Thr Glu Thr Ile Lys Leu Leu Leu Glu Asp Asn 1130 1135 1140

    Glu Ile Asn Tyr Ala Asp Gly His Asp Ile Arg Ile Asp Met Glu 1145 1150 1155

    Lys Met Asp Glu Asp Lys Lys Ser Glu Phe Phe Ala Gln Leu Leu 1160 1165 1170

    Ser Leu Tyr Lys Leu Thr Val Gln Met Arg Asn Ser Tyr Thr Glu 1175 1180 1185

    Ala Glu Glu Gln Glu Asn Gly Ile Ser Tyr Asp Lys Ile Ile Ser 1190 1195 1200

    Pro Val Ile Asn Asp Glu Gly Glu Phe Phe Asp Ser Asp Asn Tyr 1205 1210 1215

    Lys Glu Ser Asp Asp Lys Glu Cys Lys Met Pro Lys Asp Ala Asp 1220 1225 1230

    Ala Asn Gly Ala Tyr Cys Ile Ala Leu Lys Gly Leu Tyr Glu Val 1235 1240 1245

    Leu Lys Ile Lys Ser Glu Trp Thr Glu Asp Gly Phe Asp Arg Asn 1250 1255 1260

    Cys Leu Lys Leu Pro His Ala Glu Trp Leu Asp Phe Ile Gln Asn 1265 1270 1275

    Lys Arg Tyr Glu Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln 1280 1285 1290

    Ala Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr 1295 1300 1305

    Pro Asp Tyr Ala 1325

    Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val

    1310 1315 1320 <210> 240 <211> 1418 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 240

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Val 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Asp Arg Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met His Gln Lys 35 40 45

    Val Lys Val Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Glu Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly 100 105 110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Ala Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Thr Thr 195 200 205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Pro Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met 290 295 300

    Ser Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys 325 330 335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Val Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe 545 550 555 560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn 565 570 575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Val Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Ser Ile Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Tyr Leu Glu Val Arg Lys Gln Phe Pro Lys Val Phe Phe 625 630 635 640

    Ser Lys Glu Ala Ile Ala Ile Asn Tyr His Pro Ser Lys Glu Leu Val 645 650 655

    Glu Ile Lys Asp Lys Gly Arg Gln Arg Ser Asp Asp Glu Arg Leu Lys 660 665 670

    Leu Tyr Arg Phe Ile Leu Glu Cys Leu Lys Ile His Pro Lys Tyr Asp

    675

    680

    685

    Lys Lys Phe Glu Gly Ala Ile Gly Asp Ile Gln Leu Phe Lys Lys Asp 690 695 700

    Lys Lys Gly Arg Glu Val Pro Ile Ser Glu Lys Asp Leu Phe Asp Lys 705 710 715 720

    Ile Asn Gly Ile Phe Ser Ser Lys Pro Lys Leu Glu Met Glu Asp Phe 725 730 735

    Phe Ile Gly Glu Phe Lys Arg Tyr Asn Pro Ser Gln Asp Leu Val Asp 740 745 750

    Gln Tyr Asn Ile Tyr Lys Lys Ile Asp Ser Asn Asp Asn Arg Lys Lys 755 760 765

    Glu Asn Phe Tyr Asn Asn His Pro Lys Phe Lys Lys Asp Leu Val Arg 770 775 780

    Tyr Tyr Tyr Glu Ser Met Cys Lys His Glu Glu Trp Glu Glu Ser Phe 785 790 795 800

    Glu Phe Ser Lys Lys Leu Gln Asp Ile Gly Cys Tyr Val Asp Val Asn 805 810 815

    Glu Leu Phe Thr Glu Ile Glu Thr Arg Arg Leu Asn Tyr Lys Ile Ser 820 825 830

    Phe Cys Asn Ile Asn Ala Asp Tyr Ile Asp Glu Leu Val Glu Gln Gly 835 840 845

    Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Lys Ala 850 855 860

    His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala Leu Phe Ser 865 870 875 880

    Glu Asp Asn Leu Ala Asp Pro Ile Tyr Lys Leu Asn Gly Glu Ala Gln 885 890 895

    Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr Thr Ile His 900 905 910

    Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn Pro Lys Lys 915 920 925

    Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr Thr Gln Asp 930 935 940

    Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly Val Gln Gly 945 950 955 960

    Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser Ile Gln Gln 965 970 975

    Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu Arg His Leu 980 985 990

    Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu Glu Gln Cys 995 1000 1005

    Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr Gln Met 1010 1015 1020

    Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu Arg 1025 1030 1035

    Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu 1040 1045 1050

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln 1055 1060 1065

    Leu Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 1070 1075 1080

    Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 1085 1090 1095

    Gln Asn Phe Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val 1100 1105 1110

    Leu Lys Asp Lys Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala 1115 1120 1125

    Leu Gln Leu Thr Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys 1130 1135 1140

    Gln Thr Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys 1145 1150 1155

    Ile Asp Pro Glu Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr 1160 1165 1170

    Glu Asn Ile Ala Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys 1175 1180 1185

    Ile Cys Tyr Asn Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp 1190 1195 1200

    Tyr Ala Lys Phe Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp 1205 1210 1215

    Thr Ile Cys Ser His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr 1220 1225 1230

    Ala Asn Gln Asn Lys Gly Ala Ala Lys Gly Ile Asn Val Asn Asp 1235 1240 1245

    Glu Leu Lys Ser Leu Phe Ala Arg His His Ile Asn Glu Lys Gln 1250 1255 1260

    Pro Asn Leu Val Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe 1265 1270 1275

    His Lys Ser Leu Met Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg 1280 1285 1290

    Tyr Ser Asn Ala Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val 1295 1300 1305

    Ala Asn Asp Glu Gly Val Phe Phe Asn Ser Ala Leu Ala Asp Asp 1310 1315 1320

    Thr Gln Pro Gln Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala 1325 1330 1335

    Leu Lys Gly Leu Trp Leu Leu Asn Glu Leu Lys Asn Ser Asp Asp 1340 1345 1350

    Leu Asn Lys Val Lys Leu Ala Ile Asp Asn Gln Thr Trp Leu Asn 1355 1360 1365

    Phe Ala Gln Asn Arg Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly

    1370

    1375

    1380

    Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp 1385 1390 1395

    Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp 1400 1405 1410

    Val Pro Asp Tyr Ala 1415 <210> 241 <211> 1308 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 241

    Met Glu Asp Tyr Ser Gly Phe Val Asn Ile Tyr Ser Ile Gln Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu His Ile Glu 20 25 30

    Lys Lys Gly Phe Leu Lys Lys Asp Lys Ile Arg Ala Glu Asp Tyr Lys 35 40 45

    Ala Val Lys Lys Ile Ile Asp Lys Tyr His Arg Ala Tyr Ile Glu Glu 50 55 60

    Val Phe Asp Ser Val Leu His Gln Lys Lys Lys Lys Asp Lys Thr Arg 65 70 75 80

    Phe Ser Thr Gln Phe Ile Lys Glu Ile Lys Glu Phe Ser Glu Leu Tyr 85 90 95

    Tyr Lys Thr Glu Lys Asn Ile Pro Asp Lys Glu Arg Leu Glu Ala Leu 100 105 110

    Ser Glu Lys Leu Arg Lys Met Leu Val Gly Ala Phe Lys Gly Glu Phe 115 120 125

    Ser Glu Glu Val Ala Glu Lys Tyr Lys Asn Leu Phe Ser Lys Glu Leu 130 135 140

    Ile Arg Asn Glu Ile Glu Lys Phe Cys Glu Thr Asp Glu Glu Arg Lys 145 150 155 160

    Gln Val Ser Asn Phe Lys Ser Phe Thr Thr Tyr Phe Thr Gly Phe His 165 170 175

    Ser Asn Arg Gln Asn Ile Tyr Ser Asp Glu Lys Lys Ser Thr Ala Ile 180 185 190

    Gly Tyr Arg Ile Ile His Gln Asn Leu Pro Lys Phe Leu Asp Asn Leu 195 200 205

    Lys Ile Ile Glu Ser Ile Gln Arg Arg Phe Lys Asp Phe Pro Trp Ser 210 215 220

    Asp Leu Lys Lys Asn Leu Lys Lys Ile Asp Lys Asn Ile Lys Leu Thr 225 230 235 240

    Glu Tyr Phe Ser Ile Asp Gly Phe Val Asn Val Leu Asn Gln Lys Gly 245 250 255

    Ile Asp Ala Tyr Asn Thr Ile Leu Gly Gly Lys Ser Glu Glu Ser Gly

    260

    265

    270

    Glu Lys Ile Gln Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Arg Gln Lys 275 280 285

    Asn Asn Ile Asp Arg Lys Asn Leu Pro Asn Val Lys Ile Leu Phe Lys 290 295 300

    Gln Ile Leu Gly Asp Arg Glu Thr Lys Ser Phe Ile Pro Glu Ala Phe 305 310 315 320

    Pro Asp Asp Gln Ser Val Leu Asn Ser Ile Thr Glu Phe Ala Lys Tyr 325 330 335

    Leu Lys Leu Asp Lys Lys Lys Lys Ser Ile Ile Ala Glu Leu Lys Lys 340 345 350

    Phe Leu Ser Ser Phe Asn Arg Tyr Glu Leu Asp Gly Ile Tyr Leu Ala 355 360 365

    Asn Asp Asn Ser Leu Ala Ser Ile Ser Thr Phe Leu Phe Asp Asp Trp 370 375 380

    Ser Phe Ile Lys Lys Ser Val Ser Phe Lys Tyr Asp Glu Ser Val Gly 385 390 395 400

    Asp Pro Lys Lys Lys Ile Lys Ser Pro Leu Lys Tyr Glu Lys Glu Lys 405 410 415

    Glu Lys Trp Leu Lys Gln Lys Tyr Tyr Thr Ile Ser Phe Leu Asn Asp 420 425 430

    Ala Ile Glu Ser Tyr Ser Lys Ser Gln Asp Glu Lys Arg Val Lys Ile 435 440 445

    Arg Leu Glu Ala Tyr Phe Ala Glu Phe Lys Ser Lys Asp Asp Ala Lys 450 455 460

    Lys Gln Phe Asp Leu Leu Glu Arg Ile Glu Glu Ala Tyr Ala Ile Val 465 470 475 480

    Glu Pro Leu Leu Gly Ala Glu Tyr Pro Arg Asp Arg Asn Leu Lys Ala 485 490 495

    Asp Lys Lys Glu Val Gly Lys Ile Lys Asp Phe Leu Asp Ser Ile Lys 500 505 510

    Ser Leu Gln Phe Phe Leu Lys Pro Leu Leu Ser Ala Glu Ile Phe Asp 515 520 525

    Glu Lys Asp Leu Gly Phe Tyr Asn Gln Leu Glu Gly Tyr Tyr Glu Glu 530 535 540

    Ile Asp Ser Ile Gly His Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr 545 550 555 560

    Gly Lys Ile Tyr Ser Lys Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser 565 570 575

    Thr Leu Leu Lys Gly Trp Asp Glu Asn Arg Glu Val Ala Asn Leu Cys 580 585 590

    Val Ile Phe Arg Glu Asp Gln Lys Tyr Tyr Leu Gly Val Met Asp Lys 595 600 605

    Glu Asn Asn Thr Ile Leu Ser Asp Ile Pro Lys Val Lys Pro Asn Glu 610 615 620

    Leu Phe Tyr Glu Lys Met Val Tyr Lys Leu Ile Pro Thr Pro His Met 625 630 635 640

    Gln Leu Pro Arg Ile Ile Phe Ser Ser Asp Asn Leu Ser Ile Tyr Asn 645 650 655

    Pro Ser Lys Ser Ile Leu Lys Ile Arg Glu Ala Lys Ser Phe Lys Glu 660 665 670

    Gly Lys Asn Phe Lys Leu Lys Asp Cys His Lys Phe Ile Asp Phe Tyr 675 680 685

    Lys Glu Ser Ile Ser Lys Asn Glu Asp Trp Ser Arg Phe Asp Phe Lys 690 695 700

    Phe Ser Lys Thr Ser Ser Tyr Glu Asn Ile Ser Glu Phe Tyr Arg Glu 705 710 715 720

    Val Glu Arg Gln Gly Tyr Asn Leu Asp Phe Lys Lys Val Ser Lys Phe 725 730 735

    Tyr Ile Asp Ser Leu Val Glu Asp Gly Lys Leu Tyr Leu Phe Gln Ile 740 745 750

    Tyr Asn Lys Asp Phe Ser Ile Phe Ser Lys Gly Lys Pro Asn Leu His 755 760 765

    Thr Ile Tyr Phe Arg Ser Leu Phe Ser Lys Glu Asn Leu Lys Asp Val 770 775 780

    Cys Leu Lys Leu Asn Gly Glu Ala Glu Met Phe Phe Arg Lys Lys Ser 785 790 795 800

    Ile Asn Tyr Asp Glu Lys Lys Lys Arg Glu Gly His His Pro Glu Leu 805 810 815

    Phe Glu Lys Leu Lys Tyr Pro Ile Leu Lys Asp Lys Arg Tyr Ser Glu 820 825 830

    Asp Lys Phe Gln Phe His Leu Pro Ile Ser Leu Asn Phe Lys Ser Lys 835 840 845

    Glu Arg Leu Asn Phe Asn Leu Lys Val Asn Glu Phe Leu Lys Arg Asn 850 855 860

    Lys Asp Ile Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu 865 870 875 880

    Tyr Leu Val Met Ile Asn Gln Lys Gly Glu Ile Leu Lys Gln Thr Leu 885 890 895

    Leu Asp Ser Met Gln Ser Gly Lys Gly Arg Pro Glu Ile Asn Tyr Lys 900 905 910

    Glu Lys Leu Gln Glu Lys Glu Ile Glu Arg Asp Lys Ala Arg Lys Ser 915 920 925

    Trp Gly Thr Val Glu Asn Ile Lys Glu Leu Lys Glu Gly Tyr Leu Ser 930 935 940

    Ile Val Ile His Gln Ile Ser Lys Leu Met Val Glu Asn Asn Ala Ile 945 950 955 960

    Val Val Leu Glu Asp Leu Asn Ile Gly Phe Lys Arg Gly Arg Gln Lys 965 970 975

    Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys

    980

    985

    990

    Leu Asn Phe Leu Val Phe Lys Glu Asn Lys Pro Thr Glu Pro Gly Gly 995 1000 1005

    Val Leu Lys Ala Tyr Gln Leu Thr Asp Glu Phe Gln Ser Phe Glu 1010 1015 1020

    Lys Leu Ser Lys Gln Thr Gly Phe Leu Phe Tyr Val Pro Ser Trp 1025 1030 1035

    Asn Thr Ser Lys Ile Asp Pro Arg Thr Gly Phe Ile Asp Phe Leu 1040 1045 1050

    His Pro Ala Tyr Glu Asn Ile Glu Lys Ala Lys Gln Trp Ile Asn 1055 1060 1065

    Lys Phe Asp Ser Ile Arg Phe Asn Ser Lys Met Asp Trp Phe Glu 1070 1075 1080

    Phe Thr Ala Asp Thr Arg Lys Phe Ser Glu Asn Leu Met Leu Gly 1085 1090 1095

    Lys Asn Arg Val Trp Val Ile Cys Thr Thr Asn Val Glu Arg Tyr 1100 1105 1110

    Phe Thr Ser Lys Thr Ala Asn Ser Ser Ile Gln Tyr Asn Ser Ile 1115 1120 1125

    Gln Ile Thr Glu Lys Leu Lys Glu Leu Phe Val Asp Ile Pro Phe 1130 1135 1140

    Ser Asn Gly Gln Asp Leu Lys Pro Glu Ile Leu Arg Lys Asn Asp 1145 1150 1155

    Ala Val Phe Phe Lys Ser Leu Leu Phe Tyr Ile Lys Thr Thr Leu 1160 1165 1170

    Ser Leu Arg Gln Asn Asn Gly Lys Lys Gly Glu Glu Glu Lys Asp 1175 1180 1185

    Phe Ile Leu Ser Pro Val Val Asp Ser Lys Gly Arg Phe Phe Asn 1190 1195 1200

    Ser Leu Glu Ala Ser Asp Asp Glu Pro Lys Asp Ala Asp Ala Asn 1205 1210 1215

    Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Met Asn Leu Leu Val 1220 1225 1230

    Leu Asn Glu Thr Lys Glu Glu Asn Leu Ser Arg Pro Lys Trp Lys 1235 1240 1245

    Ile Lys Asn Lys Asp Trp Leu Glu Phe Val Trp Glu Arg Asn Arg 1250 1255 1260

    Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys 1265 1270 1275

    Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr 1280 1285 1290

    Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala

    1295 1300 1305 <210> 242 <211> 1273 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 242

    Met Ser Lys Leu Glu Lys Phe Thr Asn Cys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Lys Ala Ile Pro Val Gly Lys Thr Gln Glu Asn Ile Asp 20 25 30

    Asn Lys Arg Leu Leu Val Glu Asp Glu Lys Arg Ala Glu Asp Tyr Lys 35 40 45

    Gly Val Lys Lys Leu Leu Asp Arg Tyr Tyr Leu Ser Phe Ile Asn Asp 50 55 60

    Val Leu His Ser Ile Lys Leu Lys Asn Leu Asn Asn Tyr Ile Ser Leu 65 70 75 80

    Phe Arg Lys Lys Thr Arg Thr Glu Lys Glu Asn Lys Glu Leu Glu Asn 85 90 95

    Leu Glu Ile Asn Leu Arg Lys Glu Ile Ala Lys Ala Phe Lys Gly Asn 100 105 110

    Glu Gly Tyr Lys Ser Leu Phe Lys Lys Asp Ile Ile Glu Thr Ile Leu 115 120 125

    Pro Glu Phe Leu Asp Asp Lys Asp Glu Ile Ala Leu Val Asn Ser Phe 130 135 140

    Asn Gly Phe Thr Thr Ala Phe Thr Gly Phe Phe Asp Asn Arg Glu Asn 145 150 155 160

    Met Phe Ser Glu Glu Ala Lys Ser Thr Ser Ile Ala Phe Arg Cys Ile 165 170 175

    Asn Glu Asn Leu Thr Arg Tyr Ile Ser Asn Met Asp Ile Phe Glu Lys 180 185 190

    Val Asp Ala Ile Phe Asp Lys His Glu Val Gln Glu Ile Lys Glu Lys 195 200 205

    Ile Leu Asn Ser Asp Tyr Asp Val Glu Asp Phe Phe Glu Gly Glu Phe 210 215 220

    Phe Asn Phe Val Leu Thr Gln Glu Gly Ile Asp Val Tyr Asn Ala Ile 225 230 235 240

    Ile Gly Gly Phe Val Thr Glu Ser Gly Glu Lys Ile Lys Gly Leu Asn 245 250 255

    Glu Tyr Ile Asn Leu Tyr Asn Gln Lys Thr Lys Gln Lys Leu Pro Lys 260 265 270

    Phe Lys Pro Leu Tyr Lys Gln Val Leu Ser Asp Arg Glu Ser Leu Ser 275 280 285

    Phe Tyr Gly Glu Gly Tyr Thr Ser Asp Glu Glu Val Leu Glu Val Phe 290 295 300

    Arg Asn Thr Leu Asn Lys Asn Ser Glu Ile Phe Ser Ser Ile Lys Lys 305 310 315 320

    Leu Glu Lys Leu Phe Lys Asn Phe Asp Glu Tyr Ser Ser Ala Gly Ile 325 330 335

    Phe Val Lys Asn Gly Pro Ala Ile Ser Thr Ile Ser Lys Asp Ile Phe 340 345 350

    Gly Glu Trp Asn Val Ile Arg Asp Lys Trp Asn Ala Glu Tyr Asp Asp 355 360 365

    Ile His Leu Lys Lys Lys Ala Val Val Thr Glu Lys Tyr Glu Asp Asp 370 375 380

    Arg Arg Lys Ser Phe Lys Lys Ile Gly Ser Phe Ser Leu Glu Gln Leu 385 390 395 400

    Gln Glu Tyr Ala Asp Ala Asp Leu Ser Val Val Glu Lys Leu Lys Glu 405 410 415

    Ile Ile Ile Gln Lys Val Asp Glu Ile Tyr Lys Val Tyr Gly Ser Ser 420 425 430

    Glu Lys Leu Phe Asp Ala Asp Phe Val Leu Glu Lys Ser Leu Lys Lys 435 440 445

    Asn Asp Ala Val Val Ala Ile Met Lys Asp Leu Leu Asp Ser Val Lys 450 455 460

    Ser Phe Glu Asn Tyr Ile Lys Ala Phe Phe Gly Glu Gly Lys Glu Thr 465 470 475 480

    Asn Arg Asp Glu Ser Phe Tyr Gly Asp Phe Val Leu Ala Tyr Asp Ile 485 490 495

    Leu Leu Lys Val Asp His Ile Tyr Asp Ala Ile Arg Asn Tyr Val Thr 500 505 510

    Gln Lys Pro Tyr Ser Lys Asp Lys Phe Lys Leu Tyr Phe Gln Asn Pro 515 520 525

    Gln Phe Met Gly Gly Trp Asp Lys Asp Lys Glu Thr Asp Tyr Arg Ala 530 535 540

    Thr Ile Leu Arg Tyr Gly Ser Lys Tyr Tyr Leu Ala Ile Met Asp Lys 545 550 555 560

    Lys Tyr Ala Lys Cys Leu Gln Lys Ile Asp Lys Asp Asp Val Asn Gly 565 570 575

    Asn Tyr Glu Lys Ile Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met 580 585 590

    Leu Pro Lys Val Phe Phe Ser Lys Lys Trp Met Ala Tyr Tyr Asn Pro 595 600 605

    Ser Glu Asp Ile Gln Lys Ile Tyr Lys Asn Gly Thr Phe Lys Lys Gly 610 615 620

    Asp Met Phe Asn Leu Asn Asp Cys His Lys Leu Ile Asp Phe Phe Lys 625 630 635 640

    Asp Ser Ile Ser Arg Tyr Pro Lys Trp Ser Asn Ala Tyr Asp Phe Asn 645 650 655

    Phe Ser Glu Thr Glu Lys Tyr Lys Asp Ile Ala Gly Phe Tyr Arg Glu 660 665 670

    Val Glu Glu Gln Gly Tyr Lys Val Ser Phe Glu Ser Ala Ser Lys Lys 675 680 685

    Glu Val Asp Lys Leu Val Glu Glu Gly Lys Leu Tyr Met Phe Gln Ile

    690

    695

    700

    Tyr Asn Lys Asp Phe Ser Asp Lys Ser His Gly Thr Pro Asn Leu His 705 710 715 720

    Thr Met Tyr Phe Lys Leu Leu Phe Asp Glu Asn Asn His Gly Gln Ile 725 730 735

    Arg Leu Ser Gly Gly Ala Glu Leu Phe Met Arg Arg Ala Ser Leu Lys 740 745 750

    Lys Glu Glu Leu Val Val His Pro Ala Asn Ser Pro Ile Ala Asn Lys 755 760 765

    Asn Pro Asp Asn Pro Lys Lys Thr Thr Thr Leu Ser Tyr Asp Val Tyr 770 775 780

    Lys Asp Lys Arg Phe Ser Glu Asp Gln Tyr Glu Leu His Ile Pro Ile 785 790 795 800

    Ala Ile Asn Lys Cys Pro Lys Asn Ile Phe Lys Ile Asn Thr Glu Val 805 810 815

    Arg Val Leu Leu Lys His Asp Asp Asn Pro Tyr Val Ile Gly Ile Asp 820 825 830

    Arg Gly Glu Arg Asn Leu Leu Tyr Ile Val Val Val Asp Gly Lys Gly 835 840 845

    Asn Ile Val Glu Gln Tyr Ser Leu Asn Glu Ile Ile Asn Asn Phe Asn 850 855 860

    Gly Ile Arg Ile Lys Thr Asp Tyr His Ser Leu Leu Asp Lys Lys Glu 865 870 875 880

    Lys Glu Arg Phe Glu Ala Arg Gln Asn Trp Thr Ser Ile Glu Asn Ile 885 890 895

    Lys Glu Leu Lys Ala Gly Tyr Ile Ser Gln Val Val His Lys Ile Cys 900 905 910

    Glu Leu Val Glu Lys Tyr Asp Ala Val Ile Ala Leu Glu Asp Leu Asn 915 920 925

    Ser Gly Phe Lys Asn Ser Arg Val Lys Val Glu Lys Gln Val Tyr Gln 930 935 940

    Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Met Val Asp Lys 945 950 955 960

    Lys Ser Asn Pro Cys Ala Thr Gly Gly Ala Leu Lys Gly Tyr Gln Ile 965 970 975

    Thr Asn Lys Phe Glu Ser Phe Lys Ser Met Ser Thr Gln Asn Gly Phe 980 985 990

    Ile Phe Tyr Ile Pro Ala Trp Leu Thr Ser Lys Ile Asp Pro Ser Thr 995 1000 1005

    Gly Phe Val Asn Leu Leu Lys Thr Lys Tyr Thr Ser Ile Ala Asp 1010 1015 1020

    Ser Lys Lys Phe Ile Ser Ser Phe Asp Arg Ile Met Tyr Val Pro 1025 1030 1035

    Glu Glu Asp Leu Phe Glu Phe Ala Leu Asp Tyr Lys Asn Phe Ser 1040 1045 1050

    Arg Thr Asp Ala Asp Tyr Ile Lys Lys Trp Lys Leu Tyr Ser Tyr 1055 1060 1065

    Gly Asn Arg Ile Arg Ile Phe Arg Asn Pro Lys Lys Asn Asn Val 1070 1075 1080

    Phe Asp Trp Glu Glu Val Cys Leu Thr Ser Ala Tyr Lys Glu Leu 1085 1090 1095

    Phe Asn Lys Tyr Gly Ile Asn Tyr Gln Gln Gly Asp Ile Arg Ala 1100 1105 1110

    Leu Leu Cys Glu Gln Ser Asp Lys Ala Phe Tyr Ser Ser Phe Met 1115 1120 1125

    Ala Leu Met Ser Leu Met Leu Gln Met Arg Asn Ser Ile Thr Gly 1130 1135 1140

    Arg Thr Asp Val Asp Phe Leu Ile Ser Pro Val Lys Asn Ser Asp 1145 1150 1155

    Gly Ile Phe Tyr Asp Ser Arg Asn Tyr Glu Ala Gln Glu Asn Ala 1160 1165 1170

    Ile Leu Pro Lys Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala 1175 1180 1185

    Arg Lys Val Leu Trp Ala Ile Gly Gln Phe Lys Lys Ala Glu Asp 1190 1195 1200

    Glu Lys Leu Asp Lys Val Lys Ile Ala Ile Ser Asn Lys Glu Trp 1205 1210 1215

    Leu Glu Tyr Ala Gln Thr Ser Val Lys His Lys Arg Pro Ala Ala 1220 1225 1230

    Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro 1235 1240 1245

    Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr 1250 1255 1260

    Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1265 1270 <210> 243 <211> 1305 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 243

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr

    435

    440

    445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Met Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu His Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Val Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys

    1145

    1150

    1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp Lys Arg Pro 1250 1255 1260

    Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gly Ser 1265 1270 1275

    Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro 1280 1285 1290

    Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1295 1300 1305 <210> 244 <211> 1368 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 244

    Met Glu Asn Tyr Gln Glu Phe Thr Asn Leu Phe Gln Leu Asn Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Cys Glu Leu Leu Glu 20 25 30

    Glu Gly Lys Ile Phe Ala Ser Gly Ser Phe Leu Glu Lys Asp Lys Val 35 40 45

    Arg Ala Asp Asn Val Ser Tyr Val Lys Lys Glu Ile Asp Lys Lys His 50 55 60

    Lys Ile Phe Ile Glu Glu Thr Leu Ser Ser Phe Ser Ile Ser Asn Asp 65 70 75 80

    Leu Leu Lys Gln Tyr Phe Asp Cys Tyr Asn Glu Leu Lys Ala Phe Lys 85 90 95

    Lys Asp Cys Lys Ser Asp Glu Glu Glu Val Lys Lys Thr Ala Leu Arg 100 105 110

    Asn Lys Cys Thr Ser Ile Gln Arg Ala Met Arg Glu Ala Ile Ser Gln 115 120 125

    Ala Phe Leu Lys Ser Pro Gln Lys Lys Leu Leu Ala Ile Lys Asn Leu 130 135 140

    Ile Glu Asn Val Phe Lys Ala Asp Glu Asn Val Gln His Phe Ser Glu

    145

    150

    155

    160

    Phe Thr Ser Tyr Phe Ser Gly Phe Glu Thr Asn Arg Glu Asn Phe Tyr 165 170 175

    Ser Asp Glu Glu Lys Ser Thr Ser Ile Ala Tyr Arg Leu Val His Asp 180 185 190

    Asn Leu Pro Ile Phe Ile Lys Asn Ile Tyr Ile Phe Glu Lys Leu Lys 195 200 205

    Glu Gln Phe Asp Ala Lys Thr Leu Ser Glu Ile Phe Glu Asn Tyr Lys 210 215 220

    Leu Tyr Val Ala Gly Ser Ser Leu Asp Glu Val Phe Ser Leu Glu Tyr 225 230 235 240

    Phe Asn Asn Thr Leu Thr Gln Lys Gly Ile Asp Asn Tyr Asn Ala Val 245 250 255

    Ile Gly Lys Ile Val Lys Glu Asp Lys Gln Glu Ile Gln Gly Leu Asn 260 265 270

    Glu His Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Arg Arg Leu Pro 275 280 285

    Phe Phe Ile Ser Leu Lys Lys Gln Ile Leu Ser Asp Arg Glu Ala Leu 290 295 300

    Ser Trp Leu Pro Asp Met Phe Lys Asn Asp Ser Glu Val Ile Lys Ala 305 310 315 320

    Leu Lys Gly Phe Tyr Ile Glu Asp Gly Phe Glu Asn Asn Val Leu Thr 325 330 335

    Pro Leu Ala Thr Leu Leu Ser Ser Leu Asp Lys Tyr Asn Leu Asn Gly 340 345 350

    Ile Phe Ile Arg Asn Asn Glu Ala Leu Ser Ser Leu Ser Gln Asn Val 355 360 365

    Tyr Arg Asn Phe Ser Ile Asp Glu Ala Ile Asp Ala Asn Ala Glu Leu 370 375 380

    Gln Thr Phe Asn Asn Tyr Glu Leu Ile Ala Asn Ala Leu Arg Ala Lys 385 390 395 400

    Ile Lys Lys Glu Thr Lys Gln Gly Arg Lys Ser Phe Glu Lys Tyr Glu 405 410 415

    Glu Tyr Ile Asp Lys Lys Val Lys Ala Ile Asp Ser Leu Ser Ile Gln 420 425 430

    Glu Ile Asn Glu Leu Val Glu Asn Tyr Val Ser Glu Phe Asn Ser Asn 435 440 445

    Ser Gly Asn Met Pro Arg Lys Val Glu Asp Tyr Phe Ser Leu Met Arg 450 455 460

    Lys Gly Asp Phe Gly Ser Asn Asp Leu Ile Glu Asn Ile Lys Thr Lys 465 470 475 480

    Leu Ser Ala Ala Glu Lys Leu Leu Gly Thr Lys Tyr Gln Glu Thr Ala 485 490 495

    Lys Asp Ile Phe Lys Lys Asp Glu Asn Ser Lys Leu Ile Lys Glu Leu 500 505 510

    Leu Asp Ala Thr Lys Gln Phe Gln His Phe Ile Lys Pro Leu Leu Gly 515 520 525

    Thr Gly Glu Glu Ala Asp Arg Asp Leu Val Phe Tyr Gly Asp Phe Leu 530 535 540

    Pro Leu Tyr Glu Lys Phe Glu Glu Leu Thr Leu Leu Tyr Asn Lys Val 545 550 555 560

    Arg Asn Arg Leu Thr Gln Lys Pro Tyr Ser Lys Asp Lys Ile Arg Leu 565 570 575

    Cys Phe Asn Lys Pro Lys Leu Met Thr Gly Trp Val Asp Ser Lys Thr 580 585 590

    Glu Lys Ser Asp Asn Gly Thr Gln Tyr Gly Gly Tyr Leu Phe Arg Lys 595 600 605

    Lys Asn Glu Ile Gly Glu Tyr Asp Tyr Phe Leu Gly Ile Ser Ser Lys 610 615 620

    Ala Gln Leu Phe Arg Lys Asn Glu Ala Val Ile Gly Asp Tyr Glu Arg 625 630 635 640

    Leu Asp Tyr Tyr Gln Pro Lys Ala Asn Thr Ile Tyr Gly Ser Ala Tyr 645 650 655

    Glu Gly Glu Asn Ser Tyr Lys Glu Asp Lys Lys Arg Leu Asn Lys Val 660 665 670

    Ile Ile Ala Tyr Ile Glu Gln Ile Lys Gln Thr Asn Ile Lys Lys Ser 675 680 685

    Ile Ile Glu Ser Ile Ser Lys Tyr Pro Asn Ile Ser Asp Asp Asp Lys 690 695 700

    Val Thr Pro Ser Ser Leu Leu Glu Lys Ile Lys Lys Val Ser Ile Asp 705 710 715 720

    Ser Tyr Asn Gly Ile Leu Ser Phe Lys Ser Phe Gln Ser Val Asn Lys 725 730 735

    Glu Val Ile Asp Asn Leu Leu Lys Thr Ile Ser Pro Leu Lys Asn Lys 740 745 750

    Ala Glu Phe Leu Asp Leu Ile Asn Lys Asp Tyr Gln Ile Phe Thr Glu 755 760 765

    Val Gln Ala Val Ile Asp Glu Ile Cys Lys Gln Lys Thr Phe Ile Tyr 770 775 780

    Phe Pro Ile Ser Asn Val Glu Leu Glu Lys Glu Met Gly Asp Lys Asp 785 790 795 800

    Lys Pro Leu Cys Leu Phe Gln Ile Ser Asn Lys Asp Leu Ser Phe Ala 805 810 815

    Lys Thr Phe Ser Ala Asn Leu Arg Lys Lys Arg Gly Ala Glu Asn Leu 820 825 830

    His Thr Met Leu Phe Lys Ala Leu Met Glu Gly Asn Gln Asp Asn Leu 835 840 845

    Asp Leu Gly Ser Gly Ala Ile Phe Tyr Arg Ala Lys Ser Leu Asp Gly 850 855 860

    Asn Lys Pro Thr His Pro Ala Asn Glu Ala Ile Lys Cys Arg Asn Val

    865

    870

    875

    880

    Ala Asn Lys Asp Lys Val Ser Leu Phe Thr Tyr Asp Ile Tyr Lys Asn 885 890 895

    Arg Arg Tyr Met Glu Asn Lys Phe Leu Phe His Leu Ser Ile Val Gln 900 905 910

    Asn Tyr Lys Ala Ala Asn Asp Ser Ala Gln Leu Asn Ser Ser Ala Thr 915 920 925

    Glu Tyr Ile Arg Lys Ala Asp Asp Leu His Ile Ile Gly Ile Asp Arg 930 935 940

    Gly Glu Arg Asn Leu Leu Tyr Tyr Ser Val Ile Asp Met Lys Gly Asn 945 950 955 960

    Ile Val Glu Gln Asp Ser Leu Asn Ile Ile Arg Asn Asn Asp Leu Glu 965 970 975

    Thr Asp Tyr His Asp Leu Leu Asp Lys Arg Glu Lys Glu Arg Lys Ala 980 985 990

    Asn Arg Gln Asn Trp Glu Ala Val Glu Gly Ile Lys Asp Leu Lys Lys 995 1000 1005

    Gly Tyr Leu Ser Gln Ala Val His Gln Ile Ala Gln Leu Met Leu 1010 1015 1020

    Lys Tyr Asn Ala Ile Ile Ala Leu Glu Asp Leu Gly Gln Met Phe 1025 1030 1035

    Val Thr Arg Gly Gln Lys Ile Glu Lys Ala Val Tyr Gln Gln Phe 1040 1045 1050

    Glu Lys Ser Leu Val Asp Lys Leu Ser Tyr Leu Val Asp Lys Lys 1055 1060 1065

    Arg Pro Tyr Asn Glu Leu Gly Gly Ile Leu Lys Ala Tyr Gln Leu 1070 1075 1080

    Ala Ser Ser Ile Thr Lys Asn Asn Ser Asp Lys Gln Asn Gly Phe 1085 1090 1095

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val 1100 1105 1110

    Thr Gly Phe Thr Asp Leu Leu Arg Pro Lys Ala Met Thr Ile Lys 1115 1120 1125

    Glu Ala Gln Asp Phe Phe Gly Ala Phe Asp Asn Ile Ser Tyr Asn 1130 1135 1140

    Asp Lys Gly Tyr Phe Glu Phe Glu Thr Asn Tyr Asp Lys Phe Lys 1145 1150 1155

    Ile Arg Met Lys Ser Ala Gln Thr Arg Trp Thr Ile Cys Thr Phe 1160 1165 1170

    Gly Asn Arg Ile Lys Arg Lys Lys Asp Lys Asn Tyr Trp Asn Tyr 1175 1180 1185

    Glu Glu Val Glu Leu Thr Glu Glu Phe Lys Lys Leu Phe Lys Asp 1190 1195 1200

    Ser Asn Ile Asp Tyr Glu Asn Cys Asn Leu Lys Glu Glu Ile Gln 1205 1210 1215

    Asn Lys Asp Asn Arg Lys Phe Phe Asp Asp Leu Ile Lys Leu Leu 1220 1225 1230

    Gln Leu Thr Leu Gln Met Arg Asn Ser Asp Asp Lys Gly Asn Asp 1235 1240 1245

    Tyr Ile Ile Ser Pro Val Ala Asn Ala Glu Gly Gln Phe Phe Asp 1250 1255 1260

    Ser Arg Asn Gly Asp Lys Lys Leu Pro Leu Asp Ala Asp Ala Asn 1265 1270 1275

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Asn Ile Arg Gln 1280 1285 1290

    Ile Lys Gln Thr Lys Asn Asp Lys Lys Leu Asn Leu Ser Ile Ser 1295 1300 1305

    Ser Thr Glu Trp Leu Asp Phe Val Arg Glu Lys Pro Tyr Leu Lys 1310 1315 1320

    Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys 1325 1330 1335

    Lys Gly Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr 1340 1345 1350

    Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala

    1355 1360 1365 <210> 245 <211> 1291 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 245

    Met Lys Thr Gln His Phe Phe Glu Asp Phe Thr Ser Leu Tyr Ser Leu 1 5 10 15

    Ser Lys Thr Ile Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu 20 25 30

    Asn Ile Lys Lys Asn Gly Leu Ile Arg Arg Asp Glu Gln Arg Leu Asp 35 40 45

    Asp Tyr Glu Lys Leu Lys Lys Val Ile Asp Glu Tyr His Glu Asp Phe 50 55 60

    Ile Ala Asn Ile Leu Ser Ser Phe Ser Phe Ser Glu Glu Ile Leu Gln 65 70 75 80

    Ser Tyr Ile Gln Asn Leu Ser Glu Ser Glu Ala Arg Ala Lys Ile Glu 85 90 95

    Lys Thr Met Arg Asp Thr Leu Ala Lys Ala Phe Ser Glu Asp Glu Arg 100 105 110

    Tyr Lys Ser Ile Phe Lys Lys Glu Leu Val Lys Lys Asp Ile Pro Val 115 120 125

    Trp Cys Pro Ala Tyr Lys Ser Leu Cys Lys Lys Phe Asp Asn Phe Thr 130 135 140

    Thr Ser Leu Val Pro Phe His Glu Asn Arg Lys Asn Leu Tyr Thr Ser 145 150 155 160

    Asn Glu Ile Thr Ala Ser Ile Pro Tyr Arg Ile Val His Val Asn Leu 165 170 175

    Pro Lys Phe Ile Gln Asn Ile Glu Ala Leu Cys Glu Leu Gln Lys Lys 180 185 190

    Met Gly Ala Asp Leu Tyr Leu Glu Met Met Glu Asn Leu Arg Asn Val 195 200 205

    Trp Pro Ser Phe Val Lys Thr Pro Asp Asp Leu Cys Asn Leu Lys Thr 210 215 220

    Tyr Asn His Leu Met Val Gln Ser Ser Ile Ser Glu Tyr Asn Arg Phe 225 230 235 240

    Val Gly Gly Tyr Ser Thr Glu Asp Gly Thr Lys His Gln Gly Ile Asn 245 250 255

    Glu Trp Ile Asn Ile Tyr Arg Gln Arg Asn Lys Glu Met Arg Leu Pro 260 265 270

    Gly Leu Val Phe Leu His Lys Gln Ile Leu Ala Lys Val Asp Ser Ser 275 280 285

    Ser Phe Ile Ser Asp Thr Leu Glu Asn Asp Asp Gln Val Phe Cys Val 290 295 300

    Leu Arg Gln Phe Arg Lys Leu Phe Trp Asn Thr Val Ser Ser Lys Glu 305 310 315 320

    Asp Asp Ala Ala Ser Leu Lys Asp Leu Phe Cys Gly Leu Ser Gly Tyr 325 330 335

    Asp Pro Glu Ala Ile Tyr Val Ser Asp Ala His Leu Ala Thr Ile Ser 340 345 350

    Lys Asn Ile Phe Asp Arg Trp Asn Tyr Ile Ser Asp Ala Ile Arg Arg 355 360 365

    Lys Thr Glu Val Leu Met Pro Arg Lys Lys Glu Ser Val Glu Arg Tyr 370 375 380

    Ala Glu Lys Ile Ser Lys Gln Ile Lys Lys Arg Gln Ser Tyr Ser Leu 385 390 395 400

    Ala Glu Leu Asp Asp Leu Leu Ala His Tyr Ser Glu Glu Ser Leu Pro 405 410 415

    Ala Gly Phe Ser Leu Leu Ser Tyr Phe Thr Ser Leu Gly Gly Gln Lys 420 425 430

    Tyr Leu Val Ser Asp Gly Glu Val Ile Leu Tyr Glu Glu Gly Ser Asn 435 440 445

    Ile Trp Asp Glu Val Leu Ile Ala Phe Arg Asp Leu Gln Val Ile Leu 450 455 460

    Asp Lys Asp Phe Thr Glu Lys Lys Leu Gly Lys Asp Glu Glu Ala Val 465 470 475 480

    Ser Val Ile Lys Lys Ala Leu Asp Ser Ala Leu Arg Leu Arg Lys Phe 485 490 495

    Phe Asp Leu Leu Ser Gly Thr Gly Ala Glu Ile Arg Arg Asp Ser Ser 500 505 510

    Phe Tyr Ala Leu Tyr Thr Asp Arg Met Asp Lys Leu Lys Gly Leu Leu

    515

    520

    525

    Lys Met Tyr Asp Lys Val Arg Asn Tyr Leu Thr Lys Lys Pro Tyr Ser 530 535 540

    Ile Glu Lys Phe Lys Leu His Phe Asp Asn Pro Ser Leu Leu Ser Gly 545 550 555 560

    Trp Asp Lys Asn Lys Glu Leu Asn Asn Leu Ser Val Ile Phe Arg Gln 565 570 575

    Asn Gly Tyr Tyr Tyr Leu Gly Ile Met Thr Pro Lys Gly Lys Asn Leu 580 585 590

    Phe Lys Thr Leu Pro Lys Leu Gly Ala Glu Glu Met Phe Tyr Glu Lys 595 600 605

    Met Glu Tyr Lys Gln Ile Ala Glu Pro Met Leu Met Leu Pro Lys Val 610 615 620

    Phe Phe Pro Lys Lys Thr Lys Pro Ala Phe Ala Pro Asp Gln Ser Val 625 630 635 640

    Val Asp Ile Tyr Asn Lys Lys Thr Phe Lys Thr Gly Gln Lys Gly Phe 645 650 655

    Asn Lys Lys Asp Leu Tyr Arg Leu Ile Asp Phe Tyr Lys Glu Ala Leu 660 665 670

    Thr Val His Glu Trp Lys Leu Phe Asn Phe Ser Phe Ser Pro Thr Glu 675 680 685

    Gln Tyr Arg Asn Ile Gly Glu Phe Phe Asp Glu Val Arg Glu Gln Ala 690 695 700

    Tyr Lys Val Ser Met Val Asn Val Pro Ala Ser Tyr Ile Asp Glu Ala 705 710 715 720

    Val Glu Asn Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 725 730 735

    Ser Pro Tyr Ser Lys Gly Ile Pro Asn Leu His Thr Leu Tyr Trp Lys 740 745 750

    Ala Leu Phe Ser Glu Gln Asn Gln Ser Arg Val Tyr Lys Leu Cys Gly 755 760 765

    Gly Gly Glu Leu Phe Tyr Arg Lys Ala Ser Leu His Met Gln Asp Thr 770 775 780

    Thr Val His Pro Lys Gly Ile Ser Ile His Lys Lys Asn Leu Asn Lys 785 790 795 800

    Lys Gly Glu Thr Ser Leu Phe Asn Tyr Asp Leu Val Lys Asp Lys Arg 805 810 815

    Phe Thr Glu Asp Lys Phe Phe Phe His Val Pro Ile Ser Ile Asn Tyr 820 825 830

    Lys Asn Lys Lys Ile Thr Asn Val Asn Gln Met Val Arg Asp Tyr Ile 835 840 845

    Ala Gln Asn Asp Asp Leu Gln Ile Ile Gly Ile Asp Arg Gly Glu Arg 850 855 860

    Asn Leu Leu Tyr Ile Ser Arg Ile Asp Thr Arg Gly Asn Leu Leu Glu 865 870 875 880

    Gln Phe Ser Leu Asn Val Ile Glu Ser Asp Lys Gly Asp Leu Arg Thr 885 890 895

    Asp Tyr Gln Lys Ile Leu Gly Asp Arg Glu Gln Glu Arg Leu Arg Arg 900 905 910

    Arg Gln Glu Trp Lys Ser Ile Glu Ser Ile Lys Asp Leu Lys Asp Gly 915 920 925

    Tyr Met Ser Gln Val Val His Lys Ile Cys Asn Met Val Val Glu His 930 935 940

    Lys Ala Ile Val Val Leu Glu Asn Leu Asn Leu Ser Phe Met Lys Gly 945 950 955 960

    Arg Lys Lys Val Glu Lys Ser Val Tyr Glu Lys Phe Glu Arg Met Leu 965 970 975

    Val Asp Lys Leu Asn Tyr Leu Val Val Asp Lys Lys Asn Leu Ser Asn 980 985 990

    Glu Pro Gly Gly Leu Tyr Ala Ala Tyr Gln Leu Thr Asn Pro Leu Phe 995 1000 1005

    Ser Phe Glu Glu Leu His Arg Tyr Pro Gln Ser Gly Ile Leu Phe 1010 1015 1020

    Phe Val Asp Pro Trp Asn Thr Ser Leu Thr Asp Pro Ser Thr Gly 1025 1030 1035

    Phe Val Asn Leu Leu Gly Arg Ile Asn Tyr Thr Asn Val Gly Asp 1040 1045 1050

    Ala Arg Lys Phe Phe Asp Arg Phe Asn Ala Ile Arg Tyr Asp Gly 1055 1060 1065

    Lys Gly Asn Ile Leu Phe Asp Leu Asp Leu Ser Arg Phe Asp Val 1070 1075 1080

    Arg Val Glu Thr Gln Arg Lys Leu Trp Thr Leu Thr Thr Phe Gly 1085 1090 1095

    Ser Arg Ile Ala Lys Ser Lys Lys Ser Gly Lys Trp Met Val Glu 1100 1105 1110

    Arg Ile Glu Asn Leu Ser Leu Cys Phe Leu Glu Leu Phe Glu Gln 1115 1120 1125

    Phe Asn Ile Gly Tyr Arg Val Glu Lys Asp Leu Lys Lys Ala Ile 1130 1135 1140

    Leu Ser Gln Asp Arg Lys Glu Phe Tyr Val Arg Leu Ile Tyr Leu 1145 1150 1155

    Phe Asn Leu Met Met Gln Ile Arg Asn Ser Asp Gly Glu Glu Asp 1160 1165 1170

    Tyr Ile Leu Ser Pro Ala Leu Asn Glu Lys Asn Leu Gln Phe Asp 1175 1180 1185

    Ser Arg Leu Ile Glu Ala Lys Asp Leu Pro Val Asp Ala Asp Ala 1190 1195 1200

    Asn Gly Ala Tyr Asn Val Ala Arg Lys Gly Leu Met Val Val Gln 1205 1210 1215

    Arg Ile Lys Arg Gly Asp His Glu Ser Ile His Arg Ile Gly Arg

    1220 1225 1230

    Ala Gln Trp Leu Arg Tyr Val Gln Glu Gly Ile Val Glu Lys Arg 1235 1240 1245

    Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gly 1250 1255 1260

    Ser Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val 1265 1270 1275

    Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1280 1285 1290 <210> 246 <211> 18 <212> PRT <213> Alicyclobacillus acidoterrestris <400> 246

    Leu Arg Val Met Ser Val Asp Leu Gly Leu Arg Thr Ser Ala Ser Ile 1 5 10 15

    Ser Val <210> 247 <211> 22 <212> PRT <213> Alicyclobacillus acidoterrestris <400> 247

    Gln Arg Thr Leu Arg Gln Leu Arg Thr Gln Leu Ala Tyr Leu Arg Leu

    1 5 10 15

    Leu Val Arg Cys Gly Ser <210> 248 <211> 12 <212> PRT <213> Alicyclobacillus acidoterrestris <400> 248

    Cys Gln Leu Ile Leu Leu Glu Glu Leu Ser Glu Tyr 1 5 10 <210> 249 <211> 16 <212> PRT <213> Alicyclobacillus acidoterrestris <400> 249

    His Gln Ile His Ala Asp Leu Asn Ala Ala Gln Asn Leu Gln Gln Arg 1 5 10 15 <210> 250 <211> 18 <212> PRT <213> Alicyclobacillus contaminans <400> 250

    Val Arg Val Met Ser Val Asp Leu Gly Val Arg Tyr Gly Ala Ala Ile 1 5 10 15

    Ser Val <210> 251 <211> 22 <212> PRT <213> Alicyclobacillus contaminans <400> 251

    Lys Gln Ala Leu Ala Ala Ile Arg Ala Glu Met Ser Ile Leu Arg Lys

    1 5 10 15

    Trp Leu Arg Val Ser Gln 20 <210> 252 <211> 12 <212> PRT <213> Alicyclobacillus contaminans <400> 252

    Cys Asp Leu Ile Leu Phe Glu Asp Leu Ser Arg Tyr 1 5 10 <210> 253 <211> 16 <212> PRT <213> Alicyclobacillus contaminans <400> 253

    Lys Cys Val His Ala Asp Ile Asn Ala Ala His Asn Leu Gln Arg Arg 1 5 10 15 <210> 254 <211> 18 <212> PRT <213> Desulfovibrio inopinatus <400> 254

    Leu Arg Val Leu Ser Val Asp Leu Gly Met Arg Thr Phe Ala Ser Cys 1 5 10 15

    Ser Val <210> 255 <211> 22 <212> PRT <213> Desulfovibrio inopinatus <400> 255

    Arg Ala Glu Ile Tyr Ala Leu Lys Arg Asp Ile Gln Arg Leu Lys Ser 1 5 10 15

    Leu Leu Arg Leu Gly Glu 20 <210> 256 <211> 12 <212> PRT <213> Desulfovibrio inopinatus <400> 256

    Cys Gln Leu Ile Leu Phe Glu Asp Leu Ala Arg Tyr 1 5 10 <210> 257 <211> 16 <212> PRT <213> Desulfovibrio inopinatus <400> 257

    Cys Val Ile His Ala Asp Met Asn Ala Ala Gln Asn Leu Gln Arg Arg 1 5 10 15 <210> 258 <211> 18 <212> PRT <213> Desulfonatronum thiodismutans <400> 258

    Leu Arg Val Leu Ser Val Asp Leu Gly Val Arg Ser Phe Ala Ala Cys 1 5 10 15

    Ser Val <210> 259 <211> 22 <212> PRT <213> Desulfonatronum thiodismutans <400> 259

    Met Glu Glu Leu Arg Ser Leu Asn Gly Asp Ile Arg Arg Leu Lys Ala 1 5 10 15

    Ile Leu Arg Leu Ser Val 20 <210> 260 <211> 12 <212> PRT <213> Desulfonatronum thiodismutans <400> 260

    Cys Arg Leu Ile Leu Phe Glu Asp Leu Ala Arg Tyr 1 5 10 <210> 261 <211> 16 <212> PRT <213> Desulfonatronum thiodismutans <400> 261

    His Val Ile His Ala Asp Ile Asn Ala Ala Gln Asn Leu Gln Arg Arg 1 5 10 15 <210> 262 <211> 18 <212> PRT <213> Tuberibacillus calidus <400> 262

    Leu Arg Val Met Ser Val Asp Leu Gly Gln Arg Gln Ala Ala Ala Ile 1 5 10 15

    Ser Ile <210> 263 <211> 22 <212> PRT <213> Tuberibacillus calidus <400> 263

    Asp Gln Ala Ile Arg Asp Leu Ser Arg Lys Leu Lys Phe Leu Lys Asn 1 5 10 15

    Val Leu Asn Met Gln Lys 20 <210> 264 <211> 12 <212> PRT <213> Tuberibacillus calidus <400> 264

    Cys Gln Leu Val Leu Phe Glu Asp Leu Ser Arg Tyr 1 5 10 <210> 265 <211> 16 <212> PRT <213> Tuberibacillus calidus <400> 265

    Val Ile Thr His Ala Asp Ile Asn Ala Ala Gln Asn Leu Gln Lys Arg 1 5 10 15 <210> 266 <211> 18 <212> PRT <213> Bacillus thermoamylovorans <400> 266

    Leu Arg Val Met Ser Ile Asp Leu Gly Gln Arg Gln Ala Ala Ala Ala

    1 5 10 15

    Ser Ile <210> 267 <211> 22 <212> PRT <213> Bacillus thermoamylovorans <400> 267

    Glu Asp Asn Leu Lys Leu Met Asn Gln Lys Leu Asn Phe Leu Arg Asn 1 5 10 15

    Val Leu His Phe Gln Gln 20 <210> 268 <211> 12 <212> PRT <213> Bacillus thermoamylovorans <400> 268

    Cys Gln Ile Ile Leu Phe Glu Asp Leu Ser Asn Tyr 1 5 10 <210> 269 <211> 16 <212> PRT <213> Bacillus thermoamylovorans <400> 269

    Val Thr Thr His Ala Asp Ile Asn Ala Ala Gln Asn Leu Gln Lys Arg 1 5 10 15 <210> 270 <211> 18 <212> PRT <213> Bacillus sp.

    <400> 270

    Phe Arg Val Met Ser Ile Asp Leu Gly Leu Arg Ala Ala Ala Ala Thr

    1 5 10 15

    Ser Ile <210> 271 <211> 22 <212> PRT <213> Bacillus sp.

    <400> 271

    Phe Gln Leu His Gln Arg Val Lys Phe Gln Ile Arg Val Leu Ala Gln 1 5 10 15

    Ile Met Arg Met Ala Asn 20 <210> 272 <211> 12 <212> PRT <213> Bacillus sp.

    <400> 272

    Cys Gln Val Ile Leu Phe Glu Asn Leu Ser Gln Tyr 1 5 10 <210> 273 <211> 16 <212> PRT <213> Bacillus sp.

    <400> 273

    Val Phe Leu Gln Ala Asp Ile Asn Ala Ala His Asn Leu Gln Lys Arg

    1 5 10 15 <210> 274 <211> 18 <212> PRT <213> Methylobacterium nodulans <400> 274

    Leu Arg Val Leu Ser Ile Asp Leu Gly Val Arg Ser Phe Ala Thr Cys 1 5 10 15

    Ser Val <210> 275 <211> 22 <212> PRT <213> Methylobacterium nodulans <400> 275

    Asp Ala Glu Leu Arg Gln Leu Arg Gly Gly Leu Asn Arg His Arg Gln 1 5 10 15

    Leu Leu Arg Ala Ala Thr 20 <210> 276 <211> 12 <212> PRT <213> Methylobacterium nodulans <400> 276

    Cys His Val Ile Leu Phe Glu Asp Leu Ser Arg Tyr 1 5 10 <210> 277 <211> 16 <212> PRT <213> Methylobacterium nodulans <400> 277

    Ser Arg Ile His Ala Asp Ile Asn Ala Ala Gln Asn Leu Gln Arg Arg

    1 5 10 15 <210> 278 <211> 18 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 278

    Leu Lys Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Ile Tyr Val 1 5 10 15

    Thr Met <210> 279 <211> 22 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 279

    Arg Lys Ala Leu Asp Val Arg Glu Tyr Asp Asn Lys Glu Ala Arg Arg 1 5 10 15

    Asn Trp Thr Lys Val Glu 20 <210> 280 <211> 13 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 280

    Asn Ala Ile Ile Val Met Glu Asp Leu Asn His Gly Phe <210> 281 <211> 16 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 281

    Leu Pro Gln Asp Ser Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Lys 1 5 10 15 <210> 282 <211> 18 <212> PRT <213> Synergistes jonesii <400> 282

    Val Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Val Tyr Val 1 5 10 15

    Ser Leu <210> 283 <211> 22 <212> PRT <213> Synergistes jonesii <400> 283

    His Ala Lys Leu Asn Gln Lys Glu Lys Glu Arg Asp Thr Ala Arg Lys

    1 5 10 15

    Ser Trp Lys Thr Ile Gly <210> 284 <211> 13 <212> PRT <213> Synergistes jonesii <400> 284

    Asn Ala Val Ile Val Met Glu Asp Leu Asn Ile Gly Phe 1 5 10 <210> 285 <211> 16 <212> PRT <213> Synergistes jonesii <400> 285

    Leu Pro Ile Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys 1 5 10 15 <210> 286 <211> 18 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 286

    Pro Tyr Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Ile 1 5 10 15

    Val Val <210> 287 <211> 22 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 287

    His Ser Leu Leu Asp Lys Lys Glu Lys Glu Arg Phe Glu Ala Arg Gln 1 5 10 15

    Asn Trp Thr Ser Ile Glu 20 <210> 288 <211> 13 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 288

    Asp Ala Val Ile Ala Leu Glu Asp Leu Asn Ser Gly Phe 1 5 10 <210> 289 <211> 16 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 289

    Leu Pro Lys Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys 1 5 10 15 <210> 290 <211> 18 <212> PRT <213> Francisella tularensis <400> 290

    Val His Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr 1 5 10 15

    Thr Leu <210> 291 <211> 22 <212> PRT <213> Francisella tularensis <400> 291

    His Asp Lys Leu Ala Ala Ile Glu Lys Asp Arg Asp Ser Ala Arg Lys 1 5 10 15

    Asp Trp Lys Lys Ile Asn 20 <210> 292 <211> 13 <212> PRT <213> Francisella tularensis <400> 292

    Asn Ala Ile Val Val Phe Glu Asp Leu Asn Phe Gly Phe 1 5 10 <210> 293 <211> 16 <212> PRT <213> Francisella tularensis <400> 293

    Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly Leu Lys

    1 5 10 15 <210> 294 <211> 18 <212> PRT <213> Moraxella caprae <400> 294

    Val Asn Val Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Leu 1 5 10 15

    Thr Val <210> 295 <211> 22 <212> PRT <213> Moraxella caprae <400> 295

    His Lys Ile Leu Asp Lys Arg Glu Ile Glu Arg Leu Asn Ala Arg Val 1 5 10 15

    Gly Trp Gly Glu Ile Glu 20 <210> 296 <211> 13 <212> PRT <213> Moraxella caprae <400> 296

    Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly Phe 1 5 10 <210> 297 <211> 16 <212> PRT <213> Moraxella caprae <400> 297

    Gln Pro Gln Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys

    1 5 10 15 <210> 298 <211> 18 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 298

    Met His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Ile Tyr Leu 1 5 10 15

    Cys Met <210> 299 <211> 22 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 299

    His Gln Leu Leu Lys Thr Arg Glu Asp Glu Asn Lys Ser Ala Arg Gln 1 5 10 15

    Ser Trp Gln Thr Ile His 20 <210> 300 <211> 13 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 300

    Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly Phe

    1 5 10 <210> 301 <211> 16 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 301

    Met Pro Leu Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys 1 5 10 15 <210> 302 <211> 18 <212> PRT <213> Prevotella albensis <400> 302

    Thr His Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Leu 1 5 10 15

    Ser Leu <210> 303 <211> 22 <212> PRT <213> Prevotella albensis <400> 303

    His Asn Leu Leu Glu Lys Arg Glu Lys Glu Arg Thr Glu Ala Arg His

    1 5 10 15

    Ser Trp Ser Ser Ile Glu <210> 304 <211> 13 <212> PRT <213> Prevotella albensis <400> 304

    Asn Ala Ile Val Val Leu Glu Asp Leu Asn Gly Gly Phe 1 5 10 <210> 305 <211> 16 <212> PRT <213> Prevotella albensis <400> 305

    Phe Pro Glu Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys 1 5 10 15 <210> 306 <211> 18 <212> PRT <213> Smithella sp.

    <400> 306

    Ile Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Tyr 1 5 10 15

    Ala Leu <210> 307 <211> 22 <212> PRT <213> Smithella sp.

    <400> 307

    His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr Ala Arg Gln

    1 5 10 15

    Glu Trp Gly Val Ile Glu 20 <210> 308 <211> 13 <212> PRT <213> Smithella sp.

    <400> 308

    Asn Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe 1 5 10 <210> 309 <211> 16 <212> PRT <213> Smithella sp.

    <400> 309

    Met Pro Lys Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys 1 5 10 15 <210> 310 <211> 18 <212> PRT <213> Porphyromonas crevioricanis <400> 310

    Met His Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Ile 1 5 10 15

    Cys Val <210> 311 <211> 22 <212> PRT <213> Porphyromonas crevioricanis <400> 311

    His Asp Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg 1 5 10 15

    Asn Trp Gln Thr Ile Glu 20 <210> 312 <211> 13 <212> PRT <213> Porphyromonas crevioricanis <400> 312

    Lys Ala Val Val Ala Leu Glu Asp Leu Asn Met Gly Phe 1 5 10 <210> 313 <211> 16 <212> PRT <213> Porphyromonas crevioricanis <400> 313

    Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Lys 1 5 10 15 <210> 314 <211> 18 <212> PRT <213> Sulfolobus solfataricus <400> 314

    Gly Lys Val Val Ala Ile Asp Val Gly Val Glu Lys Leu Leu Ile Thr 1 5 10 15

    Ser Asp <210> 315 <211> 23 <212> PRT <213> Sulfolobus solfataricus <400> 315

    Val Lys His Ile His Arg Glu Leu Ser Arg Lys Lys Phe Leu Ser Asn 1 5 10 15

    Asn Trp Phe Lys Ala Lys Val 20 <210> 316 <211> 13 <212> PRT <213> Sulfolobus solfataricus <400> 316

    Tyr Asp Val Val Val Met Glu Gly Ile His Ala Lys Gln 1 5 10 <210> 317 <211> 16 <212> PRT <213> Sulfolobus solfataricus <400> 317

    Trp Ile Ala Asp Arg Asp Tyr Asn Ala Ser Leu Asn Ile Leu Arg Gly 1 5 10 15 <210> 318 <211> 18 <212> PRT <213> Nostoc sp.

    <400> 318

    Leu Lys Thr Ile Gly Leu Asp Val Gly Leu Asn His Phe Leu Thr Asp 1 5 10 15

    Ser Glu <210> 319 <211> 23 <212> PRT <213> Nostoc sp.

    <400> 319

    Leu Lys Arg Leu Gln Arg Arg Leu Ser Lys Thr Lys Lys Gly Ser Asn 1 5 10 15

    Asn Arg Val Lys Ala Arg Asn 20 <210> 320 <211> 13 <212> PRT <213> Nostoc sp.

    <400> 320

    Ser Asp Leu Val Ala Tyr Glu Asp Leu Gln Val Arg Asn 1 5 10 <210> 321 <211> 16 <212> PRT <213> Nostoc sp.

    <400> 321

    His Ile Gln Asp Arg Asp Trp Asn Ala Ala Arg Asn Ile Leu Glu Leu 1 5 10 15 <210> 322 <211> 18 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Nitrososphaera gargensis sequence <400> 322

    Ala Lys Pro Val Gly Ile Asp Val Gly Ile Ala Lys Phe Cys His His

    Ser Asp <210> 323 <211> 23 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Nitrososphaera gargensis sequence <400> 323

    Leu Arg Arg Ala His Arg Arg Val Ser Arg Arg Gln Ile Gly Ser Asn 1 5 10 15

    Asn Arg Lys Lys Ala Lys Arg 20 <210> 324 <211> 13 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Nitrososphaera gargensis sequence <400> 324

    Tyr Asp Leu Ile Phe Leu Glu Arg Leu Arg Val Met Asn 1 5 10 <210> 325 <211> 16 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Nitrososphaera gargensis sequence <400> 325

    Ala Ile Leu Asp Arg Asp Tyr Asn Ser Ala Ile Asn Ile Leu Lys Arg 1 5 10 15 <210> 326 <211> 18 <212> PRT <213> Helicobacter pylori <400> 326

    Lys Lys Ala Val Gly Leu Asp Met Gly Leu Arg Thr Leu Ile Val Thr 1 5 10 15

    Ser Asp <210> 327 <211> 23 <212> PRT <213> Helicobacter pylori <400> 327

    Leu Thr Lys Ala Gln Arg Arg Leu Ser Lys Lys Val Lys Asp Ser Asn 1 5 10 15

    Asn Arg Lys Lys Gln Ala Lys 20 <210> 328 <211> 13 <212> PRT <213> Helicobacter pylori <400> 328

    Tyr Asp Leu Ile Gly Val Glu Thr Leu Asn Val Lys Ala 1 5 10 <210> 329 <211> 16 <212> PRT <213> Helicobacter pylori <400> 329

    Thr Thr His His Arg Asp Tyr Asn Ala Ser Val Asn Ile Arg Asn Tyr 1 5 10 15 <210> 330 <211> 18 <212> PRT <213> Flexibacter litoralis <400> 330

    Asn Gln Ala Val Gly Ile Asp Met Gly Ile Thr Phe Phe Cys Ile Asp 1 5 10 15

    Ser Asn <210> 331 <211> 23 <212> PRT <213> Flexibacter litoralis <400> 331

    Leu Arg Ile Ala Asn Arg Ser Leu Ser Arg Lys Lys Lys Phe Ser Asn 1 5 10 15

    Gly Trp Tyr Lys Lys Lys Val 20 <210> 332 <211> 13 <212> PRT <213> Flexibacter litoralis <400> 332

    Asn Ser Leu Val Val Val Glu Asp Leu Lys Val Lys Asn

    1 5 10 <210> 333 <211> 16 <212> PRT <213> Flexibacter litoralis <400> 333

    His Glu Thr Asn Ala Asp Glu Asn Ala Ser Lys Asn Ile Leu Ser Glu 1 5 10 15 <210> 334 <211> 18 <212> PRT <213> Escherichia coli <400> 334

    Ala Ser Met Val Gly Leu Asp Ala Gly Val Ala Lys Leu Ala Thr Leu 1 5 10 15

    Ser Asp <210> 335 <211> 23 <212> PRT <213> Escherichia coli <400> 335

    Leu Ala Arg Leu Gln Arg Gln Leu Ser Arg Lys Val Lys Phe Ser Asn 1 5 10 15

    Asn Trp Gln Lys Gln Lys Arg 20 <210> 336 <211> 13 <212> PRT <213> Escherichia coli <400> 336

    His Ala Met Ile Val Ile Glu Asp Leu Lys Val Ser Asn 1 5 10 <210> 337 <211> 16 <212> PRT <213> Escherichia coli <400> 337

    Tyr Thr Ala Asn Ala Asp Val Asn Gly Ala Arg Asn Ile Leu Ala Ala 1 5 10 15 <210> 338 <211> 18 <212> PRT <213> Clostridium botulinum <400> 338

    Asn Lys Lys Val Gly Ile Asp Val Gly Leu Lys Glu Phe Ala Thr Thr 1 5 10 15

    Ser Asp <210> 339 <211> 23 <212> PRT <213> Clostridium botulinum <400> 339

    Leu Ala Lys Leu Gln Lys Asp Leu Ser Arg Lys Lys Lys Asn Ser Asn

    1 5 10 15

    Asn Arg Lys Lys Ala Arg Leu <210> 340 <211> 13 <212> PRT <213> Clostridium botulinum <400> 340

    Asn Gln Ala Ile Val Ile Glu Asn Leu Lys Val Ser Asn 1 5 10 <210> 341 <211> 16 <212> PRT <213> Clostridium botulinum <400> 341

    Met Ile Met Asp Arg Asp Leu Asn Ala Ser Lys Asn Leu Leu Asn Leu 1 5 10 15 <210> 342 <211> 18 <212> PRT <213> Acidaminococcus sp.

    <400> 342

    Met Tyr Tyr Leu Gly Leu Asp Ile Gly Thr Asn Ser Val Gly Tyr Ala 1 5 10 15

    Val Thr

    Gln Gln Arg Val Lys Leu <210> 343 <211> 22 <212> PRT <213> Acidaminococcus sp.

    <400> 343

    Ala Glu Arg Arg Ser Phe Arg Thr Ser Arg Arg Arg Leu Asp Arg Arg

    1 5 10 15 <210> 344 <211> 13 <212> PRT <213> Acidaminococcus sp.

    <400> 344

    Pro Lys Arg Ile Phe Ile Glu Met Ala Arg Asp Gly Glu 1 5 10 <210> 345 <211> 16 <212> PRT <213> Acidaminococcus sp.

    <400> 345

    Leu His His Ala Lys Asp Ala Phe Leu Ala Ile Val Thr Gly Asn Val 1 5 10 15 <210> 346 <211> 18 <212> PRT <213> Coprococcus catus <400> 346

    Glu Tyr Phe Leu Gly Leu Asp Met Gly Thr Gly Ser Leu Gly Trp Ala 1 5 10 15

    Val Thr <210> 347 <211> 22 <212> PRT <213> Coprococcus catus <400> 347

    Glu Glu Arg Arg Met Phe Arg Thr Ala Arg Arg Arg Leu Asp Arg Arg 1 5 10 15

    Asn Trp Arg Ile Gln Val 20 <210> 348 <211> 13 <212> PRT <213> Coprococcus catus <400> 348

    Pro Lys Arg Val Phe Val Glu Met Ala Arg Glu Lys Gln 1 5 10 <210> 349 <211> 16 <212> PRT <213> Coprococcus catus <400> 349

    Leu His His Ala Lys Asp Ala Tyr Leu Asn Ile Val Val Gly Asn Ala 1 5 10 15 <210> 350 <211> 18 <212> PRT <213> Treponema denticola <400> 350

    Asp Tyr Phe Leu Gly Leu Asp Val Gly Thr Gly Ser Val Gly Trp Ala 1 5 10 15

    Val Thr <210> 351 <211> 22 <212> PRT <213> Treponema denticola <400> 351

    Glu Val Arg Arg Leu His Arg Gly Ala Arg Arg Arg Ile Glu Arg Arg 1 5 10 15

    Lys Lys Arg Ile Lys Leu 20 <210> 352 <211> 13 <212> PRT <213> Treponema denticola <400> 352

    Pro Lys Lys Ile Phe Ile Glu Met Ala Lys Gly Ala Glu 1 5 10 <210> 353 <211> 16 <212> PRT <213> Treponema denticola <400> 353

    Phe His His Ala His Asp Ala Tyr Leu Asn Ile Val Val Gly Asn Val 1 5 10 15 <210> 354 <211> 18 <212> PRT <213> Mycoplasma mobile <400> 354

    Lys Val Val Leu Gly Leu Asp Leu Gly Ile Ala Ser Val Gly Trp Cys 1 5 10 15

    Leu Thr <210> 355 <211> 22 <212> PRT <213> Mycoplasma mobile <400> 355

    Glu Thr Arg Arg Lys Lys Arg Gly Gln Arg Arg Arg Asn Arg Arg Leu 1 5 10 15

    Phe Thr Arg Lys Arg Asp 20 <210> 356 <211> 13 <212> PRT <213> Mycoplasma mobile <400> 356

    Ile Glu Lys Ile Val Val Glu Val Thr Arg Ser Ser Asn 1 5 10 <210> 357 <211> 16 <212> PRT <213> Mycoplasma mobile <400> 357

    Gly His His Ala Glu Asp Ala Tyr Phe Ile Thr Ile Ile Ser Gln Tyr 1 5 10 15

    Ile Leu <210> 358 <211> 18 <212> PRT <213> Streptococcus thermophilus <400> 358

    Asp Leu Val Leu Gly Leu Asp Ile Gly Ile Gly Ser Val Gly Val Gly

    1 5 10 15 <210> 359 <211> 22 <212> PRT <213> Streptococcus thermophilus <400> 359

    Leu Val Arg Arg Thr Asn Arg Gln Gly Arg Arg Leu Thr Arg Arg Lys 1 5 10 15

    Lys His Arg Ile Val Arg 20 <210> 360 <211> 13 <212> PRT <213> Streptococcus thermophilus <400> 360

    Phe Asp Asn Ile Val Ile Glu Met Ala Arg Glu Thr Asn 1 5 10 <210> 361 <211> 16 <212> PRT <213> Streptococcus thermophilus <400> 361

    His His His Ala Val Asp Ala Leu Ile Ile Ala Ala Ser Ser Gln Leu 1 5 10 15 <210> 362 <211> 18 <212> PRT <213> Campylobacter jejuni <400> 362

    Ala Arg Ile Leu Ala Phe Asp Ile Gly Ile Ser Ser Ile Gly Trp Ala

    1 5 10 15

    Phe Ser <210> 363 <211> 22 <212> PRT <213> Campylobacter jejuni <400> 363

    Leu Pro Arg Arg Leu Ala Arg Ser Ala Arg Lys Arg Leu Ala Arg Arg 1 5 10 15

    Lys Ala Arg Leu Asn His 20 <210> 364 <211> 13 <212> PRT <213> Campylobacter jejuni <400> 364

    Val His Lys Ile Asn Ile Glu Leu Ala Arg Glu Val Gly 1 5 10 <210> 365 <211> 16 <212> PRT <213> Campylobacter jejuni <400> 365

    Leu His His Ala Ile Asp Ala Val Ile Ile Ala Tyr Ala Asn Asn Ser 1 5 10 15 <210> 366 <211> 18 <212> PRT <213> Clostridium perfringens <400> 366

    Asn Tyr Ala Leu Gly Leu Asp Ile Gly Ile Thr Ser Val Gly Trp Ala

    Val Ile <210> 367 <211> 22 <212> PRT <213> Clostridium perfringens <400> 367

    Leu Pro Arg Arg Leu Ala Arg Gly Arg Arg Arg Leu Leu Arg Arg Lys 1 5 10 15

    Ala Tyr Arg Val Glu Arg 20 <210> 368 <211> 13 <212> PRT <213> Clostridium perfringens <400> 368

    Pro Val Arg Ile Asn Ile Glu Leu Ala Arg Asp Leu Ala 1 5 10 <210> 369 <211> 16 <212> PRT <213> Clostridium perfringens <400> 369

    Lys His His Ala Leu Asp Ala Ala Val Val Gly Val Thr Thr Gln Gly

    1 5 10 15 <210> 370 <211> 18 <212> PRT <213> Akkermansia muciniphila <400> 370

    Ser Leu Thr Phe Ser Phe Asp Ile Gly Tyr Ala Ser Ile Gly Trp Ala 1 5 10 15

    Val Ile <210> 371 <211> 22 <212> PRT <213> Akkermansia muciniphila <400> 371

    Phe Lys Arg Arg Glu Tyr Arg Arg Leu Arg Arg Asn Ile Arg Ser Arg 1 5 10 15

    Arg Val Arg Ile Glu Arg 20 <210> 372 <211> 13 <212> PRT <213> Akkermansia muciniphila <400> 372

    Ile Ser Arg Val Cys Val Glu Val Gly Lys Glu Leu Thr 1 5 10 <210> 374 <210> 373 <211> 16 <212> PRT <213> Akkermansia muciniphila <400> 373

    Leu His His Ala Leu Asp Ala Cys Val Leu Gly Leu Ile Pro Tyr Ile

    1 5 10 15 <211> 18 <212> PRT <213> Bifidobacterium longum <400> 374

    Arg Tyr Arg Ile Gly Ile Asp Val Gly Leu Asn Ser Val Gly Leu Ala 1 5 10 15

    Ala Val <210> 375 <211> 22 <212> PRT <213> Bifidobacterium longum <400> 375

    Asn Met Ser Gly Val Ala Arg Arg Thr Arg Arg Met Arg Arg Arg Lys 1 5 10 15

    Arg Glu Arg Leu His Lys 20 <210> 376 <211> 13 <212> PRT <213> Bifidobacterium longum <400> 376

    Pro Val Ser Val Asn Ile Glu His Val Arg Ser Ser Phe 1 5 10 <210> 377 <211> 16 <212> PRT <213> Bifidobacterium longum <400> 377

    Arg His His Ala Val Asp Ala Ser Val Ile Ala Met Met Asn Thr Ala

    1 5 10 15 <210> 378 <211> 18 <212> PRT <213> Wolinella succinogenes <400> 378

    Val Ser Pro Ile Ser Val Asp Leu Gly Gly Lys Asn Thr Gly Phe Phe 1 5 10 15

    Ser Phe <210> 379 <211> 22 <212> PRT <213> Wolinella succinogenes <400> 379

    Val Gly Arg Arg Ser Lys Arg His Ser Lys Arg Asn Asn Leu Arg Asn 1 5 10 15

    Lys Leu Val Lys Arg Leu 20 <210> 380 <211> 13 <212> PRT <213> Wolinella succinogenes <400> 380

    Lys Val Pro Ile Ile Leu Glu Gln Asn Ala Phe Glu Tyr

    1 5 10 <210> 381 <211> 16 <212> PRT <213> Wolinella succinogenes <400> 381

    Ser Ser His Ala Ile Asp Ala Val Met Ala Phe Val Ala Arg Tyr Gln 1 5 10 15 <210> 382 <211> 18 <212> PRT <213> Legionella pneumophila <400> 382

    Leu Ser Pro Ile Gly Ile Asp Leu Gly Gly Lys Phe Thr Gly Val Cys 1 5 10 15

    Leu Ser <210> 383 <211> 22 <212> PRT <213> Legionella pneumophila <400> 383

    Ala Gln Arg Arg Ala Thr Arg His Arg Val Arg Asn Lys Lys Arg Asn 1 5 10 15

    Gln Phe Val Lys Arg Val 20 <210> 384 <211> 13 <212> PRT <213> Legionella pneumophila <400> 384

    Leu Ile Pro Ile Tyr Leu Glu Gln Asn Arg Phe Glu Phe 1 5 10 <210> 385 <211> 15 <212> PRT <213> Legionella pneumophila <400> 385

    Pro Ser His Ala Ile Asp Ala Thr Leu Thr Met Ser Ile Gly Leu 1 5 10 15 <210> 386 <211> 18 <212> PRT <213> Francisella tularensis <400> 386

    Ile Leu Pro Ile Ala Ile Asp Leu Gly Val Lys Asn Thr Gly Val Phe 1 5 10 15

    Ser Ala <210> 387 <211> 22 <212> PRT <213> Francisella tularensis <400> 387

    Asn Asn Arg Thr Ala Arg Arg His Gln Arg Arg Gly Ile Asp Arg Lys 1 5 10 15

    Gln Leu Val Lys Arg Leu 20 <210> 388 <211> 13 <212> PRT <213> Francisella tularensis <400> 388

    His Ile Pro Ile Ile Thr Glu Ser Asn Ala Phe Glu Phe 1 5 10 <210> 389 <211> 16 <212> PRT <213> Francisella tularensis <400> 389

    Tyr Ser His Leu Ile Asp Ala Met Leu Ala Phe Cys Ile Ala Ala Asp 1 5 10 15 <210> 390 <211> 18 <212> PRT <213> Streptococcus pyogenes <400> 390

    Lys Tyr Ser Ile Gly Leu Asp Ile Gly Thr Asn Ser Val Gly Trp Ala 1 5 10 15

    Val Ile <210> 391 <211> 22 <212> PRT <213> Streptococcus pyogenes <400> 391

    Glu Ala Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg 1 5 10 15

    Lys Asn Arg Ile Cys Tyr 20 <210> 392 <211> 13 <212> PRT <213> Streptococcus pyogenes <400> 392

    Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln

    1 5 10 <210> 393 <211> 16 <212> PRT <213> Streptococcus pyogenes <400> 393

    Tyr His His Ala His Asp Ala Tyr Leu Asn Ala Val Val Gly Thr Ala 1 5 10 15 <210> 394 <211> 18 <212> PRT <213> Lactobacillus delbrueckii <400> 394

    Lys Val Ser Leu Gly Val Asp Thr Gly Gln Arg His Ile Gly Phe Ala 1 5 10 15

    Ile Val <210> 395 <211> 23 <212> PRT <213> Lactobacillus delbrueckii <400> 395

    Tyr Thr Arg Lys Ile Tyr Arg Arg Ser Lys Arg Asn Arg Lys Thr Arg 1 5 10 15

    Tyr Arg Gln Ala Arg Phe Leu 20 <210> 396 <211> 13 <212> PRT <213> Lactobacillus delbrueckii <400> 396

    Asn Pro Asp Leu His Ile Glu Val Gly Lys Phe Asp Met 1 5 10 <210> 397 <211> 15 <212> PRT <213> Lactobacillus delbrueckii <400> 397

    Lys Gly His Phe Met Asp Ala Ile Ala Ile Ser Gly Ile Lys Pro 1 5 10 15 <210> 398 <211> 18 <212> PRT <213> Methanohalobium evestigatum <400> 398

    Pro Val Val Ala Gly Met Asp Ser Gly Ser Lys His Ile Gly Cys Ala 1 5 10 15

    Ala Val <210> 399 <211> 23 <212> PRT <213> Methanohalobium evestigatum <400> 399

    Lys Asp Arg Ala Asp Tyr Arg Arg Asn Arg Arg Ser Arg Lys Thr Arg

    1 5 10 15

    Tyr Arg Lys Pro Arg Phe Asp <210> 400 <211> 13 <212> PRT <213> Methanohalobium evestigatum <400> 400

    Val Lys Lys Trp Ile Val Glu Thr Ala Ser Phe Asp Ile 1 5 10 <210> 401 <211> 15 <212> PRT <213> Methanohalobium evestigatum <400> 401

    Lys Thr His Tyr Asn Asp Ala Val Ala Ile Cys Cys Asp Glu Asn 1 5 10 15 <210> 402 <211> 18 <212> PRT <213> Clostridium botulinum <400> 402

    Pro Ile Thr Leu Gly Ile Asp Ser Gly Tyr Leu Asn Ile Gly Phe Ser 1 5 10 15

    Ala Ile

    Arg Lys Pro Arg Phe Asn <210> 403 <211> 22 <212> PRT <213> Clostridium botulinum <400> 403

    Lys Glu Lys Ala Met Tyr Arg Arg Gln Arg Arg Ser Arg Leu Arg Tyr

    1 5 10 15 <210> 404 <211> 13 <212> PRT <213> Clostridium botulinum <400> 404

    Ile Thr Asn Ile Ile Ile Glu Val Ala Asn Phe Asp Thr 1 5 10 <210> 405 <211> 15 <212> PRT <213> Clostridium botulinum <400> 405

    Lys Thr His Tyr Asn Asp Ala Phe Cys Ile Ala Gly Ser Ser Asn 1 5 10 15 <210> 406 <211> 18 <212> PRT <213> Geobacillus thermoleovorans <400> 406

    Pro Val Ser Leu Gly Val Asp Met Gly Thr Arg His Val Gly Ile Ser 1 5 10 15

    Ala Thr <210> 407 <211> 23 <212> PRT <213> Geobacillus thermoleovorans <400> 407

    Ala Ile Arg Arg Gln Phe Arg Arg Ser Arg Arg Asn Arg Lys Thr Arg 1 5 10 15

    Tyr Arg Glu Ala Arg Phe Leu 20 <210> 408 <211> 13 <212> PRT <213> Geobacillus thermoleovorans <400> 408

    Val Thr Ser Val Thr Ile Glu Val Ala Ala Phe Asp Thr 1 5 10 <210> 409 <211> 15 <212> PRT <213> Geobacillus thermoleovorans <400> 409

    Lys Ser His Met Val Asp Ala Arg Cys Ile Ser Gly Asn Pro Leu 1 5 10 15 <210> 410 <211> 18 <212> PRT <213> Ammonifex degensii <400> 410

    Ser Leu Arg Ala Lys Val Asp Asp Gly Ser Arg Tyr Val Gly Ile Ala 1 5 10 15

    Leu Val <210> 411 <211> 23 <212> PRT <213> Ammonifex degensii <400> 411

    Thr Leu Arg Arg Glu Tyr Arg Arg Gly Arg Arg Tyr Arg Ile Val Arg 1 5 10 15

    His Arg Pro Cys Arg Asn Arg 20 <210> 412 <211> 13 <212> PRT <213> Ammonifex degensii <400> 412

    Ile Ser Gly Val Asp Val Glu Leu Val Ser Ser Gly Val 1 5 10 <210> 413 <211> 15 <212> PRT <213> Ammonifex degensii <400> 413

    Lys Ser His Thr Asn Asp Ala Leu Ser Leu Phe Leu Pro Gly Gly 1 5 10 15 <210> 414 <211> 18 <212> PRT <213> Polaromonas sp.

    <400> 414

    Pro Leu Arg Ile Lys Leu Asp Pro Gly Ser Lys Thr Thr Gly Val Ala 1 5 10 15

    Leu Val <210> 415 <211> 22 <212> PRT <213> Polaromonas sp.

    <400> 415

    Thr Ala Arg Arg Gln Met Arg Arg Arg Arg Arg Ser Asn Leu Arg Cys 1 5 10 15

    Arg Ala Pro Arg Phe Leu 20 <210> 416 <211> 13 <212> PRT <213> Polaromonas sp.

    <400> 416

    Val Arg Ala Ile Ser Ser Glu Leu Val Arg Phe Asp Met 1 5 10 <210> 417 <211> 15 <212> PRT <213> Polaromonas sp.

    <400> 417

    Lys Thr His Ala Leu Asp Ala Ala Cys Val Gly Gln Val Arg Phe 1 5 10 15

    Leu Val <210> 418 <211> 18 <212> PRT <213> Anabaena variabilis <400> 418

    Asp Leu Arg Ile Lys Leu Asp Pro Gly Ala Lys Ile Thr Gly Ile Ala

    1 5 10 15 <210> 419 <211> 23 <212> PRT <213> Anabaena variabilis <400> 419

    Ile Ser Arg Arg Gln Leu Arg Arg Thr Arg Arg Asn Arg Lys Thr Arg 1 5 10 15

    Tyr Arg Lys Pro Arg Phe Leu 20 <210> 420 <211> 13 <212> PRT <213> Anabaena variabilis <400> 420

    Ile Thr Ala Ile Ser Thr Glu Leu Val Lys Phe Asp Met 1 5 10 <210> 421 <211> 15 <212> PRT <213> Anabaena variabilis <400> 421

    Lys Thr His Trp Leu Asp Ala Ala Cys Val Gly Gln Ser Thr Pro 1 5 10 15 <210> 422 <211> 18 <212> PRT <213> Nostoc sp.

    <400> 422

    Pro Leu Arg Leu Lys Phe Asp Pro Gly Ala Lys Tyr Thr Gly Ile Ala

    1 5 10 15

    Leu Val <210> 423 <211> 23 <212> PRT <213> Nostoc sp.

    <400> 423

    Thr Ser Arg Arg Gln Leu Arg Arg Ser Arg Arg Ser Arg Lys Thr Arg 1 5 10 15

    Tyr Arg Gln Pro Arg Phe Phe 20 <210> 424 <211> 13 <212> PRT <213> Nostoc sp.

    <400> 424

    Ile Thr Ala Ile Ser Gln Glu Leu Val Lys Phe Asp Thr 1 5 10 <210> 425 <211> 15 <212> PRT <213> Nostoc sp.

    <400> 425

    Lys Ser His Trp Leu Asp Ala Cys Cys Val Gly Ala Ser Thr Pro 1 5 10 15 <210> 426 <211> 18 <212> PRT <213> Thermus thermophilus <400> 426

    Met Val Val Ala Gly Ile Asp Pro Gly Ile Thr His Leu Gly Leu Gly

    Val Val <210> 427 <211> 13 <212> PRT <213> Thermus thermophilus <400> 427

    Pro Glu Ala Val Ala Val Glu Glu Gln Phe Phe Tyr Arg 1 5 10 <210> 428 <211> 15 <212> PRT <213> Thermus thermophilus <400> 428

    Pro Ser His Leu Ala Asp Ala Leu Ala Ile Ala Leu Thr His Ala 1 5 10 15 <210> 429 <211> 10 <212> PRT <213> Lactococcus lactis <400> 429

    Phe Leu Val Asn His Asn Tyr Tyr Ser Phe 1 5 10 <210> 430 <211> 16 <212> PRT <213> Lactococcus lactis <400> 430

    Leu Gln Lys Phe Thr Gly Asp Ile Glu Asn Leu Val Lys Ala Ser Leu

    1 5 10 15 <210> 431 <211> 9 <212> PRT <213> Lactococcus lactis <400> 431

    Val Ile Val Pro Glu Leu Thr Phe Gly 1 5 <210> 432 <211> 15 <212> PRT <213> Lactococcus lactis <400> 432

    Trp Ile Arg Ala Gly Trp Phe Ile Arg Asn Arg Ser Ala His Tyr 1 5 10 15 <210> 433 <211> 13 <212> PRT <213> Lactococcus lactis <400> 433

    Asn Lys Asp Leu Phe Ala Phe Met Leu Ser Ile Lys Gln 1 5 10 <210> 434 <211> 10 <212> PRT <213> Lactococcus lactis <400> 434

    Phe Leu His Lys Asn Ser Tyr Phe Arg Phe 1 5 10 <210> 435 <211> 16 <212> PRT <213> Lactococcus lactis <400> 435

    Leu Phe Ile Phe Ser Thr Arg Leu Glu Ile Phe Trp Lys Lys Lys Ile 1 5 10 15 <210> 436 <211> 9 <212> PRT <213> Lactococcus lactis <400> 436

    Ala Leu Val Glu Glu Leu Thr Phe Gly 1 5 <210> 437 <211> 15 <212> PRT <213> Lactococcus lactis <400> 437

    Trp Met Asn Val Val Arg Leu Tyr Arg Asn Lys Ser Ala His Gly 1 5 10 15 <210> 438 <211> 13 <212> PRT <213> Lactococcus lactis <400> 438

    Lys Ser Tyr Leu Tyr Gly Ala Leu Tyr Val Phe Lys His 1 5 10 <210> 439 <211> 10 <212> PRT <213> Corynebacterium diphtheriae <400> 439

    Leu Leu Ala Gln Leu Asn Tyr Tyr Arg Leu 1 5 10 <210> 440 <211> 16 <212> PRT <213> Corynebacterium diphtheriae <400> 440

    Val Phe Ile Glu Leu Asp Arg Val Glu Leu Ala Ile Gln Thr Arg Leu 1 5 10 15 <210> 441 <211> 9 <212> PRT <213> Corynebacterium diphtheriae <400> 441

    Ala Ala Val Glu Val Met Asp Trp Gly 1 5 <210> 442 <211> 15 <212> PRT <213> Corynebacterium diphtheriae <400> 442

    Trp Leu Lys Ser Leu Asn Ile Leu Arg Asn Tyr Ala Ala His His 1 5 10 15 <210> 443 <211> 13 <212> PRT <213> Corynebacterium diphtheriae <400> 443

    Gly Gln Leu Ser Met Ile Gln Tyr Leu His His Gln Leu 1 5 10 <210> 444 <211> 12 <212> PRT <213> Shewanella baltica <400> 444

    Met Leu Ile Glu Asn Asp Leu Asp Gly Ile Glu Asn 1 5 10 <210> 445 <211> 16 <212> PRT <213> Shewanella baltica <400> 445

    Asn Tyr Gln Leu Phe Tyr Phe Leu Glu Lys Thr Ile Arg Asn Gln Ile 1 5 10 15 <210> 446 <211> 15 <212> PRT <213> Shewanella baltica <400> 446

    Val Met Phe Asn Leu Asn Thr Leu Arg Asn Pro Ile Ala His Cys 1 5 10 15 <210> 447 <211> 13 <212> PRT <213> Shewanella baltica <400> 447

    Asp Glu Lys Leu Arg Leu Glu Ile Ser Leu Arg Asp Trp 1 5 10 <210> 448 <211> 12 <212> PRT <213> Lactococcus lactis <400> 448

    Leu Arg Glu Ile Asn Ile Lys Ala Ser Lys Ser Arg 1 5 10 <210> 449 <211> 16 <212> PRT <213> Lactococcus lactis <400> 449

    Leu Leu Pro Leu Leu His Lys Tyr Glu Trp Ser Leu Arg Lys Leu Ile 1 5 10 15 <210> 450 <211> 9 <212> PRT <213> Lactococcus lactis <400> 450

    Tyr Asp Phe Glu Glu Tyr Leu Phe Gly 1 5 <210> 451 <211> 15 <212> PRT <213> Lactococcus lactis <400> 451

    Asp Met Arg Leu Ile Arg Asp Gly Arg Asn Ile Val Gly His Asn 1 5 10 15 <210> 452 <211> 13 <212> PRT <213> Lactococcus lactis <400> 452

    Leu Ser Lys Gly Leu Lys Lys Tyr Ile Lys Lys Leu Asp 1 5 10 <210> 453 <211> 12 <212> PRT <213> Geobacter bemidjiensis <400> 453

    Arg Leu Pro Leu Thr Ser His Ile Gln Lys Gln Asp 1 5 10 <210> 454 <211> 16 <212> PRT <213> Geobacter bemidjiensis <400> 454

    Ile Tyr Pro Lys Leu Asn Arg Ile Glu Asn Arg Leu Arg His Tyr Leu 1 5 10 15 <210> 455 <211> 9 <212> PRT <213> Geobacter bemidjiensis <400> 455

    Phe Glu Leu Gly Lys Ile Val Tyr Ala 1 5 <210> 456 <211> 15 <212> PRT <213> Geobacter bemidjiensis <400> 456

    Lys Trp Ile Arg Leu Glu Glu Ile Arg His Lys Val Ala His Asn 1 5 10 15 <210> 457 <211> 13 <212> PRT <213> Geobacter bemidjiensis <400> 457

    Ala Asn Glu Tyr Ile Asp Ser Leu Gln Ser Ile Ile Asp 1 5 10 <210> 458 <211> 12 <212> PRT <213> Salmonella enterica <400> 458

    Phe Val Thr Ser Leu Glu His Leu Arg Gln Gln Gln 1 5 10 <210> 459 <211> 16 <212> PRT <213> Salmonella enterica <400> 459

    Ala Gln Arg Gln Leu Arg Ala Ile Glu Leu Thr Leu Lys Ala Leu Ile 1 5 10 15 <210> 460 <211> 9 <212> PRT <213> Salmonella enterica <400> 460

    Asn His Tyr Leu Lys Gln His Phe Gly 1 5 <210> 461 <211> 15 <212> PRT <213> Salmonella enterica <400> 461

    Phe Leu Asp Asp Cys Arg Leu Ala Arg Asn Glu Val Ile Ala Arg 1 5 10 15 <210> 462 <211> 13 <212> PRT <213> Salmonella enterica <400> 462

    Leu Met Leu Leu Asn Val Gln Tyr Gln Gln Ile Val Arg 1 5 10 <210> 463 <211> 12 <212> PRT <213> Shigella flexneri <400> 463

    Phe Leu Trp Gln Leu Glu Tyr Leu Arg Glu Lys Gln 1 5 10 <210> 464 <211> 16 <212> PRT <213> Shigella flexneri <400> 464

    Ser Leu Gln Gln Val Arg Ala Leu Glu Leu Thr Ile Arg Ser Leu Ile 1 5 10 15 <210> 465 <211>9 <212> PRT <213> Shigella flexneri <400> 465

    Leu Glu His Leu Asn Lys Leu Phe Gly 1 5 <210> 466 <211> 15 <212> PRT <213> Shigella flexneri <400> 466

    Phe Leu Asp Asp Ile Arg Val Ile Arg Asn Arg Leu Ala His His

    1 5 10 15 <210> 467 <211> 13 <212> PRT <213> Shigella flexneri <400> 467

    Thr Thr Leu Val Asn Tyr Tyr Tyr Arg Glu Ile Thr Glu 1 5 10 <210> 468 <211> 16 <212> PRT <213> Streptomyces avermitilis <400> 468

    Ala Tyr Ile Trp Leu Asn Leu Val Glu Gln Arg Leu Arg Ala Val Val 1 5 10 15 <210> 469 <211> 9 <212> PRT <213> Streptomyces avermitilis <400> 469

    Asn Val Leu Ser Phe Leu Thr Leu Pro 1 5 <210> 470 <211> 11 <212> PRT <213> Streptomyces avermitilis <400> 470

    Leu Glu Val Thr Arg Asn Val Val Ser Arg Asn 1 5 10 <210> 471 <211> 13 <212> PRT <213> Streptomyces avermitilis <400> 471

    Arg Tyr Gly Asp Val Val Gly Val His Pro Asp Arg Val 1 5 10 <210> 472 <211> 10 <212> PRT <213> Helicobacter pylori <400> 472

    Ser Ile Ser Val Leu His Tyr Asp Tyr Leu 1 5 10 <210> 473 <211> 16 <212> PRT <213> Helicobacter pylori <400> 473

    Leu Phe Leu Trp Ile His Phe Phe Glu Thr Ala Leu Arg Ser Lys Met 1 5 10 15 <210> 474 <211> 9 <212> PRT <213> Helicobacter pylori <400> 474

    Gln Ile Leu Asn Leu Phe Thr Leu Gly 1 5 <210> 475 <211> 15 <212> PRT <213> Helicobacter pylori <400> 475

    Thr Phe Ser Leu Ile Arg Lys Ala Arg Asn Asp Leu Phe His Asn 1 5 10 15 <210> 476 <211> 13 <212> PRT <213> Helicobacter pylori <400> 476

    Thr Leu Lys Leu Glu Arg Ala Ile Phe Phe Lys Thr Ile 1 5 10 <210> 477 <211> 11 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methylomirabilis oxyfera sequence <400> 477

    Gly Pro Pro Glu Tyr Tyr Tyr Arg Leu Cys Arg 1 5 10 <210> 478 <211> 16 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methylomirabilis oxyfera sequence <400> 478

    Ala Asp Ser Lys Leu Lys Asp Thr Val Ser Glu Met Arg Lys Phe Ile

    1 5 10 15 <210> 479 <211> 15 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methylomirabilis oxyfera sequence <400> 479

    Trp Met Asn Arg Ile Asn Glu Leu Arg Arg Ile Pro Ala His Pro 1 5 10 15 <210> 480 <211> 13 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methylomirabilis oxyfera sequence <400> 480

    Asp Phe Glu Tyr Ile Asp Phe Ile Tyr Asp Glu Leu Met 1 5 10 <210> 481 <211> 12 <212> PRT <213> Novosphingobium aromaticivorans <400> 481

    Thr Ala Val Lys Gln Gln Ser Phe Gly Met Glu Ala 1 5 10 <210> 482 <211> 16 <212> PRT <213> Novosphingobium aromaticivorans <400> 482

    Ala Ala Ala Lys Val Thr Gln Ile His Lys Lys Leu Phe Asn Tyr Val 1 5 10 15 <210> 483 <211> 15 <212> PRT <213> Novosphingobium aromaticivorans <400> 483

    Trp Ile Lys Val Leu Asn Asp Ile Arg Gln Tyr Thr Ala His Pro 1 5 10 15 <210> 484 <211> 13 <212> PRT <213> Novosphingobium aromaticivorans <400> 484

    Gln Val Ser Phe Val Asn Glu Val Tyr Glu Lys Val Glu 1 5 10 <210> 485 <211> 11 <212> PRT <213> Elizabethkingia anophelis <400> 485

    Gly Glu Ile Lys Tyr Trp Arg Thr Phe Gln Lys 1 5 10 <210> 486 <211> 16 <212> PRT <213> Elizabethkingia anophelis <400> 486

    Ala Ile Ala Tyr Ile Arg Asp Ile Glu Thr Glu Phe Lys Ser Asp Phe 1 5 10 15 <210> 487 <211> 15 <212> PRT <213> Elizabethkingia anophelis <400> 487

    Trp Met Val Lys Leu Glu Arg Ile Arg Asn Gln Asn Phe His Ser <210> 488 <211> 13 <212> PRT <213> Elizabethkingia anophelis <400> 488

    Glu Leu Ser Phe Leu Glu Glu Leu His Asp Trp Ile Tyr 1 5 10 <210> 489 <211> 12 <212> PRT <213> Escherichia coli <400> 489

    Phe Ser Ala Leu Pro Arg Ile Ile Glu Tyr Ala Tyr 1 5 10 <210> 490 <211> 16 <212> PRT <213> Escherichia coli <400> 490

    Pro Phe Leu Leu Leu Ser Glu Ile Glu Asn His Ile Arg Lys Leu Ile 1 5 10 15 <210> 491 <211> 9 <212> PRT <213> Escherichia coli <400> 491

    Glu Ser Val Ala Asp Leu Thr Phe Gly 1 5 <210> 492 <211> 15 <212> PRT <213> Escherichia coli <400> 492

    Glu Leu Asp Lys Val Arg Ile Ile Arg Asn Asp Val Met His Phe 1 5 10 15 <210> 493 <211> 13 <212> PRT <213> Escherichia coli <400> 493

    Asn His Glu Leu Leu His Asn Phe Val Arg Phe Ile His 1 5 10 <210> 494 <211> 12 <212> PRT <213> Haloarcula marismortui <400> 494

    Phe Glu Leu Phe Asp Thr Leu Ala Glu Asp Asp Tyr 1 5 10 <210> 495 <211> 16 <212> PRT <213> Haloarcula marismortui <400> 495

    Pro Phe Leu Gln Ile Gly Glu Ile Glu Glu Ser Leu Arg His Leu Phe 1 5 10 15 <210> 496 <211> 9 <212> PRT <213> Haloarcula marismortui <400> 496

    Asp Arg Pro Glu Asp Phe Ser Phe Asp <210> 497 <211> 15 <212> PRT <213> Haloarcula marismortui <400> 497

    Leu Leu Glu Asp Ile Arg Glu Thr Arg Asn Ala Leu Leu His Phe 1 5 10 15 <210> 498 <211> 13 <212> PRT <213> Haloarcula marismortui <400> 498

    Asp Arg Asp Gln Leu Asp Met Ala His Gly Tyr Phe Thr 1 5 10 <210> 499 <211> 12 <212> PRT <213> Nostoc sp.

    <400> 499

    Met Lys Leu Leu Pro Ile Leu Gln Gln Asn Pro Arg 1 5 10 <210> 500 <211> 15 <212> PRT <213> Nostoc sp.

    <400> 500

    Phe Gly Leu Val Thr Leu Leu Glu Met Asn Leu Leu Arg Leu Val 1 5 10 15 <210> 501 <211> 9 <212> PRT <213> Nostoc sp.

    <400> 501

    Asp Leu Leu Asp Tyr Leu Gln Phe Cys 1 5 <210> 502 <211> 15 <212> PRT <213> Nostoc sp.

    <400> 502

    Phe Leu Lys Ser Ala Glu Gln Leu Arg Asn Arg Leu Ala His Ala 1 5 10 15 <210> 503 <211> 13 <212> PRT <213> Nostoc sp.

    <400> 503

    Ser Trp Asn Asp Leu Ile Ser Leu Ala Glu Ala Met Glu 1 5 10 <210> 504 <211> 10 <212> PRT <213> Xanthobacter autotrophicus <400> 504

    Val Phe Glu Gly Met Glu Leu Leu Pro Ala 1 5 10 <210> 505 <211> 14 <212> PRT <213> Xanthobacter autotrophicus <400> 505

    Ala Leu Ile Pro Phe Val Glu Lys Arg Leu Glu Thr Ser Leu <210> 506 <211> 8 <212> PRT <213> Xanthobacter autotrophicus <400> 506

    Glu Ala Phe Lys Ala Val Leu Gly 1 5 <210> 507 <211> 15 <212> PRT <213> Xanthobacter autotrophicus <400> 507

    Leu Val Asn Glu Leu Gly Asp Val Arg Asn Lys Leu Ser His Asn 1 5 10 15 <210> 508 <211> 13 <212> PRT <213> Xanthobacter autotrophicus <400> 508

    Tyr Asp Asp Ala Glu Arg Ala Leu Asp Thr Met Arg Arg 1 5 10 <210> 509 <211> 10 <212> PRT <213> Methanospirillum hungatei <400> 509

    Val Gly Arg Ala Met Asp Gln Leu Lys Thr 1 5 10 <210> 510 <211> 14 <212> PRT <213> Methanospirillum hungatei <400> 510

    Gly Leu Met Arg Phe Val Glu Arg Glu Met Lys Ser Ala Tyr 1 5 10 <210> 511 <211> 8 <212> PRT <213> Methanospirillum hungatei <400> 511

    Lys Val Phe Ser Gln Ile Leu Gly 1 5 <210> 512 <211> 15 <212> PRT <213> Methanospirillum hungatei <400> 512

    Leu Val Ser Glu Leu Arg Glu Thr Arg Asn Gln Trp Ala His Gln 1 5 10 15 <210> 513 <211> 13 <212> PRT <213> Methanospirillum hungatei <400> 513

    Thr Asn Asp Thr Leu Arg Ala Leu Asp Ser Thr Ala Arg 1 5 10 <210> 514 <211> 10 <212> PRT <213> Roseiflexus sp.

    <400> 514

    Ile Gly Lys Ala Leu Asp Leu Leu Arg Gln <210> 515 <211> 14 <212> PRT <213> Roseiflexus sp.

    <400> 515

    Gly Leu Gln Pro Phe Ile Glu Arg Glu Leu Gln Asn His Tyr 1 5 10 <210> 516 <211> 8 <212> PRT <213> Roseiflexus sp.

    <400> 516

    Asp Val Phe Arg Lys Thr Leu Gly 1 5 <210> 517 <211> 15 <212> PRT <213> Roseiflexus sp.

    <400> 517

    Leu Val Ser Glu Leu Arg Glu Trp Arg Asn Lys Trp Ala His Gln 1 5 10 15 <210> 518 <211> 13 <212> PRT <213> Roseiflexus sp.

    <400> 518

    Thr Asp Asp Thr Tyr Arg Val Leu Asp Ser Ala Ala Arg 1 5 10 <210> 519 <211> 10 <212> PRT <213> Plasmodium yoelii <400> 519

    Ile Leu Asn Ile Phe His Ile Leu Ser Ala 1 5 10 <210> 520 <211> 14 <212> PRT <213> Plasmodium yoelii <400> 520

    His Leu Ser Pro Ile Ile Glu Gln Ile Met Glu Met Glu Tyr 1 5 10 <210> 521 <211> 7 <212> PRT <213> Plasmodium yoelii <400> 521

    Asp Ile Phe Glu Asn Arg Ile 1 5 <210> 522 <211> 15 <212> PRT <213> Plasmodium yoelii <400> 522

    Ile Leu Glu Asn Leu Gln Lys Ala Ser Ile Phe Trp Ala Asn Gln 1 5 10 15 <210> 523 <211> 13 <212> PRT <213> Plasmodium yoelii <400> 523

    Glu Phe Phe Leu Ser Asn Leu Val Ser Ser Tyr Phe Phe <210> 524 <211> 10 <212> PRT <213> Theileria parva <400> 524

    Val Val Met Ile Phe Gln Cys Val Cys Asp 1 5 10 <210> 525 <211> 14 <212> PRT <213> Theileria parva <400> 525

    Ala Phe Gln Pro Phe Ile Ser Lys Cys Met Leu Lys Lys Phe 1 5 10 <210> 526 <211> 7 <212> PRT <213> Theileria parva <400> 526

    Asp Ile Phe Glu Gln Val Leu 1 5 <210> 527 <211> 15 <212> PRT <213> Theileria parva <400> 527

    His Leu Asn Thr Ile Gln Thr Ala Ser Ile Tyr Trp Ala Asn Gln 1 5 10 15 <210> 528 <211> 8 <212> PRT <213> Theileria parva <400> 528

    Asn Tyr Gly Lys Cys Arg Lys Ile 1 5 <210> 529 <211> 10 <212> PRT <213> Daphnia pulex <400> 529

    Ser Ser Lys Glu Ser Ala Ala Ile Ala Ile 1 5 10 <210> 530 <211> 14 <212> PRT <213> Daphnia pulex <400> 530

    Gly His Ile Val Phe Asp Thr Phe Leu Glu Asp Val Ala Pro 1 5 10 <210> 531 <211> 8 <212> PRT <213> Daphnia pulex <400> 531

    Asp Cys Phe Ile Ile Pro Pro Gly 1 5 <210> 532 <211> 15 <212> PRT <213> Daphnia pulex <400> 532

    Ile Leu Glu Arg Ala Met Asp Gly Arg His Ala Val Ser His His <210> 533 <211> 13 <212> PRT <213> Daphnia pulex <400> 533

    Trp Glu Gln His Leu Lys Asp Tyr Val Tyr Ile Leu Thr 1 5 10 <210> 534 <211> 10 <212> PRT <213> Homo sapiens <400> 534

    Ala Gly His Cys Leu Leu Leu Leu Arg Ser 1 5 10 <210> 535 <211> 16 <212> PRT <213> Homo sapiens <400> 535

    Cys Leu Gln Gly Phe Val Gly Arg Glu Val Leu Ser Phe His Arg Gly 1 5 10 15 <210> 536 <211> 15 <212> PRT <213> Homo sapiens <400> 536

    Lys Val Thr Glu Val Ile Lys Cys Arg Asn Glu Ile Met His Ser 1 5 10 15 <210> 537 <211> 13 <212> PRT <213> Homo sapiens <400> 537

    Ser Ser Thr Trp Leu Arg Asp Phe Gln Met Lys Ile Gln 1 5 10 <210> 538 <211> 10 <212> PRT <213> Branchiostoma floridae <400> 538

    Val Gly Ile Ala Leu Leu Thr Thr Arg Asp 1 5 10 <210> 539 <211> 16 <212> PRT <213> Branchiostoma floridae <400> 539

    Gly Leu Thr Asn Val Thr Glu Gln Ala Ala Lys Glu Leu Gln Ala Glu 1 5 10 15 <210> 540 <211> 15 <212> PRT <213> Branchiostoma floridae <400> 540

    Pro Leu Lys Asn Val Ile Glu Val Arg Asn Lys Thr Met His Ser 1 5 10 15 <210> 541 <211> 13 <212> PRT <213> Branchiostoma floridae <400> 541

    Asp Arg Gln Thr Phe Asn Glu Tyr Met Asp Lys Met Glu <210> 542 <211> 10 <212> PRT <213> Homo sapiens <400> 542

    Val Ser Asp Leu Glu Lys Ser Leu Gly Thr 1 5 10 <210> 543 <211> 14 <212> PRT <213> Homo sapiens <400> 543

    Gly Leu Ser Ser Ile Leu Glu Thr Glu Met Lys Ile Ala Phe 1 5 10 <210> 544 <211> 8 <212> PRT <213> Homo sapiens <400> 544

    Lys His Trp Leu Ala Val Phe Gly 1 5 <210> 545 <211> 16 <212> PRT <213> Homo sapiens <400> 545

    Thr Ile Glu Ser Leu Tyr Lys Asn Leu Arg Lys Ala Asn Lys Ala Val 1 5 10 15 <210> 546 <211> 13 <212> PRT <213> Homo sapiens <400> 546

    Ser Arg Ser Leu Leu His Ala Phe Ser Thr Arg Ser Asn 1 5 10 <210> 547 <211> 10 <212> PRT <213> Ostreococcus lucimarinus <400> 547

    Met Glu Arg Leu Met Met Val Leu Asp His 1 5 10 <210> 548 <211> 14 <212> PRT <213> Ostreococcus lucimarinus <400> 548

    Val Leu Ala Ile Val Leu Glu Gly Gly Leu Arg Ala Glu Phe 1 5 10 <210> 549 <211> 8 <212> PRT <213> Ostreococcus lucimarinus <400> 549

    Ala Asn Trp Gly Ser Leu Phe Ser 1 5 <210> 550 <211> 14 <212> PRT <213> Ostreococcus lucimarinus <400> 550

    Glu Ile Glu Val Leu Leu Asp Ala Ala Ile Arg Gln Arg Lys <210> 551 <211> 13 <212> PRT <213> Ostreococcus lucimarinus <400> 551

    Ala Arg Asp Val Ser Ser Ala Ala Val Ala Leu Leu Asn 1 5 10 <210> 552 <211> 10 <212> PRT <213> Branchiostoma floridae <400> 552

    Leu Cys Gly Met Lys Thr Leu Leu Lys Ala 1 5 10 <210> 553 <211> 14 <212> PRT <213> Branchiostoma floridae <400> 553

    Val Leu Ala Val Val Leu Glu Thr Glu Met Lys Ala Val Phe 1 5 10 <210> 554 <211> 8 <212> PRT <213> Branchiostoma floridae <400> 554

    Lys His Trp Ile Ala Val Phe Gly 1 5 <210> 555 <211> 17 <212> PRT <213> Branchiostoma floridae <400> 555

    His Leu Asp Ser Leu Val Lys His Phe Thr Arg Gly Arg Ser Tyr Gly 1 5 10 15

    Val <210>556 <211> 13 <212> PRT <213> Branchiostoma floridae <400> 556

    Ala Leu Gln Leu Val Arg Gln Leu His Asn His Ser Thr 1 5 10 <210> 557 <211> 10 <212> PRT <213> Microcystis aeruginosa <400> 557

    Leu Asn Trp Leu Asp Gln Leu His Asp Asp 1 5 10 <210> 558 <211> 16 <212> PRT <213> Microcystis aeruginosa <400> 558

    Leu Ile Glu Leu Cys Gly Trp Ile Glu Glu Thr Met Asp Asp Ile Val 1 5 10 15 <210>559 <211>9 <212> PRT <213> Microcystis aeruginosa <400> 559

    Phe Arg Lys Met Leu Met Met Val Ile 1 5 <210> 560 <211> 15 <212> PRT <213> Microcystis aeruginosa <400> 560

    Tyr Leu Gly Asn Leu Lys Asp Ser Arg Asn Arg Ala Ala His Thr 1 5 10 15 <210> 561 <211> 13 <212> PRT <213> Microcystis aeruginosa <400> 561

    Phe Asp Lys Ile Tyr Gly Leu Leu Lys Glu Leu Asp Ala 1 5 10 <210> 562 <211> 12 <212> PRT <213> Lactococcus lactis <400> 562

    Leu Ser Glu Leu His Glu Phe Ile Lys Lys Leu Asn 1 5 10 <210> 563 <211> 16 <212> PRT <213> Lactococcus lactis <400> 563

    Val Ile Arg Ser Cys Gly Ile Ile Glu Gln Leu Thr Lys Thr Leu Ile 1 5 10 15 <210> 564 <211> 9 <212> PRT <213> Lactococcus lactis <400> 564

    Ile Asn Gly Leu Ile Asp Thr Phe Asp 1 5 <210> 565 <211> 15 <212> PRT <213> Lactococcus lactis <400> 565

    His Ile Asp Ser Leu Arg Gln Leu Arg Asn Ser Ile Ala His Gly 1 5 10 15 <210> 566 <211> 13 <212> PRT <213> Lactococcus lactis <400> 566

    Met Gly Tyr Phe Asp Ser Cys Ile Ile Leu Met Phe Arg 1 5 10 <210> 567 <211> 12 <212> PRT <213> Frankia sp.

    <400> 567

    Leu Ser Glu Leu Ala Ala Leu Val Gln Asp Gln Ala 1 5 10 <210> 568 <211> 16 <212> PRT <213> Frankia sp.

    <400> 568

    Val Ile Arg Ser Cys Gly Tyr Leu Glu Gln Thr Val Ala Gly Thr Phe 1 5 10 15 <210> 569 <211> 9 <212> PRT <213> Frankia sp.

    <400> 569

    Leu Glu Thr Leu Ala Gly Arg Phe Asp 1 5 <210> 570 <211> 15 <212> PRT <213> Frankia sp.

    <400> 570

    Glu Leu Ala Thr Leu Val Asp Arg Arg Asn Arg Ile Ala His Gly 1 5 10 15 <210> 571 <211> 13 <212> PRT <213> Frankia sp.

    <400> 571

    Leu Glu Leu His Arg Val Ala Cys Glu Ala Ala Asp Trp 1 5 10 <210> 572 <211> 10 <212> PRT <213> Neisseria meningitidis <400> 572

    Cys Cys Ser Ile Phe Ser Asp Phe Arg Met 1 5 10 <210> 573 <211> 16 <212> PRT <213> Neisseria meningitidis <400> 573

    Leu Phe His Val Val Ser Ile Phe Glu Ile Val Leu Arg Asn Lys Ile 1 5 10 15 <210> 574 <211> 9 <212> PRT <213> Neisseria meningitidis <400> 574

    Gln Leu Val Ala Gly Leu Gly Phe Gly 1 5 <210> 575 <211> 15 <212> PRT <213> Neisseria meningitidis <400> 575

    Glu Leu Ser Asn Ile Asn Lys Phe Arg Asn Arg Leu Ala His His 1 5 10 15 <210> 576 <211> 13 <212> PRT <213> Neisseria meningitidis <400> 576

    Asp Val Asp Thr Ala Ser Val Phe Ser His Phe Ser Asp 1 5 10 <210> 577 <211> 10 <212> PRT <213> Pseudomonas syringae <400> 577

    Leu Glu Lys His Phe Ser Ser Ala Arg Leu 1 5 10 <210> 578 <211> 16 <212> PRT <213> Pseudomonas syringae <400> 578

    Met Met Pro Met Leu Ser Val Leu Glu Ile Ala Leu Lys Asn Gly Ile 1 5 10 15 <210> 579 <211> 9 <212> PRT <213> Pseudomonas syringae <400> 579

    Lys Ile Val Ala Glu Leu Ala Phe Gly 1 5 <210> 580 <211> 15 <212> PRT <213> Pseudomonas syringae <400> 580

    Ala Leu Asn Leu Ile Arg Asn Leu Arg Asn Arg Val Phe His His 1 5 10 15 <210> 581 <211> 13 <212> PRT <213> Pseudomonas syringae <400> 581

    Asp Pro Gln Leu Val Pro Trp Leu Ala Gln Tyr Asp Arg 1 5 10 <210> 582 <211> 10 <212> PRT <213> Geobacter uraniireducens <400> 582

    Leu Arg Arg Ala Ile Ser His Glu Arg Leu 1 5 10 <210> 583 <211> 16 <212> PRT <213> Geobacter uraniireducens <400> 583

    Leu Tyr Thr Pro Leu Gln Cys Leu Glu Val Cys Leu Arg Asn Ser Ile 1 5 10 15 <210> 584 <211> 9 <212> PRT <213> Geobacter uraniireducens <400> 584

    Arg Ile Ile Pro Glu Leu Thr Phe Gly 1 5 <210> 585 <211> 15 <212> PRT <213> Geobacter uraniireducens <400> 585

    Arg Phe Asn His Ile Arg Thr Leu Arg Asn Arg Ile Phe His His 1 5 10 15 <210> 586 <211> 13 <212> PRT <213> Geobacter uraniireducens <400> 586

    Asn Pro Ala Met Met Thr Phe Val Glu Pro Phe Asp Ser 1 5 10 <210> 587 <211> 16 <212> PRT <213> Sulfuricurvum kujiense <400> 587

    Glu Glu Lys Ser Glu Phe Ile Arg Glu Phe Phe Lys Arg Thr Leu His 1 5 10 15 <210> 588 <211> 9 <212> PRT <213> Sulfuricurvum kujiense <400> 588

    Thr Gln Thr Ile Asn Ser Phe Leu Gly 1 5 <210> 589 <211> 14 <212> PRT <213> Sulfuricurvum kujiense <400> 589

    Phe Arg Asn Tyr Leu Lys Arg Leu Arg Asn Ala Val Ser His 1 5 10 <210> 590 <211> 13 <212> PRT <213> Sulfuricurvum kujiense <400> 590

    Val Asn Leu Leu Ile Thr Leu Leu Ser Arg Asn Ile Leu 1 5 10 <210> 591 <211> 13 <212> PRT <213> Dethiobacter alkaliphilus <400> 591

    Gln Val Val Glu Lys Asp Phe Val Ala Arg Thr Met His 1 5 10 <210> 592 <211> 9 <212> PRT <213> Dethiobacter alkaliphilus <400> 592

    Thr Leu Leu Ile Asn Cys Leu Leu Gly 1 5 <210> 593 <211> 14 <212> PRT <213> Dethiobacter alkaliphilus <400> 593

    Ala Ser Arg Phe Leu Gln Cys Met Arg Asn Ser Val Ala His 1 5 10 <210> 594 <211> 10 <212> PRT <213> Dethiobacter alkaliphilus <400> 594

    Leu Ala Thr Lys Leu Ala Gln Tyr Val Gln 1 5 10 <210> 595 <211> 13 <212> PRT <213> Klebsiella pneumoniae <400> 595

    Ser Asp Phe Glu Thr Asp Phe Val Gln Arg Thr Leu Ala 1 5 10 <210> 596 <211> 9 <212> PRT <213> Klebsiella pneumoniae <400> 596

    Thr Leu Thr Leu Asn Cys Leu Leu Gly 1 5 <210> 597 <211> 14 <212> PRT <213> Klebsiella pneumoniae <400> 597

    Leu Arg Gln Leu Ile His Lys Met Arg Asn Ser Val Ala His 1 5 10 <210> 598 <211> 13 <212> PRT <213> Klebsiella pneumoniae <400> 598

    Leu Leu Pro Phe Leu Lys Tyr Tyr Ala Thr Leu Leu Leu 1 5 10 <210> 599 <211> 10 <212> PRT <213> Lactobacillus casei <400> 599

    Lys Ile Asp Arg Glu Met Phe Trp Arg Arg 1 5 10 <210> 600 <211> 16 <212> PRT <213> Lactobacillus casei <400> 600

    Tyr Leu Leu Leu Tyr Ser Ser Trp Glu Gly Phe Ile Arg Ser Ile Ala 1 5 10 15 <210> 601 <211> 9 <212> PRT <213> Lactobacillus casei <400> 601

    Leu Ala Arg Ile Val Ser Val Leu Asp 1 5 <210> 602 <211> 14 <212> PRT <213> Lactobacillus casei <400> 602

    Asp Arg Asp Leu Leu Lys Val Arg Asn Glu Ile Ala His Gly 1 5 10 <210> 603 <211> 13 <212> PRT <213> Lactobacillus casei <400> 603

    Thr Val Ser His Val Leu Glu Met Met Asp Leu Phe Ser 1 5 10 <210> 604 <211> 10 <212> PRT <213> Caulobacter sp.

    <400> 604

    Asp Leu Asp Ala Ala Arg Leu Arg Arg Ala 1 5 10 <210> 605 <211> 16 <212> PRT <213> Caulobacter sp.

    <400> 605

    Ile Val Leu Ala Tyr Ser His Trp Glu Gly Phe Tyr Asn Glu Cys Ile 1 5 10 15 <210> 606 <211> 9 <212> PRT <213> Caulobacter sp.

    <400> 606

    Leu Lys Glu Asn Phe Arg Ile Leu Gly 1 5 <210> 607 <211> 14 <212> PRT <213> Caulobacter sp.

    <400> 607

    Asn Lys Glu Leu Val Gly Trp Arg His Ser Ile Ala His Gly 1 5 10 <210> 608 <211> 13 <212> PRT <213> Caulobacter sp.

    <400> 608

    His Ile Ile Leu Thr Asn Ser Leu Leu Leu Thr Leu Ser 1 5 10 <210> 609 <211> 10 <212> PRT <213> Microcystis aeruginosa <400> 609

    Asn Leu Asp Glu Asp Met Ala Trp Arg Ile 1 5 10 <210> 610 <211> 16 <212> PRT <213> Microcystis aeruginosa <400> 610

    Ile Thr Thr Leu Tyr Ala His Trp Glu Gly Phe Ile Lys Tyr Ala Ala 1 5 10 15 <210> 611 <211> 9 <212> PRT <213> Microcystis aeruginosa <400> 611

    Phe Thr Asp Ile Cys Thr Ile Leu Gly 1 5 <210> 612 <211> 14 <212> PRT <213> Microcystis aeruginosa <400> 612

    Asp Glu Gln Leu Leu Thr Gln Arg Asn Lys Ile Ala His Gly 1 5 10 <210> 613 <211> 13 <212> PRT <213> Microcystis aeruginosa <400> 613

    Thr Tyr Asn Leu Val Ile Lys Leu Ile Arg Asp Phe Lys 1 5 10 <210> 614 <211> 11 <212> PRT <213> Arabidopsis thaliana <400> 614

    Pro Trp Leu Ser Trp Glu Glu Trp Asp Ser Val 1 5 10 <210> 615 <211> 15 <212> PRT <213> Arabidopsis thaliana <400> 615

    Gly Ser Leu Pro Ala Pro Val Asp Val Thr Cys Ser Leu Ile Glu 1 5 10 15 <210> 616 <211> 9 <212> PRT <213> Arabidopsis thaliana <400> 616

    Ile Ala Asp Ala Ala Arg Ala Ile Gly 1 5 <210> 617 <211> 15 <212> PRT <213> Arabidopsis thaliana <400> 617

    Ile Pro Arg Lys Leu Ile Asp Leu Arg His Glu Gly Ser His Arg 1 5 10 15 <210> 618 <211> 13 <212> PRT <213> Arabidopsis thaliana <400> 618

    Ala Ala Asp Glu Ala Leu Glu Trp Leu Lys Ser Tyr Tyr 1 5 10 <210> 619 <211> 11 <212> PRT <213> Homo sapiens <400> 619

    Ala Trp Leu Ser Arg Ala Glu Trp Asp Gln Val 1 5 10 <210> 620 <211> 16 <212> PRT <213> Homo sapiens <400> 620

    Gly Asn Glu Leu Pro Leu Ala Val Ala Ser Thr Ala Asp Leu Ile Arg 1 5 10 15 <210> 621 <211> 9 <212> PRT <213> Homo sapiens <400> 621

    Leu Lys Cys Leu Ala Gln Glu Val Asn 1 5 <210> 622 <211> 15 <212> PRT <213> Homo sapiens <400> 622

    Ile Pro Asp Trp Ile Val Asp Leu Arg His Glu Leu Thr His Lys 1 5 10 15 <210> 623 <211> 13 <212> PRT <213> Homo sapiens <400> 623

    Gly Cys Tyr Phe Val Leu Asp Trp Leu Gln Lys Thr Tyr 1 5 10 <210> 624 <211> 11 <212> PRT <213> Saccharomyces cerevisiae <400> 624

    Pro Trp Arg Asp Phe Ala Glu Leu Glu Glu Leu 1 5 10 <210> 625 <211> 16 <212> PRT <213> Saccharomyces cerevisiae <400> 625

    Ser Gln Tyr Leu Pro His Val Val Asp Ser Thr Ala Gln Ile Thr Cys 1 5 10 15 <210> 626 <211> 9 <212> PRT <213> Saccharomyces cerevisiae <400> 626

    Leu His Thr Leu Ala Ala Lys Ile Gly 1 5 <210> 627 <211> 15 <212> PRT <213> Saccharomyces cerevisiae <400> 627

    Leu Pro Ser Trp Phe Val Asp Leu Arg His Trp Gly Thr His Glu 1 5 10 15 <210> 628 <211> 13 <212> PRT <213> Saccharomyces cerevisiae <400> 628

    Ala Ala Asn Glu Ala Leu Ser Trp Leu Tyr Asp His Tyr 1 5 10 <210> 629 <211> 11 <212> PRT <213> Streptococcus pneumoniae <400> 629

    Ser Lys Pro Cys Ile Glu Ala Glu Asn Met Ile 1 5 10 <210> 630 <211> 16 <212> PRT <213> Streptococcus pneumoniae <400> 630

    Ala Phe Met Ala Arg Arg Ala Leu Glu Gln Ala Val His Trp Ile Tyr 1 5 10 15 <210> 631 <211> 8 <212> PRT <213> Streptococcus pneumoniae <400> 631

    Ser Ser Leu Val Trp Asp Asp Asp 1 5 <210> 632 <211> 15 <212> PRT <213> Streptococcus pneumoniae <400> 632

    Gln Ile Val Leu Leu Ile Arg Trp Gly Asn His Ala Ala His Gly 1 5 10 15 <210> 633 <211> 13 <212> PRT <213> Streptococcus pneumoniae <400> 633

    Ala Leu His His Leu Tyr Gln Phe Val Asn Phe Ile Asp 1 5 10 <210> 634 <211> 11 <212> PRT <213> Microcystis aeruginosa <400> 634

    Tyr Asp His Ala Ser Gln Ala Glu Gly Leu Val 1 5 10 <210> 635 <211> 16 <212> PRT <213> Microcystis aeruginosa <400> 635

    Cys Phe Tyr Thr Arg Phe Val Leu Glu Gln Met Val Cys Trp Leu Tyr 1 5 10 15 <210> 636 <211> 8 <212> PRT <213> Microcystis aeruginosa <400> 636

    Gly Ala Leu Ile His Glu Gln Thr 1 5 <210> 637 <211> 15 <212> PRT <213> Microcystis aeruginosa <400> 637

    Lys Ile Arg Thr Ile His Lys Val Gly Asn Asn Ala Ala His Asp 1 5 10 15 <210> 638 <211> 13 <212> PRT <213> Microcystis aeruginosa <400> 638

    Leu Ile Glu Glu Leu Phe His Leu Thr Tyr Trp Leu Val 1 5 10 <210> 639 <211> 11 <212> PRT <213> Escherichia coli <400> 639

    Tyr Ala Ile Ala Cys Ala Ala Glu Asn Asn Tyr 1 5 10 <210> 640 <211> 16 <212> PRT <213> Escherichia coli <400> 640

    Leu Ile Lys Met Arg Met Phe Gly Glu Ala Thr Ala Lys His Leu Gly 1 5 10 15 <210> 641 <211> 8 <212> PRT <213> Escherichia coli <400> 641

    His Asp Leu Leu Arg Glu Leu Gly 1 5 <210> 642 <211> 15 <212> PRT <213> Escherichia coli <400> 642

    Val Phe His Lys Leu Arg Arg Ile Gly Asn Gln Ala Val His Glu 1 5 10 15 <210> 643 <211> 13 <212> PRT <213> Escherichia coli <400> 643

    Cys Leu Arg Leu Gly Phe Arg Leu Ala Val Trp Tyr Tyr 1 5 10 <210> 644 <211> 11 <212> PRT <213> Bradyrhizobium japonicum <400> 644

    Val Gln Lys Leu Ile Lys Ala Ser Gln Leu Ala 1 5 10 <210> 645 <211> 16 <212> PRT <213> Bradyrhizobium japonicum <400> 645

    Leu Thr Glu Val Arg Arg Ala Met Lys Ala Ala Ala Asp Leu Phe Trp 1 5 10 15 <210> 646 <211> 10 <212> PRT <213> Bradyrhizobium japonicum <400> 646

    Leu Asn Arg Leu Gln Glu Phe Ala Arg Val 1 5 10 <210> 647 <211> 13 <212> PRT <213> Bradyrhizobium japonicum <400> 647

    Arg Arg Leu Asn Asp Leu Ala Ser Lys Gly Val His Ala 1 5 10 <210> 648 <211> 13 <212> PRT <213> Bradyrhizobium japonicum <400> 648

    Ala Glu Ala Arg Gln Gly Leu Val Gly Leu Tyr Phe Phe 1 5 10 <210> 649 <211> 11 <212> PRT <213> Leptospira meyeri <400> 649

    Leu Pro Lys Phe Ser Ala Ile Tyr Ser Asn Leu 1 5 10 <210> 650 <211> 16 <212> PRT <213> Leptospira meyeri <400> 650

    Val His Ser Cys Arg Arg Leu Leu Gln Ser Val Ala Asp Lys Leu Met 1 5 10 15 <210> 651 <211> 10 <212> PRT <213> Leptospira meyeri <400> 651

    Ile Asn Arg Leu Ile Tyr Tyr Ile Glu Thr 1 5 10 <210> 652 <211> 13 <212> PRT <213> Leptospira meyeri <400> 652

    Asp Ser Val Phe Gln Ala Ser Gln Lys Gly Ser His Ser 1 5 10 <210> 653 <211> 13 <212> PRT <213> Leptospira meyeri <400> 653

    Gln Glu Ala Asp Arg Tyr Val Ile His Thr Phe Leu Leu 1 5 10 <210> 654 <211> 11 <212> PRT <213> Bacteroides coprosuis <400> 654

    Val Val Asp Asp Arg Asp Phe Ser Leu Leu Ala 1 5 10 <210> 655 <211> 16 <212> PRT <213> Bacteroides coprosuis <400> 655

    Leu Asp Arg Leu His Thr Tyr Val Ile Lys Phe Ile Arg Gln Leu Cys 1 5 10 15 <210> 656 <211> 9 <212> PRT <213> Bacteroides coprosuis <400> 656

    Phe Gly Lys Tyr Val Lys Phe Ile Val 1 5 <210> 657 <211> 16 <212> PRT <213> Bacteroides coprosuis <400> 657

    Ile Glu Ala Phe Asn Asp Ile Arg Asn Asn Lys Ser Phe Ala His Asp

    1 5 10 15 <210> 658 <211> 13 <212> PRT <213> Bacteroides coprosuis <400> 658

    Tyr Ala Glu Ser Val Leu Ile Phe Asn Asn Val Thr Asn 1 5 10 <210> 659 <211> 10 <212> PRT <213> Escherichia coli <400> 659

    Asn Val Asn Glu Asn Ile Tyr Gln Ala Leu 1 5 10 <210> 660 <211> 16 <212> PRT <213> Escherichia coli <400> 660

    Tyr Asp Arg Val His Thr Ala Leu His Ala Ser Leu Arg Gln Met Cys 1 5 10 15 <210> 661 <211> 9 <212> PRT <213> Escherichia coli <400> 661

    Leu Ser Leu Ile Thr Ala His Leu Lys 1 5 <210> 662 <211> 16 <212> PRT <213> Escherichia coli <400> 662

    Leu His Gly Ile Asn Asn Leu Arg Asn Asn Tyr Ser Met Ala His Pro 1 5 10 15 <210> 663 <211> 13 <212> PRT <213> Escherichia coli <400> 663

    Glu Ala Asp Ala Arg Phe Ala Ile Asn Leu Val Arg Ser 1 5 10 <210> 664 <211> 11 <212> PRT <213> Lactococcus lactis <400> 664

    Ile Met Asn Ile Gly Tyr Val Glu Lys Ile Leu 1 5 10 <210> 665 <211> 16 <212> PRT <213> Lactococcus lactis <400> 665

    Val Thr Lys Ser Arg Thr Ile Ile Glu Thr Val Phe Ile Ala Ile Leu 1 5 10 15 <210> 666 <211> 9 <212> PRT <213> Lactococcus lactis <400> 666

    Arg Ser Leu Val Asn Lys Thr Leu Gly 1 5 <210> 667 <211> 16 <212> PRT <213> Lactococcus lactis <400> 667

    Val Asp Ser Ile Thr Thr Met Arg Asn Ile Asn Ser Asp Ser His Gly 1 5 10 15 <210> 668 <211> 13 <212> PRT <213> Lactococcus lactis <400> 668

    Glu Ala Glu Ala Glu Leu Ile Leu Asn Ser Ala Val Asn 1 5 10 <210> 669 <211> 11 <212> PRT <213> Peptoniphilus indolicus <400> 669

    Phe Leu Tyr Leu Lys Thr Leu Lys Asn Lys Glu 1 5 10 <210> 670 <211> 16 <212> PRT <213> Peptoniphilus indolicus <400> 670

    Arg Gly Ile Thr Pro Leu Val Thr Glu Leu Phe Ile Leu Ile Ile Asp 1 5 10 15 <210> 671 <211> 9 <212> PRT <213> Peptoniphilus indolicus <400> 671

    Leu Ile Glu Ile Ile Lys Asn Glu Arg 1 5 <210> 672 <211> 15 <212> PRT <213> Peptoniphilus indolicus <400> 672

    Ile Arg Asp Val Glu Gly Lys Leu Arg Asn Arg Ala Ala His Glu 1 5 10 15 <210> 673 <211> 13 <212> PRT <213> Peptoniphilus indolicus <400> 673

    Gly Asn Asn His Tyr Asp Ser Tyr Asp Leu Met Asn Lys 1 5 10 <210> 674 <211> 11 <212> PRT <213> Mycobacterium tuberculosis <400> 674

    Ile Ser Ala Leu Ala Leu Leu Ala Lys Arg Glu 1 5 10 <210> 675 <211> 16 <212> PRT <213> Mycobacterium tuberculosis <400> 675

    Arg Ser Ala Thr Pro Ala Ile Thr Ile Val Leu Arg Ala Ala Val Ala 1 5 10 15 <210> 676 <211>9 <212> PRT <213> Mycobacterium tuberculosis <400> 676

    Trp Leu Ala Leu Leu Arg Gln Phe Ala 1 5 <210> 677 <211> 15 <212> PRT <213> Mycobacterium tuberculosis <400> 677

    Leu Gly Arg Phe Glu Ser Arg Val Arg Asn Thr Ala Ala His Glu 1 5 10 15 <210> 678 <211> 11 <212> PRT <213> Mycobacterium tuberculosis <400> 678

    Ala Asp Leu Thr Leu Tyr Asp Arg Leu Asn Asp 1 5 10 <210> 679 <211> 12 <212> PRT <213> Streptococcus thermophilus <400> 679

    Tyr Leu Met Ile Asp Val Leu Lys Glu Arg Glu His 1 5 10 <210> 680 <211> 16 <212> PRT <213> Streptococcus thermophilus <400> 680

    Ile Glu Glu Ile Ile Lys Lys Asp His Glu Gly Leu Ile Val Phe Asp

    1 5 10 15 <210> 681 <211>9 <212> PRT <213> Streptococcus thermophilus <400> 681

    Tyr Leu Asn Ile Leu Glu Phe Tyr Glu 1 5 <210> 682 <211> 14 <212> PRT <213> Streptococcus thermophilus <400> 682

    Ile Leu Ser Leu Asn Gly Glu Arg Asn Lys Val Ala His Gly 1 5 10 <210> 683 <211> 13 <212> PRT <213> Streptococcus thermophilus <400> 683

    Asp Ser Ser Tyr Phe Asn Tyr Tyr Asp Lys Gln Asn Lys 1 5 10 <210> 684 <211> 10 <212> PRT <213> Synechocystis sp.

    <400> 684

    Leu Ile Ser Val Val Ala Phe Arg Leu Gly 1 5 10 <210> 685 <211> 16 <212> PRT <213> Synechocystis sp.

    <400> 685

    Ile Leu Asp His Arg Lys Gln Ile Asn Phe Ala Leu Asn Asn Gly Gly 1 5 10 15 <210> 686 <211> 10 <212> PRT <213> Synechocystis sp.

    <400> 686

    Thr Glu Ile Arg Asn Asp Leu Ala His Cys 1 5 10 <210> 687 <211> 12 <212> PRT <213> Synechocystis sp.

    <400> 687

    Asn Lys Ile Phe Pro Gln Leu Glu Glu Ile Ala Asn 1 5 10 <210> 688 <211> 5 <212> PRT <213> Methanocaldococcus jannaschii <400> 688

    Lys Asn Thr Leu Phe

    1 5 <210> 689 <211> 14 <212> PRT <213> Methanocaldococcus jannaschii <400> 689

    Lys Glu Asn Pro Asn Ser Gln Tyr Ile Lys Asn Glu Ile Ser 1 5 10 <210> 690 <211> 15 <212> PRT <213> Methanocaldococcus jannaschii <400> 690

    Glu Asn Ile Asp Lys Phe Lys Ile Arg Asn Phe Leu Ala His Ala 1 5 10 15 <210> 691 <211> 13 <212> PRT <213> Methanocaldococcus jannaschii <400> 691

    Ser Glu Lys Thr Ser Leu Arg Tyr Asn Lys Asn Tyr Ile 1 5 10 <210> 692 <211> 11 <212> PRT <213> Pyrococcus furiosus <400> 692

    Ser Lys Ile Phe Glu Ser Leu Pro Arg Ile Gly 1 5 10 <210> 693 <211> 15 <212> PRT <213> Pyrococcus furiosus <400> 693

    Arg Gln Val Glu Trp Leu Arg Asn Leu Val Tyr Gly Arg Leu Trp 1 5 10 15 <210> 694 <211> 15 <212> PRT <213> Pyrococcus furiosus <400> 694

    Thr Ile Glu Ser Pro Asn Val Val Arg Asn Phe Ile Ala His Ser 1 5 10 15 <210> 695 <211> 13 <212> PRT <213> Pyrococcus furiosus <400> 695

    Asp Lys Glu Lys Ala Ala Asn Leu Ala Tyr Glu Ala Leu 1 5 10 <210> 696 <211> 5 <212> PRT <213> Sulfolobus solfataricus <400> 696

    Ala Glu Thr Tyr Ala 1 5 <210> 697 <211> 13 <212> PRT <213> Sulfolobus solfataricus <400> 697

    Asp Lys Val Thr Arg Ala Ile Ile Glu Asn Glu Val Asp 1 5 10 <210> 698 <211> 13 <212> PRT <213> Sulfolobus solfataricus <400> 698

    Gly Lys Gly Phe Asp Lys Arg Ile Leu Tyr Ala His Gly 1 5 10 <210> 699 <211> 10 <212> PRT <213> Sulfolobus solfataricus <400> 699

    Asp Lys Ile Asp Glu Ile Glu Arg Gln Ile 1 5 10 <210> 700 <211> 12 <212> PRT <213> Desulfococcus oleovorans <400> 700

    Phe Ala Asn Ala Glu Arg Arg Phe Asp Glu Gly Lys 1 5 10 <210> 701 <211> 16 <212> PRT <213> Desulfococcus oleovorans <400> 701

    Val Leu Arg Leu Tyr Arg Ile Val Glu Met Ala Gly Gln Gln Arg Leu 1 5 10 15 <210> 702 <211> 9 <212> PRT <213> Desulfococcus oleovorans <400> 702

    Gly Tyr Ser Leu Leu Lys Glu Met Gly 1 5 <210> 703 <211> 17 <212> PRT <213> Desulfococcus oleovorans <400> 703

    Ser Phe Leu Lys Ile Gln Asp Ser Arg Asn His Ser Phe Leu Ala His 1 5 10 15

    Gly <210> 704 <211> 13 <212> PRT <213> Desulfococcus oleovorans <400> 704

    Tyr Met Ser Leu Arg Asp Phe Ile Val Ser Leu Asn Ile 1 5 10 <210> 705 <211> 12 <212> PRT <213> Oscillochloris trichoides <400> 705

    Leu Arg Asn Ala Glu Arg Arg Ala Ala Arg Ala Arg 1 5 10 <210> 706 <211> 16 <212> PRT <213> Oscillochloris trichoides <400> 706

    Val Ala Arg Leu Tyr Arg Ala Thr Glu Leu Phe Ala Gln Ile Arg Leu 1 5 10 15 <210> 707 <211> 9 <212> PRT <213> Oscillochloris trichoides <400> 707

    Ser Tyr Ala Leu Leu Gly Lys Leu Asp 1 5 <210> 708 <211> 17 <212> PRT <213> Oscillochloris trichoides <400> 708

    Pro Leu Asn Asn Ala Leu Thr Arg Arg Asn Gln Ser Ile Leu Ala His 1 5 10 15

    Gly <210> 709 <211> 13 <212> PRT <213> Oscillochloris trichoides <400> 709

    Tyr His Asp Leu Ala Ser His Leu Tyr Thr Leu Ile Asn 1 5 10 <210> 710 <211> 12 <212> PRT <213> Homo sapiens <400> 710

    Phe Pro Glu Ile Phe Asp Ala Leu Glu Ser Leu Gln 1 5 10 <210> 711 <211> 14 <212> PRT <213> Homo sapiens <400> 711

    Lys Leu Thr Ser Cys Leu Glu Arg Ala Leu Gly Asp Val Phe 1 5 10 <210> 712 <211> 9 <212> PRT <213> Homo sapiens <400> 712

    Ser Glu Glu Leu Ala Gln Val Phe Ser 1 5 <210> 713 <211> 15 <212> PRT <213> Homo sapiens <400> 713

    Gly Ser Pro Cys Gly Leu Asn Leu Arg Asn Val Leu Trp His Gly 1 5 10 15 <210> 714 <211> 13 <212> PRT <213> Homo sapiens <400> 714

    Tyr Cys Ser Met Met Ile Leu Leu Thr Ala Gly Leu Gly 1 5 10 <210> 715 <211> 12 <212> PRT <213> Entamoeba histolytica <400> 715

    Trp Phe Glu Ser Phe Gln Glu Ile Ile Gln Thr Pro 1 5 10 <210> 716 <211> 14 <212> PRT <213> Entamoeba histolytica <400> 716

    Leu Leu Ser Val Gln Phe Asn Val His Leu Lys Asp Asn Ile 1 5 10 <210> 717 <211> 9 <212> PRT <213> Entamoeba histolytica <400> 717

    Lys Met Tyr Glu Glu His Thr Val Pro 1 5 <210> 718 <211> 15 <212> PRT <213> Entamoeba histolytica <400> 718

    Gly Pro Pro Thr Gly Leu Asn Leu Arg Asn Leu Leu Trp His Gly 1 5 10 15 <210> 719 <211> 13 <212> PRT <213> Entamoeba histolytica <400> 719

    His Ile Cys Leu Leu Ile Ile Leu Tyr Gln Thr Ile Gln

    1 5 10 <210> 720 <211> 12 <212> PRT <213> Staphylococcus aureus <400> 720

    Ile Glu His Gly Ile Ser Arg Phe Leu Glu Lys Asp

    1 5 10 <210> 721 <211> 14 <212> PRT <213> Staphylococcus aureus <400> 721

    Ile Leu Val Pro Gln Phe Glu Ser Thr Val Arg Arg Met Phe 1 5 10 <210> 722 <211>9 <212> PRT <213> Staphylococcus aureus <400> 722

    Arg Asp Asp Val Lys Ser Thr Leu Gly 1 5 <210> 723 <211> 15 <212> PRT <213> Staphylococcus aureus <400> 723

    Val Glu Gln Ser Gly Leu Asn Leu Arg Asn Glu Ile Ala His Gly 1 5 10 15 <210> 724 <211> 12 <212> PRT <213> Staphylococcus aureus <400> 724

    Lys Cys Ile Leu Val Ile Tyr Leu Phe Leu Ile Leu 1 5 10 <210> 725 <211> 12 <212> PRT <213> Cyanothece sp.

    <400> 725

    Leu Leu Lys Gly Ile Gln Ala Tyr Leu Glu Glu Asp 1 5 10 <210> 726 <211> 14 <212> PRT <213> Cyanothece sp.

    <400> 726

    Leu Leu Ile Pro Gln Ile Glu Ala Ala Ile Arg Asn Leu Val 1 5 10 <210> 727 <211> 9 <212> PRT <213> Cyanothece sp.

    <400> 727

    Ser Glu Gln Val Lys Gln Ser Leu Gly 1 5 <210> 728 <211> 15 <212> PRT <213> Cyanothece sp.

    <400> 728

    Thr Asp Gln Arg Gly Trp Asn Val Arg Asn Asn Val Cys His Gly 1 5 10 15 <210> 729 <211> 12 <212> PRT <213> Cyanothece sp.

    <400> 729

    Leu Thr Glu Arg Leu Ile His Ile Leu Leu Ile Leu 1 5 10 <210> 730 <211> 9 <212> PRT <213> Sulfolobus solfataricus <400> 730

    Ile Ser Thr Ser Ala Glu Val Tyr Tyr 1 5 <210> 731 <211> 16 <212> PRT <213> Sulfolobus solfataricus <400> 731

    Cys Glu Lys Tyr Tyr Lys Ala Ala Glu Glu Ala Ile Lys Leu Leu Val 1 5 10 15 <210> 732 <211> 8 <212> PRT <213> Sulfolobus solfataricus <400> 732

    Lys Leu Leu Arg Ser Asn Asn Thr 1 5 <210> 733 <211> 15 <212> PRT <213> Sulfolobus solfataricus <400> 733

    Leu Trp Lys Ser Ala Trp Thr Leu His Val Glu Gly Phe His Glu

    1 5 10 15 <210> 734 <211> 13 <212> PRT <213> Sulfolobus solfataricus <400> 734

    Leu Lys Glu Asp Val Arg Lys Leu Val Ile Phe Ala Val 1 5 10 <210> 735 <211> 9 <212> PRT <213> Pyrobaculum aerophilum <400> 735

    Tyr Ala Glu Ala Ala Arg Glu Leu Leu 1 5 <210> 736 <211> 16 <212> PRT <213> Pyrobaculum aerophilum <400> 736

    Ser Glu Lys Ala Trp Gly Ala Ala Ala Leu Ala Val Lys Ala Tyr Ala 1 5 10 15 <210> 737 <211> 7 <212> PRT <213> Pyrobaculum aerophilum <400> 737

    Lys Ile Ala Gly Glu Leu Gly 1 5 <210> 738 <211> 14 <212> PRT <213> Pyrobaculum aerophilum <400> 738

    Ala Trp Ala Gln Ala Asn Ala Met His Ile Asn Phe Tyr Glu 1 5 10 <210> 739 <211> 13 <212> PRT <213> Pyrobaculum aerophilum <400> 739

    Ala Leu Lys Lys Val Ser Arg Leu Val Glu Glu Leu Thr 1 5 10 <210> 740 <211> 11 <212> PRT <213> Homo sapiens <400> 740

    Arg Arg Trp Leu Arg Gln Ala Arg Ala Asn Phe 1 5 10 <210> 741 <211> 16 <212> PRT <213> Homo sapiens <400> 741

    Asn Glu Trp Val Cys Phe Lys Cys Tyr Leu Ser Thr Lys Leu Ala Leu 1 5 10 15 <210> 742 <211> 8 <212> PRT <213> Homo sapiens <400> 742

    Ala Gln Lys Ile Glu Glu Tyr Ser 1 5 <210> 743 <211> 15 <212> PRT <213> Homo sapiens <400> 743

    Val His Thr Leu Glu Ala Tyr Gly Val Asp Ser Leu Lys Thr Arg 1 5 10 15 <210> 744 <211> 13 <212> PRT <213> Homo sapiens <220>

    <221> MOD_RES <222> (2)..(2) <223> Any amino acid <400> 744

    Val Xaa Glu Cys Thr Ala Cys Ile Ile Ile Lys Leu Glu 1 5 10 <210> 745 <211> 11 <212> PRT <213> Haemophilus influenzae <400> 745

    Lys Leu Asn Leu Asn Val Leu Asp Ala Ala Phe 1 5 10 <210> 746 <211> 16 <212> PRT <213> Haemophilus influenzae <220>

    <221> MOD_RES <222> (14)..(15) <223> Any amino acid <400> 746

    Ile Gln Lys Phe Glu Phe Val Tyr Glu Leu Ser Leu Lys Xaa Xaa Lys 1 5 10 15 <210> 747 <211> 8 <212> PRT <213> Haemophilus influenzae <400> 747

    Leu Arg Glu Ala Leu Arg Phe Gly 1 5 <210> 748 <211> 15 <212> PRT <213> Haemophilus influenzae <220>

    <221> MOD_RES <222> (8)..(8) <223> Any amino acid <400> 748

    Lys Trp Val Ala Tyr Arg Asp Xaa Arg Asn Ile Thr Ser His Thr 1 5 10 15 <210> 749 <211> 13 <212> PRT <213> Haemophilus influenzae <400> 749

    Asp Phe Leu Ile Glu Ser Ser Phe Leu Leu Glu Gln Leu

    1 5 10 <210> 750 <211> 6 <212> PRT <213> Thermus thermophilus <220>

    <221> MOD_RES <222> (1)..(1) <223> Any amino acid <400> 750

    Xaa Ala Glu Lys Ala Leu 1 5 <210> 751 <211> 16 <212> PRT <213> Thermus thermophilus <400> 751

    Ile Gln Arg Phe Glu Tyr Thr Phe Glu Ala Phe Trp Lys Ala Leu Gln 1 5 10 15 <210> 752 <211>8 <212> PRT <213> Thermus thermophilus <400> 752

    Ile Arg Leu Ala Arg Glu Val Gly 1 5 <210> 753 <211> 15 <212> PRT <213> Thermus thermophilus <220>

    <221> MOD_RES <222> (5)..(5) <223> Any amino acid <400> 753

    Leu Ala Leu Gly Xaa Val Asp Asp Arg Ser Leu Thr Val His Thr 1 5 10 15 <210> 754 <211> 13 <212> PRT <213> Thermus thermophilus <220>

    <221> MOD_RES <222> (12)..(12) <223> Any amino acid <400> 754

    Ile Phe Arg Arg Leu Pro Asp Tyr Ala Arg Leu Xaa Glu 1 5 10 <210> 755 <211> 11 <212> PRT <213> Rhodococcus equi <400> 755

    Val Asn Leu Leu Arg Arg Ala Asp Gly Leu Leu 1 5 10 <210> 756 <211> 16 <212> PRT <213> Rhodococcus equi <400> 756

    Phe Cys Ala Ala Tyr Val Gly Ala Leu Arg Gly Ala Ala Ala Val Leu

    1 5 10 15 <210> 757 <211> 8 <212> PRT <213> Rhodococcus equi <400> 757

    Trp Val Leu Met Ala Arg Ala Glu 1 5 <210> 758 <211> 15 <212> PRT <213> Rhodococcus equi <400> 758

    Tyr Phe Ala Gly Tyr Ser Gly Leu Arg Ala Asp Leu Glu Ala Gly 1 5 10 15 <210> 759 <211> 13 <212> PRT <213> Rhodococcus equi <400> 759

    Asp Ala Glu Glu Val Asp Gly Phe Tyr Ala Glu Val Gly 1 5 10 <210> 760 <211> 11 <212> PRT <213> Streptomyces avermitilis <400> 760

    Leu Asp Leu Leu Ala Gln Ala Arg Ala Gly Leu 1 5 10 <210> 761 <211> 16 <212> PRT <213> Streptomyces avermitilis <400> 761

    Tyr Ala Thr Ala His Leu Ala Ala Leu Arg Thr Ala Ala Ala Val Leu

    1 5 10 15 <210> 762 <211> 8 <212> PRT <213> Streptomyces avermitilis <400> 762

    Trp Glu Val Leu Pro Glu Ile Ala 1 5 <210> 763 <211> 15 <212> PRT <213> Streptomyces avermitilis <400> 763

    Leu Phe Ala Ser Gly Ala Gly Arg Arg Ala Arg Ala Glu Ala Gly 1 5 10 15 <210> 764 <211> 13 <212> PRT <213> Streptomyces avermitilis <400> 764

    Ser Asn Arg Asp Ala Asp Asp Leu Ile Arg Asp Val Ala 1 5 10 <210> 765 <211> 11 <212> PRT <213> Staphylococcus aureus <400> 765

    Ala Leu Ile Val Glu Glu Leu Phe Glu Tyr Ala

    1 5 10 <210> 766 <211> 16 <212> PRT <213> Staphylococcus aureus <400> 766

    Pro Ser Leu Thr Val Gln Val Ala Met Ala Gly Ala Met Leu Ile Gly 1 5 10 15 <210> 767 <211>8 <212> PRT <213> Staphylococcus aureus <400> 767

    Thr Glu Ala Val Lys Gln Ser Asp 1 5 <210> 768 <211> 10 <212> PRT <213> Staphylococcus aureus <400> 768

    His Leu Cys Gln Phe Val Met Ser Gly Gln 1 5 10 <210> 769 <211> 13 <212> PRT <213> Staphylococcus aureus <400> 769

    Ser Glu Lys Leu Leu Glu Ser Leu Glu Asn Phe Trp Asn 1 5 10 <210> 770 <211> 11 <212> PRT <213> Enterococcus faecium <400> 770

    Asn Phe Leu Leu Cys Asn Phe Ser Asn Leu Trp 1 5 10 <210> 771 <211> 16 <212> PRT <213> Enterococcus faecium <400> 771

    Leu Glu Leu Leu Ser Gln Leu Gln Lys Asn Thr Leu Gln Leu Ile Arg 1 5 10 15 <210> 772 <211> 10 <212> PRT <213> Enterococcus faecium <400> 772

    Lys Lys Phe Ala Lys Thr Thr Ala Arg Leu 1 5 10 <210> 773 <211> 13 <212> PRT <213> Enterococcus faecium <400> 773

    Lys Val Glu Leu Phe Glu Ala Tyr Lys Asn Ser Leu Leu 1 5 10 <210> 774 <211> 9 <212> PRT <213> Escherichia coli <400> 774

    Gly Val Tyr Ala Asn Glu Leu Arg Ala

    1 5 <210> 775 <211> 16 <212> PRT <213> Escherichia coli <400> 775

    Gly Gly Ile Arg Glu Ile Glu Phe Ile Val Gln Val Phe Gln Leu Ile 1 5 10 15 <210> 776 <211>8 <212> PRT <213> Escherichia coli <400> 776

    Thr Leu Ser Ala Ile Ala Glu Leu 1 5 <210> 777 <211> 15 <212> PRT <213> Escherichia coli <400> 777

    Glu Gln Leu Arg Val Ala Tyr Leu Phe Leu Arg Arg Leu Glu Asn 1 5 10 15 <210> 778 <211> 13 <212> PRT <213> Escherichia coli <400> 778

    Leu Thr Gly His Met Thr Asn Val Arg Arg Val Phe Asn 1 5 10 <210> 779 <211> 11 <212> PRT <213> Sebaldella termitidis <400> 779

    Ser Arg Cys Met Lys Ile Ala Gln Ser Gly Gln 1 5 10 <210> 780 <211> 16 <212> PRT <213> Sebaldella termitidis <400> 780

    Ile Ala Glu Ala Glu Phe Ile Asn Glu Ser Ile Tyr Met Ile Tyr Leu 1 5 10 15 <210> 781 <211> 8 <212> PRT <213> Sebaldella termitidis <400> 781

    Lys Asp Met Gln Phe Leu Pro Ile 1 5 <210> 782 <211> 14 <212> PRT <213> Sebaldella termitidis <400> 782

    Asn Leu Leu Asn Asn Leu Ile Ser Ile Gln Asn Ser Glu Lys 1 5 10 <210> 783 <211> 13 <212> PRT <213> Sebaldella termitidis <400> 783

    Ala Glu Lys Ile Cys Gly Leu Ile Ile Asn Glu Leu Lys

    1 5 10 <210> 784 <211> 10 <212> PRT <213> Streptomyces coelicolor <400> 784

    Ala Arg Leu Asp Ala Tyr Ala Asn Ser His 1 5 10 <210> 785 <211> 16 <212> PRT <213> Streptomyces coelicolor <400> 785

    Leu Asp Ala Ala Asp Ser Ile Gly Phe Leu Leu Glu Leu Leu Phe Ala 1 5 10 15 <210> 786 <211> 8 <212> PRT <213> Streptomyces coelicolor <400> 786

    Trp Glu Leu Asp Arg Phe Pro Leu 1 5 <210> 787 <211> 14 <212> PRT <213> Streptomyces coelicolor <400> 787

    Glu Leu Leu Ala Thr Leu Gly Arg Ile Thr Gly Ala Gly Gly 1 5 10 <210> 788 <211> 13 <212> PRT <213> Streptomyces coelicolor <400> 788

    Gln Arg Glu Leu Phe Gly Arg Val Glu Ala Ala Ala Arg

    1 5 10 <210> 789 <211> 11 <212> PRT <213> Flavobacterium psychrophilum <400> 789

    Tyr Ser Ile Tyr Lys Asn Ala Arg Gln Leu Arg 1 5 10 <210> 790 <211> 16 <212> PRT <213> Flavobacterium psychrophilum <400> 790

    Thr Ser Leu Leu Ile Leu Ser Ser Glu Glu Val Ile Lys Ser Ile Leu 1 5 10 15 <210> 791 <211> 8 <212> PRT <213> Flavobacterium psychrophilum <400> 791

    Gln Leu Ile Glu Leu Ser Ile Gly 1 5 <210> 792 <211> 15 <212> PRT <213> Flavobacterium psychrophilum <400> 792

    Lys Leu Thr Glu Phe Asp Asp Lys Lys Asn Gln Gly Phe Tyr Val 1 5 10 15 <210> 793 <211> 13 <212> PRT <213> Flavobacterium psychrophilum <400> 793

    Lys Thr Glu Phe Thr Glu Thr Lys Val Val Val Asp Arg 1 5 10 <210> 794 <211> 10 <212> PRT <213> Lactococcus lactis <400> 794

    Lys Cys Ile Asp His Ile Ser Val Leu Ile 1 5 10 <210> 795 <211> 16 <212> PRT <213> Lactococcus lactis <400> 795

    Thr Phe Ile Ser Ile Thr Ile Ile Glu Glu Val Gly Lys Thr His Ile 1 5 10 15 <210> 796 <211>8 <212> PRT <213> Lactococcus lactis <400> 796

    Ser Leu Pro Thr Ile Lys Met Gly 1 5 <210> 797 <211> 14 <212> PRT <213> Lactococcus lactis <400> 797

    Thr Gly Glu Leu Ile Ser Ile Arg Glu Ser Ser Leu Tyr Ala

    1 5 10 <210> 798 <211> 13 <212> PRT <213> Lactococcus lactis <400> 798

    Lys Glu Gln Ser Arg Ala Leu Leu Leu Tyr Ala Ile Glu 1 5 10 <210> 799 <211> 11 <212> PRT <213> Pseudomonas putida <400> 799

    Asp Ala Leu Leu Thr Asn Ala Ala Ser Leu Ile 1 5 10 <210> 800 <211> 16 <212> PRT <213> Pseudomonas putida <400> 800

    Phe Ala Leu Ala His Leu Ala Arg Glu Glu Ile Ala Lys Thr Leu Met 1 5 10 15 <210> 801 <211> 8 <212> PRT <213> Pseudomonas putida <400> 801

    Thr Ile Asn Ser Ile Val Phe Cys 1 5 <210> 802 <211> 12 <212> PRT <213> Pseudomonas putida <400> 802

    Phe Arg Asn Asp Leu Lys Asn Asn Ser Leu Tyr Val 1 5 10 <210> 803 <211> 13 <212> PRT <213> Pseudomonas putida <400> 803

    Ala Glu Arg Ala Leu Arg Thr Ile Thr Leu Ala Trp Asp 1 5 10 <210> 804 <211> 11 <212> PRT <213> Selenomonas sputigena <400> 804

    Gln Ile Ala Tyr Tyr Leu Tyr Phe Met Tyr Leu 1 5 10 <210> 805 <211> 16 <212> PRT <213> Selenomonas sputigena <400> 805

    Met Thr Ser Phe Ala Tyr Tyr Lys Ser Tyr Phe Asp Arg Val Thr Ala 1 5 10 15 <210> 806 <211> 10 <212> PRT <213> Selenomonas sputigena <400> 806

    Arg Leu Cys Glu Phe Tyr Glu Glu Phe Asp 1 5 10 <210> 807 <211> 17 <212> PRT <213> Selenomonas sputigena <400> 807

    Ile Ile Asp Lys Ala Gln Ala Leu Arg Tyr Ala Asn Pro Leu Thr His 1 5 10 15

    Ser <210> 808 <211> 13 <212> PRT <213> Selenomonas sputigena <400> 808

    Ile Arg Glu Leu Ser Thr Leu Leu Asp Arg Tyr Ile Ala 1 5 10 <210> 809 <211> 11 <212> PRT <213> Lactobacillus helveticus <400> 809

    Trp Ile Ser Tyr Tyr Leu Tyr Phe Glu Ser Ile 1 5 10 <210> 810 <211> 16 <212> PRT <213> Lactobacillus helveticus <400> 810

    Leu Thr Ser Tyr Ala Phe Phe Lys Asn Tyr Phe Asp Arg Thr Thr Ala

    1 5 10 15 <210> 811 <211> 10 <212> PRT <213> Lactobacillus helveticus <400> 811

    Gln Leu Gln Lys Val Tyr Arg Ile Leu Asn 1 5 10 <210> 812 <211> 17 <212> PRT <213> Lactobacillus helveticus <400> 812

    Ile Ile Ser Lys Ala Asn Asp Leu Arg Asn Asn Asn Pro Leu Ser His 1 5 10 15

    Ala <210> 813 <211> 13 <212> PRT <213> Lactobacillus helveticus <400> 813

    Ile Ala Thr Met Arg Ser Leu Phe Lys Leu Leu Val Glu 1 5 10 <210> 814 <211> 11 <212> PRT <213> Lactococcus lactis <400> 814

    Lys Ile Leu Asn Phe Ile Tyr Phe Arg Ala Lys 1 5 10 <210> 815 <211> 16 <212> PRT <213> Lactococcus lactis <400> 815

    Leu Glu Ser Phe Ala Tyr Tyr Lys Asn Tyr Phe Asp Arg Phe Val Ala 1 5 10 15 <210> 816 <211> 10 <212> PRT <213> Lactococcus lactis <400> 816

    Lys Leu Ile Asp Gly Leu Lys Gln Leu Asn 1 5 10 <210> 817 <211> 17 <212> PRT <213> Lactococcus lactis <400> 817

    Ile Ile Asn Glu Ala His Lys Ile Arg Asn Ser Asn Pro Val Ser His 1 5 10 15

    Ser <210> 818 <211> 13 <212> PRT <213> Lactococcus lactis <400> 818

    Leu Asn Asp Leu Lys Ile Ile Ile Glu Gln Leu Ser Thr 1 5 10 <210> 819 <211> 11 <212> PRT <213> Pseudomonas sp.

    <400> 819

    Lys Trp Leu Phe Ile Asp Gln Met Val Asp Leu 1 5 10 <210> 820 <211> 12 <212> PRT <213> Pseudomonas sp.

    <400> 820

    Phe Lys Phe Arg Glu Ile Arg Ile Glu Tyr Ser Gln 1 5 10 <210> 821 <211> 9 <212> PRT <213> Pseudomonas sp.

    <400> 821

    Tyr Glu Tyr Ala Gln Glu Ile Arg Ser 1 5 <210> 822 <211> 14 <212> PRT <213> Pseudomonas sp.

    <400> 822

    Arg Lys Ile Pro Asp Phe Arg Gly Lys Tyr Ala Ala His Ile 1 5 10 <210> 823 <211> 13 <212> PRT <213> Pseudomonas sp.

    <400> 823

    Lys Ala Leu Glu Phe Tyr Asn Trp Ile His Ser Asn Glu <210> 824 <211> 11 <212> PRT <213> Vibrio paracholerae <400> 824

    Glu Glu Ile Leu Ser Gly Leu Ile Gly Asp Leu 1 5 10 <210> 825 <211> 12 <212> PRT <213> Vibrio paracholerae <400> 825

    Arg Lys Tyr Val Glu Leu Asn Gln Lys Tyr Gly Lys 1 5 10 <210> 826 <211> 10 <212> PRT <213> Vibrio paracholerae <400> 826

    Gly Val Tyr Asn Asn Glu Ile Asn Lys Asn 1 5 10 <210> 827 <211> 14 <212> PRT <213> Vibrio paracholerae <400> 827

    Thr Ala Ile Lys Lys Leu Arg Asn His Cys Val Ala His Val 1 5 10 <210> 828 <211> 13 <212> PRT <213> Vibrio paracholerae <400> 828

    Phe Ala Asp Glu Phe Leu Asp Trp Ile Cys Pro Asp Asn 1 5 10 <210> 829 <211> 11 <212> PRT <213> Escherichia coli <400> 829

    Thr Met Ala Asp His Met Val Asn Glu Ala Trp 1 5 10 <210> 830 <211> 16 <212> PRT <213> Escherichia coli <400> 830

    Phe Asn Leu Ile Leu Gln Ser Ile Glu Phe Arg Leu Lys Gly Leu Ile 1 5 10 15 <210> 831 <211> 10 <212> PRT <213> Escherichia coli <400> 831

    Lys Val Tyr Asn Thr Phe Ala Ser Lys Ser 1 5 10 <210> 832 <211> 14 <212> PRT <213> Escherichia coli <400> 832

    Trp Phe Asn Ser Met Arg Ile Leu Arg Asn Arg Phe Met His <210> 833 <211> 13 <212> PRT <213> Escherichia coli <400> 833

    Asp Ile Met Pro Glu Leu Ile Phe Thr Ser Val Val Arg 1 5 10 <210> 834 <211> 11 <212> PRT <213> Geobacter sulfurreducens <400> 834

    Leu Asn Tyr Glu Ala Leu Tyr Val Lys Ser Lys 1 5 10 <210> 835 <211> 16 <212> PRT <213> Geobacter sulfurreducens <400> 835

    Gln Leu Trp Ala Ser Met Ala Leu Glu Leu Leu Ala Lys Ser Ser Leu 1 5 10 15 <210> 836 <211> 9 <212> PRT <213> Geobacter sulfurreducens <400> 836

    Gln Arg Leu Gly His Ile Ser Lys Leu 1 5 <210> 837 <211> 15 <212> PRT <213> Geobacter sulfurreducens <400> 837

    Phe Cys Glu Gln Leu Ser Leu Arg Arg Asn Ser Glu Ile His Ser 1 5 10 15 <210> 838 <211> 13 <212> PRT <213> Geobacter sulfurreducens <400> 838

    Asp Ala Trp Glu Val Lys Tyr Trp Tyr Ala Ile Glu Val 1 5 10 <210> 839 <211> 11 <212> PRT <213> Streptomyces coelicolor <400> 839

    Asp Val Ser Tyr Thr Pro Val Ser Asn Gly Met 1 5 10 <210> 840 <211> 16 <212> PRT <213> Streptomyces coelicolor <400> 840

    Val Leu His Leu Gln Ala Ala Thr Glu Val Leu Leu Lys Ala Arg Leu 1 5 10 15 <210> 841 <211> 10 <212> PRT <213> Streptomyces coelicolor <400> 841

    Asp Arg Leu Arg Asp Ile Ala Arg Leu Asp <210> 842 <211> 15 <212> PRT <213> Streptomyces coelicolor <400> 842

    Arg Ile Lys Glu Pro Gly Glu Ser Arg Asn Ala Leu Gln His Tyr 1 5 10 15 <210> 843 <211> 13 <212> PRT <213> Streptomyces coelicolor <400> 843

    Tyr Ala Ile Glu Ser Arg Ala Ala Arg Val Leu Asp Phe 1 5 10 <210> 844 <211> 10 <212> PRT <213> Leptospira interrogans <400> 844

    Cys Thr Arg Leu Tyr Asn Gln Ile Leu Glu 1 5 10 <210> 845 <211> 16 <212> PRT <213> Leptospira interrogans <400> 845

    Tyr Thr Lys Leu Phe Asn Ile Leu Asp Lys Val Ala Ala Ile Val Tyr 1 5 10 15 <210> 846 <211> 6 <212> PRT <213> Leptospira interrogans <400> 846

    Phe Pro Ser Thr Phe Gly 1 5 <210> 847 <211> 13 <212> PRT <213> Leptospira interrogans <400> 847

    His His Leu Arg Val Arg Arg Asn Asn Ile Val His Trp 1 5 10 <210> 848 <211> 13 <212> PRT <213> Leptospira interrogans <400> 848

    Glu Glu Asp Val Gln Arg Leu Phe Leu Ile Ser Lys Ala 1 5 10 <210> 849 <211> 10 <212> PRT <213> Shigella boydii <400> 849

    Met Glu Met Val Leu Asn Arg Leu Lys Ser 1 5 10 <210> 850 <211> 16 <212> PRT <213> Shigella boydii <400> 850

    Phe Arg Leu Cys Phe Gly Ile Leu Asp Lys Ile Ala Val Ala Ile Cys <210> 851 <211> 8 <212> PRT <213> Shigella boydii <400> 851

    Pro Gln Lys Asn Ile Tyr Phe Gln 1 5 <210> 852 <211> 15 <212> PRT <213> Shigella boydii <400> 852

    Glu Leu Ala Phe Tyr Lys Glu Trp Arg Asn Gly Leu Glu His Lys 1 5 10 15 <210> 853 <211> 13 <212> PRT <213> Shigella boydii <400> 853

    Ile His His Phe Glu His Leu Leu Gln Ile Thr Arg Ser 1 5 10 <210> 854 <211> 10 <212> PRT <213> Enterococcus faecalis <400> 854

    Phe Tyr Ser Leu Phe Asn Gln Ile Lys Gln 1 5 10 <210> 855 <211> 16 <212> PRT <213> Enterococcus faecalis <400> 855

    Tyr Arg Ser Val Tyr Ser Ile Phe Asp Lys Ile Ala Tyr Phe Leu Asn 1 5 10 15 <210> 856 <211> 8 <212> PRT <213> Enterococcus faecalis <400> 856

    Pro Lys Asn Leu Ile Thr Phe His 1 5 <210> 857 <211> 15 <212> PRT <213> Enterococcus faecalis <400> 857

    Asn Leu Glu Lys Ile Ala Glu Ile Arg Asn Ala Met Glu His Lys 1 5 10 15 <210> 858 <211> 13 <212> PRT <213> Enterococcus faecalis <400> 858

    Glu Lys Ile Thr Leu Glu Leu Phe Lys Leu Thr Arg Glu 1 5 10 <210> 859 <211> 10 <212> PRT <213> Ruminiclostridium thermocellum <400> 859

    Phe Asn Asn Arg Ala Phe Asp Leu Ile Val <210> 860 <211> 16 <212> PRT <213> Ruminiclostridium thermocellum <400> 860

    Tyr Thr Arg Phe Glu Gly Leu Ile Asp Thr Ile Tyr His Ile Ile Asn 1 5 10 15 <210> 861 <211> 7 <212> PRT <213> Ruminiclostridium thermocellum <400> 861

    Lys Pro Ser Ser Glu Phe Arg 1 5 <210> 862 <211> 15 <212> PRT <213> Ruminiclostridium thermocellum <400> 862

    Val Tyr Lys Lys Ile Asn Lys Phe Arg Asn Asn Ile Val His Asn 1 5 10 15 <210> 863 <211> 13 <212> PRT <213> Ruminiclostridium thermocellum <400> 863

    Tyr Thr Thr Ser Thr Glu Phe Leu Asn Asn Ile Lys Asp 1 5 10 <210> 864 <211> 10 <212> PRT <213> Bacillus cereus <400> 864

    Leu Asn Asn Arg Ile Phe Gln Leu Asp Leu 1 5 10 <210> 865 <211> 16 <212> PRT <213> Bacillus cereus <400> 865

    Phe Pro Lys Ala Phe Thr Ala Leu Asp Leu Leu Ala His Leu Leu Phe 1 5 10 15 <210> 866 <211> 7 <212> PRT <213> Bacillus cereus <400> 866

    Lys Thr Glu Lys Lys Ile Lys 1 5 <210> 867 <211> 15 <212> PRT <213> Bacillus cereus <400> 867

    Glu Phe Gln Lys Ala Ser Lys Val Arg Asn Asp Ile Ile His Asn 1 5 10 15 <210> 868 <211> 13 <212> PRT <213> Bacillus cereus <400> 868

    Tyr Thr Pro Ser Lys Glu Ile Leu Asn Ile Ala Arg Gly <210> 869 <211> 10 <212> PRT <213> Pseudomonas syringae <400> 869

    Glu Tyr Leu Arg Cys Lys Asp Ala Phe Glu 1 5 10 <210> 870 <211> 16 <212> PRT <213> Pseudomonas syringae <400> 870

    Ser Ser Phe Ile His His Leu Tyr Glu Leu Tyr Met Ala Leu Phe Ala 1 5 10 15 <210> 871 <211> 8 <212> PRT <213> Pseudomonas syringae <400> 871

    Ser Ile Asp Arg Gly Ala Val Ser 1 5 <210> 872 <211> 16 <212> PRT <213> Pseudomonas syringae <400> 872

    Phe Gly Pro Ala Phe Arg Ser Met Arg Asn Lys Ile Ala Gly His Val 1 5 10 15 <210> 873 <211> 13 <212> PRT <213> Pseudomonas syringae <400> 873

    Val Lys Leu Thr Glu Phe Phe Gln Lys Tyr His Pro Tyr 1 5 10 <210> 874 <211> 10 <212> PRT <213> Burkholderia xenovorans <400> 874

    Glu Tyr Leu Arg Cys Asp Asp Ala Leu His 1 5 10 <210> 875 <211> 16 <212> PRT <213> Burkholderia xenovorans <400> 875

    Ala Arg Phe Ile His His Leu Tyr Glu Phe Asn Ile Ala Cys Ala Gln 1 5 10 15 <210> 876 <211> 8 <212> PRT <213> Burkholderia xenovorans <400> 876

    Arg Val Arg Arg Gln Ala Tyr Asn 1 5 <210> 877 <211> 16 <212> PRT <213> Burkholderia xenovorans <400> 877

    Phe Ala Lys Ala Phe Arg Thr Ala Arg Asn Thr Thr Asn Gly His Ala <210> 878 <211> 13 <212> PRT <213> Burkholderia xenovorans <400> 878

    Leu Asn Leu Ser Asp Phe Phe Thr Arg Tyr His Arg Phe 1 5 10 <210> 879 <211> 10 <212> PRT <213> Microcystis aeruginosa <400> 879

    Glu His Leu Asp Cys Glu Leu Trp Glu Arg 1 5 10 <210> 880 <211> 16 <212> PRT <213> Microcystis aeruginosa <400> 880

    Ile Arg Asn Ala Thr Val Ile Leu Glu Asp Arg Met Arg Lys Leu Gly 1 5 10 15 <210> 881 <211> 8 <212> PRT <213> Microcystis aeruginosa <400> 881

    Gly Ile Val Asn Leu Ile Phe Gly 1 5 <210> 882 <211> 15 <212> PRT <213> Microcystis aeruginosa <400> 882

    Tyr Ser Gly Thr Met Lys Ile Phe Arg Asn Arg Tyr Ala His Arg 1 5 10 15 <210> 883 <211> 13 <212> PRT <213> Microcystis aeruginosa <400> 883

    Ile Ile Val Phe Ile Asp Leu Leu Leu Lys Met Leu Asp 1 5 10 <210> 884 <211> 11 <212> PRT <213> Vibrio parahaemolyticus <400> 884

    Ser Arg Asn Val His Pro Asp Val Leu Lys Tyr 1 5 10 <210> 885 <211> 16 <212> PRT <213> Vibrio parahaemolyticus <400> 885

    Val Phe Glu Ala Thr Lys Ser Val Ala Asp Lys Ile Arg Asn Lys Thr 1 5 10 15 <210> 886 <211> 8 <212> PRT <213> Vibrio parahaemolyticus <400> 886

    Val Leu Val Asp Glu Ala Phe Ser <210> 887 <211> 15 <212> PRT <213> Vibrio parahaemolyticus <400> 887

    Leu Lys Gly Leu Phe Gly Thr Phe Arg Asn Thr Thr Ala His Ala 1 5 10 15 <210> 888 <211> 13 <212> PRT <213> Vibrio parahaemolyticus <400> 888

    Ile Leu Ser Met Val Ser Leu Val His Arg Arg Leu Asp 1 5 10 <210> 889 <211> 11 <212> PRT <213> Lactococcus lactis <400> 889

    Ala Leu Glu Leu His Ser Glu Val Thr Lys Tyr 1 5 10 <210> 890 <211> 16 <212> PRT <213> Lactococcus lactis <400> 890

    Val Phe Glu Ser Cys Lys Gly Leu Phe Asp Arg Ile Arg Leu Ile Ser

    1 5 10 15 <210> 891 <211> 8 <212> PRT <213> Lactococcus lactis <400> 891

    Thr Leu Ile Asn Gln Ala Phe Asn 1 5 <210> 892 <211> 15 <212> PRT <213> Lactococcus lactis <400> 892

    Ile Lys Thr Cys Leu Tyr Leu Tyr Arg Asn His Gln Ala His Val 1 5 10 15 <210> 893 <211> 13 <212> PRT <213> Lactococcus lactis <400> 893

    Gly Leu Met Ser Ile Ser Leu Ala His Glu Leu Leu Asp 1 5 10 <210> 894 <211> 11 <212> PRT <213> Nematostella vectensis <400> 894

    Ser Thr Thr Leu Thr Thr Phe Leu Asn Leu His 1 5 10 <210> 895 <211> 16 <212> PRT <213> Nematostella vectensis <400> 895

    Glu Asp Tyr Asp Ile Thr Leu Leu Thr Cys Leu Leu Arg Asn Ile Cys <210> 896 <211> 8 <212> PRT <213> Nematostella vectensis <400> 896

    Asp Lys Leu Pro Pro Ala Tyr Asp 1 5 <210> 897 <211> 15 <212> PRT <213> Nematostella vectensis <400> 897

    Val Val Arg Leu Arg His Tyr Arg Asn Asp Leu Tyr Ala His Ile 1 5 10 15 <210> 898 <211> 13 <212> PRT <213> Nematostella vectensis <400> 898

    Trp Ala Asp Ile Ser Ala Ala Leu Leu Ser Leu Gly Gly 1 5 10 <210> 899 <211> 11 <212> PRT <213> Branchiostoma floridae <400> 899

    Pro Pro Ser Leu Pro Ala Gln Leu Lys Lys His 1 5 10 <210> 900 <211> 16 <212> PRT <213> Branchiostoma floridae <400> 900

    Glu Glu Phe Asp Ile Ser Leu Leu Leu Leu Leu Leu Lys Glu Leu Val 1 5 10 15 <210> 901 <211> 8 <212> PRT <213> Branchiostoma floridae <400> 901

    Gly Arg Asp Ala Pro Tyr Ser Asp

    1 5 <210> 902 <211> 13 <212> PRT <213> Branchiostoma floridae <400> 902

    Lys Leu Gly Gln Phe Arg Asn Lys Asn Tyr Gly His Ile 1 5 10 <210> 903 <211> 13 <212> PRT <213> Branchiostoma floridae <400> 903

    Trp Asp Glu Leu Thr Glu Ile Leu Val Asp Leu Gly Gly 1 5 10 <210> 904 <211> 11 <212> PRT <213> Homo sapiens <400> 904

    Pro Pro Leu Leu Lys Lys Glu Leu Leu Ile His <210> 905 <211> 16 <212> PRT <213> Homo sapiens <400> 905

    Lys Gln Phe Asp Leu Cys Leu Leu Leu Ala Leu Ile Lys His Leu Asn 1 5 10 15 <210> 906 <211> 8 <212> PRT <213> Homo sapiens <400> 906

    Asn Met Glu Pro Pro Ser Ser Asp 1 5 <210> 907 <211> 15 <212> PRT <213> Homo sapiens <400> 907

    Ile Leu Arg Leu Cys Lys Tyr Arg Asp Ile Leu Leu Ser Glu Ile 1 5 10 15 <210> 908 <211> 13 <212> PRT <213> Homo sapiens <400> 908

    Trp Lys Lys Val Ser Asp Ile Leu Leu Arg Leu Gly Met 1 5 10 <210> 909 <211> 11 <212> PRT <213> Escherichia coli <400> 909

    Val Thr Ala Glu Lys Leu Leu Val Ser Gly Leu 1 5 10 <210> 910 <211> 16 <212> PRT <213> Escherichia coli <400> 910

    Leu Tyr Pro Glu Leu Arg Thr Ile Glu Gly Val Leu Lys Ser Lys Met 1 5 10 15 <210> 911 <211> 8 <212> PRT <213> Escherichia coli <400> 911

    Tyr Ile Leu Lys Pro Gln Phe Ala 1 5 <210> 912 <211> 14 <212> PRT <213> Escherichia coli <400> 912

    Ala Tyr Thr Phe Phe Asn Val Glu Arg His Ser Leu Phe His 1 5 10 <210> 913 <211> 13 <212> PRT <213> Escherichia coli <400> 913

    Met Ile Ser Asp Met Ala Arg Leu Met Gly Lys Ala Thr <210> 914 <211> 11 <212> PRT <213> Photobacterium profundum <400> 914

    Asp Thr Tyr Arg Ser Leu Leu Ser Ser Ser Tyr 1 5 10 <210> 915 <211> 16 <212> PRT <213> Photobacterium profundum <400> 915

    Ile Tyr Pro Asp Leu Arg Val Leu Glu Gly Val Ile Lys Glu Ala Met 1 5 10 15 <210> 916 <211> 8 <212> PRT <213> Photobacterium profundum <400> 916

    Thr Glu Leu Lys Thr Glu Tyr Asn 1 5 <210> 917 <211> 14 <212> PRT <213> Photobacterium profundum <400> 917

    Cys Tyr Ala Tyr Phe Lys Ala His Arg His Ser Leu Phe His 1 5 10 <210> 918 <211> 13 <212> PRT <213> Photobacterium profundum <400> 918

    Thr Thr Asp Thr Ile Gly Glu Val Met Gln Met Ser Glu 1 5 10 <210> 919 <211> 11 <212> PRT <213> Geobacillus thermoglucosidasius <400> 919

    Leu Tyr Asp Arg Asp Arg Ile Glu Ala Ser Glu 1 5 10 <210> 920 <211> 16 <212> PRT <213> Geobacillus thermoglucosidasius <400> 920

    Val Ser Gly Thr Leu Arg Ala Phe Glu Gly Phe Phe Lys Lys Leu Leu 1 5 10 15 <210> 921 <211> 8 <212> PRT <213> Geobacillus thermoglucosidasius <400> 921

    Asp Ile Ser Glu Lys Val Phe Asn 1 5 <210> 922 <211> 14 <212> PRT <213> Geobacillus thermoglucosidasius <400> 922

    Met Leu Asn His Met Ser Gln Asp Arg Asn Pro Tyr Ser His <210> 923 <211> 13 <212> PRT <213> Geobacillus thermoglucosidasius <400> 923

    Pro Leu Arg Thr Leu Asn Gln Ala Ile Ser Leu His Asn 1 5 10 <210> 924 <211> 12 <212> PRT <213> Teredinibacter turnerae <400> 924

    Cys Arg Ser Ile Arg Lys Leu Leu Asn Met Asn Ala 1 5 10 <210> 925 <211> 16 <212> PRT <213> Teredinibacter turnerae <400> 925

    Ser Tyr Pro Leu Ile Tyr Glu Ile Glu Asn Leu Val Arg Lys Leu Ile 1 5 10 15 <210> 926 <211> 9 <212> PRT <213> Teredinibacter turnerae <400> 926

    Ile Gln Leu Ser Asn Phe Leu Phe Asp 1 5 <210> 927 <211> 15 <212> PRT <213> Teredinibacter turnerae <400> 927

    Arg Trp Gly Lys Leu Tyr Lys Leu Arg Cys Lys Ile Ala His Asn 1 5 10 15 <210> 928 <211> 13 <212> PRT <213> Teredinibacter turnerae <400> 928

    Thr Thr Lys Leu Val Glu Glu Val Lys Leu Lys Ile Leu 1 5 10 <210> 929 <211> 5 <212> PRT <213> Methanococcus maripaludis <400> 929

    Phe Arg Leu Met Tyr

    1 5 <210> 930 <211> 16 <212> PRT <213> Methanococcus maripaludis <400> 930

    Phe Leu Asp Ser Val Leu Ala Leu Glu Ile Tyr His Thr Leu Lys Phe 1 5 10 15 <210> 931 <211> 10 <212> PRT <213> Methanococcus maripaludis <400> 931

    Phe Ile Asn Lys Met Lys Asp Val Phe Asn <210> 932 <211> 15 <212> PRT <213> Methanococcus maripaludis <400> 932

    Ile Cys Arg Ile Ile Arg Asp Thr Arg Asn Lys Leu Val His Asp 1 5 10 15 <210> 933 <211> 13 <212> PRT <213> Methanococcus maripaludis <400> 933

    Pro Tyr Phe Leu Ile Glu Leu Leu Lys Asn Ile Phe Lys 1 5 10 <210> 934 <211> 11 <212> PRT <213> Novosphingobium pentaromativorans <400> 934

    Val His Arg Ala Leu Ser Trp Leu Arg Arg Ala 1 5 10 <210> 935 <211> 14 <212> PRT <213> Novosphingobium pentaromativorans <400> 935

    Phe Ile Leu Leu Trp Ile Gly Phe Asn Ala Ala Tyr Ala Gly 1 5 10 <210> 936 <211> 10 <212> PRT <213> Novosphingobium pentaromativorans <400> 936

    Glu Arg Ser Arg Thr Ala Ile Asn Tyr Ala 1 5 10 <210> 937 <211> 15 <212> PRT <213> Novosphingobium pentaromativorans <400> 937

    Leu Phe Asp Arg Leu Tyr Val Leu Arg Asn Gln Leu Val His Gly 1 5 10 15 <210> 938 <211> 13 <212> PRT <213> Novosphingobium pentaromativorans <400> 938

    Arg Asp Gln Val Arg Asp Gly Ala Ser Leu Leu Gly Cys 1 5 10 <210> 939 <211> 12 <212> PRT <213> Chlorobium chlorochromatii <400> 939

    Ile Met Glu Gln Arg Lys Ala Ile Leu Glu Pro Leu 1 5 10 <210> 940 <211> 16 <212> PRT <213> Chlorobium chlorochromatii <400> 940

    Ala Val Ala Tyr Asn His Phe Val Pro Leu Leu Ala Gln Asp Leu Ile <210> 941 <211> 6 <212> PRT <213> Chlorobium chlorochromatii <400> 941

    Lys Ile Ser Asn Lys Lys

    1 5 <210> 942 <211> 15 <212> PRT <213> Chlorobium chlorochromatii <400> 942

    Ser Glu Lys Leu Lys Thr Phe Arg Asp Lys Tyr Tyr Ala His Leu 1 5 10 15 <210> 943 <211> 13 <212> PRT <213> Chlorobium chlorochromatii <400> 943

    Phe Leu Gly Ile His Arg Lys Ser Ala Asn Glu Met Trp 1 5 10 <210> 944 <211> 12 <212> PRT <213> Lactococcus lactis <400> 944

    Asp Ala Tyr Asn Lys Leu Ile Leu Leu Lys Gln Tyr 1 5 10 <210> 945 <211> 15 <212> PRT <213> Lactococcus lactis <400> 945

    Phe Phe Tyr Asn Asn Leu Leu Asp Ser Leu Val Ile Ala Ile Phe 1 5 10 15 <210> 946 <211> 6 <212> PRT <213> Lactococcus lactis <400> 946

    Asn Tyr Thr Asn Phe Pro

    1 5 <210> 947 <211> 15 <212> PRT <213> Lactococcus lactis <400> 947

    Leu Glu Tyr Leu Tyr Ala Gln Arg Asn Lys Ile Tyr Val His Asn 1 5 10 15 <210> 948 <211> 13 <212> PRT <213> Lactococcus lactis <400> 948

    Asn Tyr Ala Trp Glu Pro Thr Asn Ile Asn Asp Trp Glu 1 5 10 <210> 949 <211> 16 <212> PRT <213> Escherichia coli <400> 949

    Glu Ser Val Ile Ala His Met Asn Glu Leu Leu Ile Ala Leu Ser Asp <210> 950 <211> 15 <212> PRT <213> Escherichia coli <400> 950

    Arg Tyr Thr Gln Gln Gln Arg Leu Arg Thr Ala Ile Ala His His 1 5 10 15 <210> 951 <211> 12 <212> PRT <213> Escherichia coli <400> 951

    Glu Ala Arg His Glu Gln Leu Thr Lys Gly Gly Thr 1 5 10 <210> 952 <211> 16 <212> PRT <213> Cronobacter sakazakii <400> 952

    Gln His Val Ile Ala Pro Met Asn Glu Leu Leu Ile Ala Leu Ser Asp 1 5 10 15 <210> 953 <211> 15 <212> PRT <213> Cronobacter sakazakii <400> 953

    Arg Tyr Asp Leu Gln Gln Gln Leu Arg Thr Ala Ile Ala His His 1 5 10 15 <210> 954 <211> 13 <212> PRT <213> Cronobacter sakazakii <400> 954

    Ala Ala Glu Arg Leu Ala Glu Leu Thr Arg Gly Gly Thr 1 5 10 <210> 955 <211> 16 <212> PRT <213> Homo sapiens <400> 955

    Glu Ser Arg Tyr Arg Thr Leu Arg Asn Val Gly Asn Glu Ser Asp Ile 1 5 10 15 <210> 956 <211> 10 <212> PRT <213> Homo sapiens <400> 956

    Leu Gln Pro Gly Pro Ser Glu His Ser Lys 1 5 10 <210> 957 <211> 14 <212> PRT <213> Homo sapiens <400> 957

    Val Gly Asp Leu Leu Lys Phe Ile Arg Asn Leu Gly Glu His 1 5 10 <210> 958 <211> 13 <212> PRT <213> Homo sapiens <400> 958

    Ile Gly Asp Pro Ser Leu Tyr Phe Gln Lys Thr Phe Pro <210> 959 <211> 16 <212> PRT <213> Arabidopsis thaliana <400> 959

    Glu Met Arg Leu Ser Phe Leu Arg Asp Ala Ser Asp Arg Val Glu Leu 1 5 10 15 <210> 960 <211> 10 <212> PRT <213> Arabidopsis thaliana <400> 960

    Met Glu Ser Thr Ala Pro Val Ala Ile Gly 1 5 10 <210> 961 <211> 15 <212> PRT <213> Arabidopsis thaliana <400> 961

    Ile Arg Asp Leu Leu Arg Val Ile Arg Asn Lys Leu Asn His His 1 5 10 15 <210> 962 <211> 13 <212> PRT <213> Arabidopsis thaliana <400> 962

    Pro Glu Gly Phe Asp Glu Tyr Phe Ala Val Arg Phe Pro 1 5 10 <210> 963 <211> 12 <212> PRT <213> Helicobacter pylori <400> 963

    Tyr Glu Leu Leu Trp Gln Glu Val Ile Arg Ala Lys 1 5 10 <210> 964 <211> 15 <212> PRT <213> Helicobacter pylori <400> 964

    Trp Val Ser Leu Gln Asn Val Met Arg Arg Ile Ile Glu Tyr Tyr 1 5 10 15 <210> 965 <211> 5 <212> PRT <213> Helicobacter pylori <400> 965

    Phe Arg Ile Leu Gly 1 5 <210> 966 <211> 17 <212> PRT <213> Helicobacter pylori <400> 966

    Lys Gln Val Phe Ser Ser Phe Ile Ser Trp Phe Asn Asp Gly Ser His 1 5 10 15

    Gly <210> 967 <211> 13 <212> PRT <213> Helicobacter pylori <400> 967

    Ile Glu Thr Tyr Leu Lys Val Phe Glu Asn Ile Phe Lys 1 5 10 <210> 968 <211> 12 <212> PRT <213> Streptococcus mutans <400> 968

    His Leu Met Leu Val Asp Glu Leu Lys Lys Ala Ile 1 5 10 <210> 969 <211> 15 <212> PRT <213> Streptococcus mutans <400> 969

    Glu Lys Tyr His Phe Asn Leu Leu Arg Asn Leu Leu Glu Lys Thr 1 5 10 15 <210> 970 <211> 5 <212> PRT <213> Streptococcus mutans <400> 970

    Ala Thr Phe Leu Gly 1 5 <210> 971 <211> 14 <212> PRT <213> Streptococcus mutans <400> 971

    Pro Ala Pro Tyr Ile Arg Arg Ile Asn Leu His Ser His Ser 1 5 10 <210> 972 <211> 13 <212> PRT <213> Streptococcus mutans <400> 972

    Lys Lys Val Leu Glu Arg Val Phe Asn Gln Phe Leu Gln 1 5 10 <210> 973 <211> 12 <212> PRT <213> Escherichia coli <400> 973

    His Leu His Leu Lys Gln Thr Ile Glu Gln Ala Ile 1 5 10 <210> 974 <211> 15 <212> PRT <213> Escherichia coli <400> 974

    Glu Arg Tyr His Phe Thr Leu Leu Arg Asn Leu Tyr Glu Lys Thr 1 5 10 15 <210> 975 <211> 5 <212> PRT <213> Escherichia coli <400> 975

    Ala Ser Phe Leu Gly

    1 5 <210> 976 <211> 13 <212> PRT <213> Escherichia coli <400> 976

    Leu Tyr Leu Ser Arg Ile Ile Asn Phe Thr Ser His Ser 1 5 10 <210> 977 <211> 13 <212> PRT <213> Escherichia coli <400> 977

    Lys Ala Thr Val Lys Leu Leu Leu Asp His Leu Lys Asn 1 5 10 <210> 978 <211> 12 <212> PRT <213> Bacteroides fragilis <400> 978

    Lys Glu Ile Glu Glu Glu Arg Thr Val Gln Asn Ile 1 5 10 <210> 979 <211> 16 <212> PRT <213> Bacteroides fragilis <400> 979

    Thr Ser Phe Gly Glu Val Thr Glu Glu Tyr His Asp Glu Leu Tyr Ser 1 5 10 15 <210> 980 <211> 8 <212> PRT <213> Bacteroides fragilis <400> 980

    Tyr Ile Lys Glu Leu Ser Asn Gly 1 5 <210> 981 <211> 15 <212> PRT <213> Bacteroides fragilis <400> 981

    Gln Lys Thr Leu Thr Glu Lys Ile Arg His Gln Ile His His Pro 1 5 10 15 <210> 982 <211> 13 <212> PRT <213> Bacteroides fragilis <400> 982

    Glu Thr Glu Ile Arg Gln Ser Ile Glu Asp Met Arg Ala 1 5 10 <210> 983 <211> 12 <212> PRT <213> Methylobacillus flagellatus <400> 983

    Ser Asn Gln Ile Pro Thr Arg Val Ser Pro Val Leu 1 5 10 <210> 984 <211> 16 <212> PRT <213> Methylobacillus flagellatus <400> 984

    Ser Ala Phe Gly Glu Ala Ser Tyr Glu Tyr His Asn Glu Leu Tyr Gly

    1 5 10 15 <210> 985 <211> 8 <212> PRT <213> Methylobacillus flagellatus <400> 985

    Tyr Asn Arg Leu Arg Arg Asp Gly 1 5 <210> 986 <211> 15 <212> PRT <213> Methylobacillus flagellatus <400> 986

    Gln Val Ile Leu Thr Glu Tyr Ile Arg His Gln Ile His His Pro 1 5 10 15 <210> 987 <211> 13 <212> PRT <213> Methylobacillus flagellatus <400> 987

    Thr Ala Glu Leu Thr Glu Ser Ile Glu Thr Met Arg Leu 1 5 10 <210> 988 <211> 12 <212> PRT <213> Campylobacter hominis <400> 988

    Lys Asp Gly Glu Gln Lys Lys Glu Val Lys Asn Val 1 5 10 <210> 989 <211> 16 <212> PRT <213> Campylobacter hominis <400> 989

    Met Ala Phe Gly Glu Ile Thr Glu Glu Tyr His Asn Glu Leu Tyr Gly 1 5 10 15 <210> 990 <211> 8 <212> PRT <213> Campylobacter hominis <400> 990

    Tyr Lys Lys Leu Lys Lys Asp Gly 1 5 <210> 991 <211> 15 <212> PRT <213> Campylobacter hominis <400> 991

    Lys Leu Thr Leu Thr Glu Tyr Ile Arg His Gln Ile His His Pro 1 5 10 15 <210> 992 <211> 13 <212> PRT <213> Campylobacter hominis <400> 992

    Leu Ser Glu Leu Lys Asp Ser Ile Glu Met Met Arg Asn 1 5 10 <210> 993 <211> 15 <212> PRT <213> Homo sapiens <400> 993

    Ile Pro Asp Trp Ile Val Asp Leu Arg His Glu Leu Thr His Lys 1 5 10 15 <210> 994 <211> 15 <212> PRT <213> Mycobacterium tuberculosis <400> 994

    Leu Gly Arg Phe Glu Ser Arg Val Arg Asn Thr Ala Ala His Glu 1 5 10 15 <210> 995 <211> 15 <212> PRT <213> Lactococcus lactis <400> 995

    Trp Ile Arg Ala Gly Trp Phe Ile Arg Asn Arg Ser Ala His Tyr 1 5 10 15 <210> 996 <211> 15 <212> PRT <213> Thermus thermophilus <220>

    <221> MOD_RES <222> (5)..(5) <223> Any amino acid <400> 996

    Leu Ala Leu Gly Xaa Val Asp Asp Arg Ser Leu Thr Val His Thr 1 5 10 15 <210> 997 <211> 22 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 997

    Leu Lys Ser Met Leu Tyr Ser Met Arg Asn Ser Ser Phe His Phe Ser

    1 5 10 15

    Thr Glu Asn Val Asp Asn 20 <210> 998 <211> 22 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 998

    Leu Lys Asp Val Ile Tyr Ser Met Arg Asn Asp Ser Phe His Tyr Ala 1 5 10 15

    Thr Glu Asn His Asn Asn 20 <210> 999 <211> 22 <212> PRT <213> Clostridium aminophilum <400> 999

    Leu Arg Lys Ala Ile Tyr Ser Leu Arg Asn Glu Thr Phe His Phe Thr 1 5 10 15

    Thr Leu Asn Lys Gly Ser 20 <210> 1000 <211> 22 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1000

    Ile Ile Gln Ile Ile Tyr Ser Leu Arg Asn Lys Ser Phe His Phe Lys 1 5 10 15

    Thr Tyr Asp His Gly Asp 20 <210> 1001 <211> 22 <212> PRT <213> Carnobacterium gallinarum <400> 1001

    Leu Arg Gly Ser Val Gln Gln Ile Arg Asn Glu Ile Phe His Ser Phe 1 5 10 15

    Asp Lys Asn Gln Lys Phe 20 <210> 1002 <211> 21 <212> PRT <213> Carnobacterium gallinarum <400> 1002

    Ile Arg Gly Ala Val Gln Arg Val Arg Asn Gln Ile Phe His Gln Gln 1 5 10 15

    Ile Asn Lys Arg His 20 <210> 1003 <211> 20 <212> PRT <213> Paludibacter propionicigenes <400> 1003

    Ile Arg Gly Ala Val Gln Gln Ile Arg Asn Asn Val Asn His Tyr Lys 1 5 10 15

    Lys Asp Ala Leu 20 <210> 1004 <211> 20 <212> PRT <213> Listeria seeligeri <400> 1004

    Leu Arg Gly Ala Ile Ala Pro Ile Arg Asn Glu Ile Ile His Leu Lys 1 5 10 15

    Lys His Ser Trp 20 <210> 1005 <211> 20 <212> PRT <213> Listeria weihenstephanensis <400> 1005

    Ile Arg Gly Ser Ile Gln Gln Ile Arg Asn Glu Val Tyr His Cys Lys 1 5 10 15

    Lys His Ser Trp 20 <210> 1006 <211> 20 <212> PRT <213> Listeria newyorkensis <400> 1006

    Ile Arg Gly Ser Ile Gln Gln Ile Arg Asn Glu Val Tyr His Cys Lys

    1 5 10 15

    Lys His Ser Trp 20 <210> 1007 <211> 21 <212> PRT <213> Leptotrichia wadei <400> 1007

    Ile Ser Tyr Ser Ile Tyr Asn Val Arg Asn Gly Val Gly His Phe Asn 1 5 10 15

    Lys Leu Ile Leu Gly 20 <210> 1008 <211> 21 <212> PRT <213> Leptotrichia wadei <400> 1008

    Met Leu Asn Ala Ile Thr Ser Ile Arg His Arg Val Val His Tyr Asn 1 5 10 15

    Met Asn Thr Asn Ser 20

    Leu Glu Leu Glu Gly 20 <210> 1009 <211> 21 <212> PRT <213> Leptotrichia wadei <400> 1009

    Ile Asp Glu Ala Ile Ser Ser Ile Arg His Gly Ile Val His Phe Asn

    1 5 10 15 <210> 1010 <211> 22 <212> PRT <213> Rhodobacter capsulatus <400> 1010

    Leu Leu Arg Tyr Leu Arg Gly Cys Arg Asn Gln Thr Phe His Leu Gly 1 5 10 15

    Ala Arg Ala Gly Phe Leu 20 <210> 1011 <211> 21 <212> PRT <213> Leptotrichia buccalis <400> 1011

    Ile Asp Glu Ala Ile Ser Ser Ile Arg His Gly Ile Val His Phe Asn 1 5 10 15

    Leu Glu Leu Glu Gly 20 <210> 1012 <211> 21 <212> PRT <213> Leptotrichia sp.

    <400> 1012

    Ile Asp Glu Ala Ile Ser Ser Ile Arg His Gly Ile Val His Phe Asn 1 5 10 15

    Leu Glu Leu Glu Gly 20 <210> 1013 <211> 16 <212> PRT <213> Leptotrichia sp.

    <400> 1013

    Phe Gln Lys Glu Gly Tyr Leu Leu Arg Asn Lys Ile Leu His Asn Ser 1 5 10 15 <210> 1014 <211> 15 <212> PRT <213> Leptotrichia shahii <400> 1014

    Phe Thr Lys Ile Gly Thr Asn Glu Arg Asn Arg Ile Leu His Ala 1 5 10 15 <210> 1015 <211> 14 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1015

    Phe Arg Asn Glu Ile Asp His Phe His Tyr Phe Tyr Asp Arg 1 5 10 <210> 1016 <211> 14 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1016

    Leu Arg Asn Tyr Ile Glu His Phe Arg Tyr Tyr Ser Ser Phe

    1 5 10 <210> 1017 <211> 14 <212> PRT <213> Clostridium aminophilum <400> 1017

    Val Arg Lys Tyr Val Asp His Phe Lys Tyr Tyr Ala Thr Ser 1 5 10 <210> 1018 <211> 14 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1018

    Leu Arg Lys Tyr Val Asp His Phe Lys Tyr Tyr Ala Tyr Gly 1 5 10 <210> 1019 <211> 14 <212> PRT <213> Carnobacterium gallinarum <400> 1019

    Ile Arg Asn Gln Thr Ala His Leu Ser Val Leu Gln Leu Glu 1 5 10 <210> 1020 <211> 14 <212> PRT <213> Carnobacterium gallinarum <400> 1020

    Ile Arg Asn Asn Ile Ala His Leu His Val Leu Arg Asn Asp

    1 5 10 <210> 1021 <211> 14 <212> PRT <213> Paludibacter propionicigenes <400> 1021

    Ile Arg Asn His Ile Ala His Phe Asn Tyr Leu Thr Lys Asp 1 5 10 <210> 1022 <211> 14 <212> PRT <213> Listeria seeligeri <400> 1022

    Lys Arg Asn Asn Ile Ser His Phe Asn Tyr Leu Asn Gly Gln 1 5 10 <210> 1023 <211> 14 <212> PRT <213> Listeria weihenstephanensis <400> 1023

    Ala Arg Asn His Ile Ala His Leu Asn Tyr Leu Ser Leu Lys 1 5 10 <210> 1024 <211> 14 <212> PRT <213> Listeria newyorkensis <400> 1024

    Ala Arg Asn His Ile Ala His Leu Asn Tyr Leu Ser Leu Lys

    1 5 10 <210> 1025 <211> 14 <212> PRT <213> Leptotrichia wadei <400> 1025

    Phe Arg Asn Tyr Ile Ala His Phe Leu His Leu His Thr Lys 1 5 10 <210> 1026 <211> 14 <212> PRT <213> Leptotrichia wadei <400> 1026

    Ile Arg Asn Tyr Ile Ala His Phe Asn Tyr Ile Pro Asp Ala 1 5 10 <210> 1027 <211> 14 <212> PRT <213> Leptotrichia wadei <400> 1027

    Ile Arg Asn Tyr Ile Ala His Phe Asn Tyr Ile Pro His Ala 1 5 10 <210> 1028 <211> 14 <212> PRT <213> Rhodobacter capsulatus <400> 1028

    Thr Arg Lys Asp Leu Ala His Phe Asn Val Leu Asp Arg Ala 1 5 10 <210> 1029 <211> 14 <212> PRT <213> Leptotrichia buccalis <400> 1029

    Ile Arg Asn Tyr Ile Ala His Phe Asn Tyr Ile Pro His Ala

    1 5 10 <210> 1030 <211> 14 <212> PRT <213> Leptotrichia sp.

    <400> 1030

    Ile Arg Asn Tyr Ile Ala His Phe Asn Tyr Ile Pro Asn Ala 1 5 10 <210> 1031 <211> 14 <212> PRT <213> Leptotrichia sp.

    <400> 1031

    Ile Arg Asn Tyr Ile Ser His Phe Tyr Ile Val Arg Asn Pro 1 5 10 <210> 1032 <211> 14 <212> PRT <213> Leptotrichia shahii <400> 1032

    Ile Arg Asn Tyr Ile Ser His Phe Tyr Ile Val Arg Asn Pro 1 5 10 <210> 1033 <211> 1200 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic consensus sequence <220>

    <221> MOD_RES <222> (7)..(7) <223> Any amino acid <220>

    <221> MOD_RES <222> (11)..(13) <223> Any amino acid <220>

    <221> MOD_RES <222> (18)..(18) <223> Ile or Leu <220>

    <221> MOD_RES <222> (20)..(21) <223> Any amino acid <220>

    <221> MOD_RES <222> (39)..(39) <223> Any amino acid <220>

    <221> MOD_RES <222> (75)..(75) <223> Any amino acid <220>

    <221> MOD_RES <222> (93)..(93) <223> Any amino acid <220>

    <221> MOD_RES <222> (100)..(100) <223> Any amino acid <220>

    <221> MOD_RES <222> (145)..(145) <223> Any amino acid <220>

    <221> MOD_RES <222> (149)..(149) <223> Any amino acid <220>

    <221> MOD_RES <222> (154)..(154) <223> Any amino acid <220>

    <221> MOD_RES <222> (216)..(216) <223> Any amino acid <220>

    <221> MOD_RES <222> (236)..(236) <223> Any amino acid <220>

    <221> MOD_RES <222> (278)..(278) <223> Any amino acid <220>

    <221> MOD_RES <222> (315)..(315) <223> Any amino acid <220>

    <221> MOD_RES <222> (317)..(317) <223> Any amino acid <220>

    <221> MOD_RES <222> (319)..(319) <223> Any amino acid <220>

    <221> MOD_RES <222> (370)..(370) <223> Any amino acid <220>

    <221> MOD_RES <222> (407)..(407) <223> Any amino acid <220>

    <221> MOD_RES <222> (419)..(419) <223> Any amino acid <220>

    <221> MOD_RES <222> (428)..(428) <223> Any amino acid <220>

    <221> MOD_RES <222> (445)..(445) <223> Any amino acid <220>

    <221> MOD_RES <222> (455)..(455) <223> Any amino acid <220>

    <221> MOD_RES <222> (563)..(563) <223> Any amino acid <220>

    <221> MOD_RES <222> (717)..(717) <223> Any amino acid <220>

    <221> MOD_RES <222> (795)..(796) <223> Any amino acid <220>

    <221> MOD_RES <222> (800)..(800) <223> Any amino acid <220>

    <221> MOD_RES <222> (942)..(942) <223> Any amino acid <220>

    <221> MOD_RES <222> (971)..(971) <223> Ile or Leu <220>

    <221> MOD_RES <222> (1045)..(1045) <223> Any amino acid <220>

    <221> MOD_RES <222> (1050)..(1050) <223> Any amino acid <220>

    <221> MOD_RES <222> (1063)..(1064) <223> Any amino acid <220>

    <221> MOD_RES <222> (1117)..(1118) <223> Any amino acid <220>

    <221> MOD_RES <222> (1132)..(1132) <223> Any amino acid <220>

    <221> MOD_RES <222> (1138)..(1138) <223> Any amino acid <220>

    <221> MOD_RES <222> (1194)..(1194) <223> Any amino acid <220>

    <221> MOD_RES <222> (1196)..(1196) <223> Any amino acid <400> 1033

    Met Leu Phe Phe Met Ser Xaa Asp Ile Thr Xaa Xaa Xaa Asn Met Met 1 5 10 15

    Met Xaa Tyr Xaa Xaa Phe Thr Asn Leu Tyr Pro Leu Ser Lys Thr Leu 20 25 30

    Arg Phe Glu Leu Lys Pro Xaa Gly Lys Thr Leu Glu Asn Ile Glu Lys 35 40 45

    Asn Gly Leu Leu Glu Lys Asp Glu Lys Arg Ala Glu Asp Tyr Lys Lys 50 55 60

    Val Lys Lys Ile Ile Asp Glu Tyr His Lys Xaa Phe Ile Glu Glu Ala 65 70 75 80

    Leu Ser Ser Val Lys Leu Ser Glu Leu Glu Glu Tyr Xaa Asp Leu Tyr 85 90 95

    Leu Lys Lys Xaa Lys Asp Asp Lys Asp Lys Lys Ala Leu Lys Lys Glu 100 105 110

    Gln Asp Lys Leu Arg Lys Glu Ile Val Lys Ala Phe Lys Ala Asp Glu 115 120 125

    Lys Tyr Lys Lys Leu Phe Lys Lys Glu Leu Ile Leu Lys Asp Leu Pro 130 135 140

    Xaa Phe Val Lys Xaa Glu Glu Asp Lys Xaa Leu Leu Lys Ser Phe Lys 145 150 155 160

    Gly Phe Thr Thr Tyr Phe Thr Gly Phe His Glu Asn Arg Lys Asn Met 165 170 175

    Tyr Ser Asp Glu Asp Lys Ser Thr Ala Ile Ala Tyr Arg Ile Ile His 180 185 190

    Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe Glu Lys Ile 195 200 205

    Lys Glu Lys Ala Glu Leu Leu Xaa Glx Ile Glu Leu Glu Glu Ile Phe 210 215 220

    Ser Leu Asp Tyr Tyr Asn Asn Val Leu Thr Gln Xaa Gly Ile Asp Lys 225 230 235 240

    Tyr Asn Ala Ile Ile Gly Gly Ile Ser Thr Glu Asp Gly Lys Ile Lys 245 250 255

    Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn Gln Gln Asn Lys Asp Lys 260 265 270

    Lys Lys Leu Pro Lys Xaa Lys Pro Leu Tyr Lys Gln Ile Leu Ser Asp 275 280 285

    Arg Glu Ser Leu Ser Phe Leu Pro Glu Lys Phe Glu Asp Asp Glu Glu 290 295 300

    Val Leu Asp Ala Ile Lys Glu Phe Tyr Asp Xaa Ile Xaa Glu Xaa Ile 305 310 315 320

    Leu Glu Lys Leu Lys Leu Leu Phe Asp Asn Leu Ser Glu Tyr Asp Leu 325 330 335

    Ser Lys Ile Tyr Ile Lys Asn Asp Ala Leu Thr Thr Ile Ser Gln Lys 340 345 350

    Val Phe Gly Asp Trp Ser Val Ile Gly Asp Ala Leu Glu Glu Tyr Tyr 355 360 365

    Asp Xaa Pro Lys Lys Lys Lys Glu Lys Tyr Glu Glu Lys Arg Lys Lys 370 375 380

    Lys Leu Lys Lys Lys Lys Ser Phe Ser Leu Glu Glu Leu Asn Glu Leu 385 390 395 400

    Leu Glu Glu Arg Ile Glu Xaa Tyr Phe Ala Thr Leu Gly Asp Leu Ile 405 410 415

    Glu Asn Xaa Tyr Leu Ala Ala Glu Lys Leu Leu Xaa Thr Glu Tyr Pro 420 425 430

    Glu Glu Lys Asn Leu Lys Lys Asp Lys Glu Ala Val Xaa Ala Ile Lys 435 440 445

    Asp Leu Leu Asp Ser Ile Xaa Asx Leu Gln His Phe Leu Lys Pro Leu 450 455 460

    Leu Gly Lys Gly Asp Glu Leu Asp Lys Asp Glu Asn Phe Tyr Gly Glu 465 470 475 480

    Phe Glu Glu Leu Tyr Glu Glu Leu Asp Glu Ile Ile Pro Leu Tyr Asn 485 490 495

    Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro Tyr Ser Thr Glu Lys Ile 500 505 510

    Lys Leu Asn Phe Glu Asn Pro Thr Leu Leu Asn Gly Trp Asp Lys Asn 515 520 525

    Lys Glu Lys Asp Asn Leu Ala Ile Ile Leu Arg Lys Asp Gly Lys Tyr

    530

    535

    540

    Tyr Leu Gly Ile Met Asn Lys Lys His Asn Lys Ile Phe Asp Asn Lys 545 550 555 560

    Pro Lys Xaa Cys Tyr Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Pro 565 570 575

    Asn Lys Met Leu Pro Lys Val Phe Phe Ser Lys Lys Asn Ile Lys Glu 580 585 590

    Tyr Asn Pro Ser Glu Glu Ile Leu Glu Ile Tyr Lys Lys Gly Thr His 595 600 605

    Lys Lys Gly Asp Asn Phe Ser Leu Lys Asp Cys His Lys Leu Ile Asp 610 615 620

    Phe Phe Lys Glu Ser Ile Glu Lys His Glu Asp Trp Lys Lys Phe Gly 625 630 635 640

    Phe Lys Phe Ser Asp Thr Glu Ser Tyr Asn Asp Ile Ser Glu Phe Tyr 645 650 655

    Arg Glu Val Glu Lys Gln Gly Tyr Lys Leu Ser Phe Thr Lys Ile Ser 660 665 670

    Glu Ser Tyr Ile Asp Ser Leu Val Glu Glu Gly Lys Leu Tyr Leu Phe 675 680 685

    Gln Ile Tyr Asn Lys Asp Phe Ser Pro Tyr Ser Lys Gly Lys Pro Asn 690 695 700

    Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Ser Glu Xaa Asn Leu Lys 705 710 715 720

    Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr Arg Lys 725 730 735

    Ala Ser Ile Lys Lys Lys Lys Ile Thr His Lys Ala Gly Glu Pro Ile 740 745 750

    Lys Asn Lys Asn Asn Pro Lys Lys Glu Ser Lys Phe Glu Tyr Asp Ile 755 760 765

    Ile Lys Asp Lys Arg Tyr Thr Glu Asp Lys Phe Phe Phe His Val Pro 770 775 780

    Ile Thr Met Asn Phe Lys Ala Ser Gly Asn Xaa Xaa Phe Asn Asp Xaa 785 790 795 800

    Val Asn Glu Tyr Ile Arg Glu Asn Asp Asp Val His Ile Ile Gly Ile 805 810 815

    Asp Arg Gly Glu Arg Asn Leu Leu Tyr Tyr Ser Val Ile Asp Ser Lys 820 825 830

    Gly Asn Ile Leu Glu Gln Asp Ser Leu Asn Ile Ile Asn Asn Lys Thr 835 840 845

    Asp Tyr His Asp Leu Leu Asp Glu Arg Glu Lys Glu Arg Asp Lys Ala 850 855 860

    Arg Lys Asn Trp Gln Thr Ile Glu Asn Ile Lys Glu Leu Lys Glu Gly 865 870 875 880

    Tyr Leu Ser Gln Val Val His Lys Ile Ala Lys Leu Met Ile Lys Tyr 885 890 895

    Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly Phe Lys Arg Gly 900 905 910

    Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met Leu 915 920 925

    Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asp Lys Glu Xaa Asp Glu 930 935 940

    Ile Gly Gly Leu Leu Asn Ala Tyr Gln Leu Thr Asn Pro Phe Glu Ser 945 950 955 960

    Phe Lys Lys Leu Gly Lys Gln Thr Gly Phe Xaa Phe Tyr Val Pro Ala 965 970 975

    Trp Asn Thr Ser Lys Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe 980 985 990

    Tyr Pro Lys Tyr Glu Asn Val Asp Lys Ala Lys Glu Phe Phe Ser Lys 995 1000 1005

    Phe Asp Ser Ile Arg Tyr Asn Asp Lys Asp Tyr Phe Glu Phe Ala 1010 1015 1020

    Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg Thr 1025 1030 1035

    Lys Trp Thr Ile Cys Thr Xaa Gly Glu Arg Ile Xaa Asn Phe Arg 1040 1045 1050

    Asn Ser Asp Lys Asn Asn Lys Trp Asp Xaa Xaa Glu Ile Asp Leu 1055 1060 1065

    Thr Glu Glu Leu Lys Glu Leu Phe Lys Asp Tyr Gly Ile Asn Tyr 1070 1075 1080

    Gly Glu Asp Leu Lys Glu Ala Ile Cys Ser Glu Asp Asp Lys Asp 1085 1090 1095

    Phe Phe Lys Ser Leu Leu Tyr Leu Leu Lys Leu Thr Leu Gln Met 1100 1105 1110

    Arg Asn Ser Xaa Xaa Asp Asp Tyr Ile Ile Ser Pro Val Ala Asn 1115 1120 1125

    Asp Asn Gly Xaa Phe Phe Asp Ser Arg Xaa Ala Lys Leu Pro Lys 1130 1135 1140

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1145 1150 1155

    Trp Leu Leu Glu Gln Ile Lys Asn Thr Asp Glu Gly Lys Lys Ala 1160 1165 1170

    Leu Ile Ser Asn Lys Glu Trp Leu Glu Phe Ala Gln Asn Arg Pro 1175 1180 1185

    Tyr Leu Lys Asp Ala Xaa Ala Xaa Asn Lys Lys His 1190 1195 1200 <210> 1034 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1034 gugccacuuc ucagaucgcu cgcucaguga uccgac <210> 1035 <211> 105 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1035 gucagaacac ugagcgagcg uucuuuuuga gaagcucaac gggcuuugcc accuggaaag uggccauugg cacacccguu gaaaaaauuc uguccucuag acaga 105 <210> 1036 <211> 105 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1036 gucagaacac ugagcgagcg uucuuuuuga gaagcucaac gggcuuugcc accuggaaag uggccauugg cacacccguu gaaaaaauuc uguccucuag acaga 105 <210> 1037 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1037 gugccacuuc ucagaucgcu cgcucaguga uccgac <210> 1038 <211> 37 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1038 gugccaauca cccaacacug accaagcuug ccgagac 37 <210> 1039 <211> 64 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1039 cuuggggaaa gcuaggcaag uuuuggauga uaagaaauaa ucaugucaca aggagggagu uuuu 64 <210> 1040 <211> 64 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1040 cuuggggaaa gcuaggcaag uuuuggauga uaagaaauaa ucaugucaca aggagggagu uuuu <210> 1041 <211> 37 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1041 gugccaauca cccaacacug accaagcuug ccgagac 37 <210> 1042 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1042 gccgcagcga augccguuuc acgaaucguc aggcgg 36 <210> 1043 <211> 75 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1043 gcuggagacg uuuuuugaaa cggcgagugc ugcggauagc gaguuucucu uggggaggcg cucgcggcca cuuuu 75 <210> 1044 <211> 75 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1044 gcuggagacg uuuuuugaaa cggcgagugc ugcggauagc gaguuucucu uggggaggcg cucgcggcca cuuuu 75 <210> 1045 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1045 gccgcagcga augccguuuc acgaaucguc aggcgg 36 <210> 1046 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1046 guccaagaaa aaagaaauga uacgaggcau uagcac 36 <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <210> 1047 <211> 107 <212> RNA <213> Artificial Sequence <400> 1047 cuggacgaug ucucuuuuau uucuuuuuuc uuggaucuga guacgagcac ccacauugga 60 cauuucgcau ggugggugcu cguacuauag guaaaacaaa ccuuuuu 107 <210> 1048 <211> 107 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1048 cuggacgaug ucucuuuuau uucuuuuuuc uuggaucuga guacgagcac ccacauugga cauuucgcau ggugggugcu cguacuauag guaaaacaaa ccuuuuu 107 <210> 1049 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1049 guccaagaaa aaagaaauga uacgaggcau uagcac 36 <210> 1050 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1050 guucgaaagc uuaguggaaa gcuucguccu uagcac <210> 1051 <211> 69 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1051 cacggauaau cacgacuuuc cacuaagcuu ucgaauuuua ugaugcgagc auccucucag gucaaaaaa 69 <210> 1052 <211> 69 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1052 cacggauaau cacgacuuuc cacuaagcuu ucgaauuuua ugaugcgagc auccucucag gucaaaaaa 69 <210> 1053 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1053 guucgaaagc uuaguggaaa gcuucguggu uagcac <210> 1054 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1054 guauugagaa aagccagaua uaguuggcaa uagac 35 <210> 1055 <211> 62 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1055 auauuuugau ucccauuuau gguuauuuac cauaaauggg aaucaacuaa aaaauauuuu uu 62 <210> 1056 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1056 guauugagaa aagccagaua uaguuggcaa uagac 35 <210> 1057 <211> 62 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1057 auauuuugau ucccauuuau gguuauuuac cauaaauggg aaucaacuaa aaaauauuuu uu 62 <210> 1058 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1058 guugaugaga agagcccaag auagagggca auaac 35 <210> 1059 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1059 gcuggagaag auagcccaag aaagagggca auaac 35 <210> 1060 <211> 78 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1060 auuauuacca uuuugguugg aaugcuauua uaaaggauca uucgauuauu accucuaccu cccuucccac gauuucuu 78 <210> 1061 <211> 78 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1061 attattacca ttttggttgg aatgctatta taaaggatca ttcgattatt acctctacct 60 cccttcccac gatttctt 78 <210> 1062 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1062 guugaugaga agagcccaag auagagggca auaac 35 <210> 1063 <211> 78 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1063 attattacca ttttggttgg aatgctatta taaaggatca ttcgattatt acctctacct 60 cccttcccac gatttctt <210> 1064 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1064 gcuggagaag auagcccaag aaagagggca auaac 35 <210> 1065 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1065 guuuggagaa cagcccgaua uagagggcaa uagac 35 <210> 1066 <211> 81 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1066 gucuuacgac cucaguauua ggaagauuuc aaccaagaaa acuuaguuuc aggcuuaaug aucgagucau gcagccaaag u <210> 1067 <211> 81 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1067 gucuuacgac cucaguauua ggaagauuuc aaccaagaaa acuuaguuuc aggcuuaaug aucgagucau gcagccaaag u 81 <210> 1068 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1068 guuuggagaa cagcccgaua uagagggcaa uagac 35 <210> 1069 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1069 guuuugagaa uagcccgaca uagagggcaa uagac 35 <210> 1070 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1070 guuaugaaaa cagcccgaca uagagggcaa uagaca 36 <210> 1071 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1071 guuauagucc ucuuacauuu agagguaguc uuuaau 36 <210> 1072 <211> 98 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1072 ucuuaagaac uucucuaccu gaaguuggau uauaaaugac ucuugcucuc auagauaucc uccuuugaaa auauacacug ccgauuaauu accguuuu 98 <210> 1073 <211> 98 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1073 ucuuaagaac uucucuaccu gaaguuggau uauaaaugac ucuugcucuc auagauaucc uccuuugaaa auauacacug ccgauuaauu accguuuu 98 <210> 1074 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1074 guuauagucc ucuuacauuu agagguaguc uuuaau 36 <210> 1075 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1075 guuauagucc ucuuacauuu agagguaguu uauauu 36 <210> 1076 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1076 guuauagucc ccuuacauuu agggguaguc uuuaau <210> 1077 <211> 102 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1077 aauauaaauu cucccuaaau auaagagaau aauaacucaa ucucuucauu cguauuuugu cuaguuaaga uaaguaccac caaauacaau caauccaaaa aa 102 <210> 1078 <211> 102 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1078 aauauaaauu cucccuaaau auaagagaau aauaacucaa ucucuucauu cguauuuugu cuaguuaaga uaaguaccac caaauacaau caauccaaaa aa 102 <210> 1079 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1079 guuauagucc ucuuacauuu agagguaguu uauauu <210> 1080 <211> 102 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1080 aauauaaauu cucccuaaau auaagagaau aauaacucaa ucucuucauu cguauuuugu cuaguuaaga uaaguaccac caaauacaau caauccaaaa aa 102 <210> 1081 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1081 guuauagucc ccuuacauuu agggguaguc uuuaau 36 <210> 1082 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1082 guuguaguuc ccuucaauuu ugggauaauc cacaag 36 <210> 1083 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1083 guuuuagucc ucuuucauau agagguaguc ucuuac 36 <210> 1084 <211> 99 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1084 augaaaagag gacuaaaacu gaaagaggac uaaaacacca gauguggaua acuauauuag uggcuauuaa aaauucgucg auauuagaga ggaaacuuu 99 <210> 1085 <211> 99 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1085 augaaaagag gacuaaaacu gaaagaggac uaaaacacca gauguggaua acuauauuag uggcuauuaa aaauucgucg auauuagaga ggaaacuuu 99 <210> 1086 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1086 guuuuagucc ucuuucauau agagguaguc ucuuac <210> 1087 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1087 guuuuagacc ucuucuauuu ugagguacuc uaaauc <210> 1088 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1088 guuuuagucc ucuuuuguuu ugagguacuc uaaauc <210> 1089 <211> 147 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1089 aagucagcgc acaacaaaga agaugacgaa caaaaucucu cgccaucuuc uuaaaauuau 60 uugccacaca gccaacauua uaagcguuaa aaccagcacc augaguacau uucacccaac aaucagaauccccguuucuccguuuuu 147 <210> 1090 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1090 guuuuagucc ucuuuuguuu ugagguacuc uaaauc 36 <210> 1091 <211> 147 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1091 aagucagcgc acaacaaaga agaugacgaa caaaaucucu cgccaucuuc uuaaaauuau uugccacaca gccaacauua uaagcguuaa aaccagcacc augaguacau uucacccaac aaucagaauc cccguuucuc cguuuuu 147

    120

    120 <210> 1092 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1092 guuuuagauc ccuucguuuu ugggguuauc uauauc 36 <210> 1093 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1093 guuuuagucc ccuucguuuu ugggguaguc uaaauc 36 <210> 1094 <211> 113 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1094 gauuuagagc accccaaaag uaaugaaaau uugcaauuaa auaaggaaua uuaaaaaaau 60 gugauuuuaa aaaaauugaa gaaauuaaau gaaaaauugu ccaaguaaaa aaa 113 <210> 1095 <211> 70 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1095 auuuagauua ccccuuuaau uuauuuuacc auauuuuucu cauaaugcaa acuaauauuc 60 caaaauuuuu <210> 1096 <211> 113 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1096 gauuuagagc accccaaaag uaaugaaaau uugcaauuaa auaaggaaua uuaaaaaaau 60 gugauuuuaa aaaaauugaa gaaauuaaau gaaaaauugu ccaaguaaaa aaa 113 <210> 1097 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1097 guuuuagucc ccuucguuuu ugggguaguc uaaauc 36 <210> 1098 <211> 70 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1098 auuuagauua ccccuuuaau uuauuuuacc auauuuuucu cauaaugcaa acuaauauuc 60 caaaauuuuu <210> 1099 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1099 guuuuagucc ccuucguuuu ugggguaguc uaaauc 36 <210> 1100 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1100 guuuuagucc ccuucgauau uggggugguc uauauc 36 <210> 1101 <211> 95 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1101 auugaugugg uauacuaaaa auggaaaauu guauuuuuga uuagaaagau guaaaauuga uuuaauuuaa aaauauuuua uuagauuaaa guaga 95 <210> 1102 <211> 95 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1102 auugaugugg uauacuaaaa auggaaaauu guauuuuuga uuagaaagau guaaaauuga uuuaauuuaa aaauauuuua uuagauuaaa guaga 95 <210> 1103 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1103 guuuuagucc ccuucgauau uggggugguc uauauc 36 <210> 1104 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1104 guucaguccg ccgucgucuu ggcggugaug ugaggc 36 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <210> 1105 <211> 36 <212> RNA <213> Artificial Sequence <400> 1105 guucaguccg ccgucauuuu ggcggugaug ugcucc <210> 1106 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1106 guucaguccg ccgucgucuu ggcggugaug ugaggc <210> 1107 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1107 guucaguccg ccgucauuuu ggcggugaug ugcucc <210> 1108 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1108 guucaguccg ccgucgucuu ggcggugaug ugaggc <210> 1109 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1109 guucaguccg ccgucauuuu ggcggugaug ugcucc 36 <210> 1110 <211> 1300 <212> PRT <213> Francisella tularensis <400> 1110

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala

    465

    470

    475

    480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly

    1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 1111 <211> 1477 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <400> 1111

    Met Ser Asn Phe Phe Lys Asn Phe Thr Asn Leu Tyr Glu Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Asp Thr Leu Thr Asn Met 20 25 30

    Lys Asp His Leu Glu Tyr Asp Glu Lys Leu Gln Thr Phe Leu Lys Asp 35 40 45

    Gln Asn Ile Asp Asp Ala Tyr Gln Ala Leu Lys Pro Gln Phe Asp Glu 50 55 60

    Ile His Glu Glu Phe Ile Thr Asp Ser Leu Glu Ser Lys Lys Ala Lys 65 70 75 80

    Glu Ile Asp Phe Ser Glu Tyr Leu Asp Leu Phe Gln Glu Lys Lys Glu 85 90 95

    Leu Asn Asp Ser Glu Lys Lys Leu Arg Asn Lys Ile Gly Glu Thr Phe 100 105 110

    Asn Lys Ala Gly Glu Lys Trp Lys Lys Glu Lys Tyr Pro Gln Tyr Glu 115 120 125

    Trp Lys Lys Gly Ser Lys Ile Ala Asn Gly Ala Asp Ile Leu Ser Cys 130 135 140

    Gln Asp Met Leu Gln Phe Ile Lys Tyr Lys Asn Pro Glu Asp Glu Lys 145 150 155 160

    Ile Lys Asn Tyr Ile Asp Asp Thr Leu Lys Gly Phe Phe Thr Tyr Phe 165 170 175

    Gly Gly Phe Asn Gln Asn Arg Ala Asn Tyr Tyr Glu Thr Lys Lys Glu

    180

    185

    190

    Ala Ser Thr Ala Val Ala Thr Arg Ile Val His Glu Asn Leu Pro Lys 195 200 205

    Phe Cys Asp Asn Val Ile Gln Phe Lys His Ile Ile Lys Arg Lys Lys 210 215 220

    Asp Gly Thr Val Glu Lys Thr Glu Arg Lys Thr Glu Tyr Leu Asn Ala 225 230 235 240

    Tyr Gln Tyr Leu Lys Asn Asn Asn Lys Ile Thr Gln Ile Lys Asp Ala 245 250 255

    Glu Thr Glu Lys Met Ile Glu Ser Thr Pro Ile Ala Glu Lys Ile Phe 260 265 270

    Asp Val Tyr Tyr Phe Ser Ser Cys Leu Ser Gln Lys Gln Ile Glu Glu 275 280 285

    Tyr Asn Arg Ile Ile Gly His Tyr Asn Leu Leu Ile Asn Leu Tyr Asn 290 295 300

    Gln Ala Lys Arg Ser Glu Gly Lys His Leu Ser Ala Asn Glu Lys Lys 305 310 315 320

    Tyr Lys Asp Leu Pro Lys Phe Lys Thr Leu Tyr Lys Gln Ile Gly Cys 325 330 335

    Gly Lys Lys Lys Asp Leu Phe Tyr Thr Ile Lys Cys Asp Thr Glu Glu 340 345 350

    Glu Ala Asn Lys Ser Arg Asn Glu Gly Lys Glu Ser His Ser Val Glu 355 360 365

    Glu Ile Ile Asn Lys Ala Gln Glu Ala Ile Asn Lys Tyr Phe Lys Ser 370 375 380

    Asn Asn Asp Cys Glu Asn Ile Asn Thr Val Pro Asp Phe Ile Asn Tyr 385 390 395 400

    Ile Leu Thr Lys Glu Asn Tyr Glu Gly Val Tyr Trp Ser Lys Ala Ala 405 410 415

    Met Asn Thr Ile Ser Asp Lys Tyr Phe Ala Asn Tyr His Asp Leu Gln 420 425 430

    Asp Arg Leu Lys Glu Ala Lys Val Phe Gln Lys Ala Asp Lys Lys Ser 435 440 445

    Glu Asp Asp Ile Lys Ile Pro Glu Ala Ile Glu Leu Ser Gly Leu Phe 450 455 460

    Gly Val Leu Asp Ser Leu Ala Asp Trp Gln Thr Thr Leu Phe Lys Ser 465 470 475 480

    Ser Ile Leu Ser Asn Glu Asp Lys Leu Lys Ile Ile Thr Asp Ser Gln 485 490 495

    Thr Pro Ser Glu Ala Leu Leu Lys Met Ile Phe Asn Asp Ile Glu Lys 500 505 510

    Asn Met Glu Ser Phe Leu Lys Glu Thr Asn Asp Ile Ile Thr Leu Lys 515 520 525

    Lys Tyr Lys Gly Asn Lys Glu Gly Thr Glu Lys Ile Lys Gln Trp Phe 530 535 540

    Asp Tyr Thr Leu Ala Ile Asn Arg Met Leu Lys Tyr Phe Leu Val Lys 545 550 555 560

    Glu Asn Lys Ile Lys Gly Asn Ser Leu Asp Thr Asn Ile Ser Glu Ala 565 570 575

    Leu Lys Thr Leu Ile Tyr Ser Asp Asp Ala Glu Trp Phe Lys Trp Tyr 580 585 590

    Asp Ala Leu Arg Asn Tyr Leu Thr Gln Lys Pro Gln Asp Glu Ala Lys 595 600 605

    Glu Asn Lys Leu Lys Leu Asn Phe Asp Asn Pro Ser Leu Ala Gly Gly 610 615 620

    Trp Asp Val Asn Lys Glu Cys Ser Asn Phe Cys Val Ile Leu Lys Asp 625 630 635 640

    Lys Asn Glu Lys Lys Tyr Leu Ala Ile Met Lys Lys Gly Glu Asn Thr 645 650 655

    Leu Phe Gln Lys Glu Trp Thr Glu Gly Arg Gly Lys Asn Leu Thr Lys 660 665 670

    Lys Ser Asn Pro Leu Phe Glu Ile Asn Asn Cys Glu Ile Leu Ser Lys 675 680 685

    Met Glu Tyr Asp Phe Trp Ala Asp Val Ser Lys Met Ile Pro Lys Cys 690 695 700

    Ser Thr Gln Leu Lys Ala Val Val Asn His Phe Lys Gln Ser Asp Asn 705 710 715 720

    Glu Phe Ile Phe Pro Ile Gly Tyr Lys Val Thr Ser Gly Glu Lys Phe 725 730 735

    Arg Glu Glu Cys Lys Ile Ser Lys Gln Asp Phe Glu Leu Asn Asn Lys 740 745 750

    Val Phe Asn Lys Asn Glu Leu Ser Val Thr Ala Met Arg Tyr Asp Leu 755 760 765

    Ser Ser Thr Gln Glu Lys Gln Tyr Ile Lys Ala Phe Gln Lys Glu Tyr 770 775 780

    Trp Glu Leu Leu Phe Lys Gln Glu Lys Arg Asp Thr Lys Leu Thr Asn 785 790 795 800

    Asn Glu Ile Phe Asn Glu Trp Ile Asn Phe Cys Asn Lys Lys Tyr Ser 805 810 815

    Glu Leu Leu Ser Trp Glu Arg Lys Tyr Lys Asp Ala Leu Thr Asn Trp 820 825 830

    Ile Asn Phe Cys Lys Tyr Phe Leu Ser Lys Tyr Pro Lys Thr Thr Leu 835 840 845

    Phe Asn Tyr Ser Phe Lys Glu Ser Glu Asn Tyr Asn Ser Leu Asp Glu 850 855 860

    Phe Tyr Arg Asp Val Asp Ile Cys Ser Tyr Lys Leu Asn Ile Asn Thr 865 870 875 880

    Thr Ile Asn Lys Ser Ile Leu Asp Arg Leu Val Glu Glu Gly Lys Leu 885 890 895

    Tyr Leu Phe Glu Ile Lys Asn Gln Asp Ser Asn Asp Gly Lys Ser Ile

    900

    905

    910

    Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp Asn Ala Ile Phe Glu 915 920 925

    Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr 930 935 940

    Arg Lys Ala Ile Ser Lys Asp Lys Leu Gly Ile Val Lys Gly Lys Lys 945 950 955 960

    Thr Lys Asn Gly Thr Glu Ile Ile Lys Asn Tyr Arg Phe Ser Lys Glu 965 970 975

    Lys Phe Ile Leu His Val Pro Ile Thr Leu Asn Phe Cys Ser Asn Asn 980 985 990

    Glu Tyr Val Asn Asp Ile Val Asn Thr Lys Phe Tyr Asn Phe Ser Asn 995 1000 1005

    Leu His Phe Leu Gly Ile Asp Arg Gly Glu Lys His Leu Ala Tyr 1010 1015 1020

    Tyr Ser Leu Val Asn Lys Asn Gly Glu Ile Val Asp Gln Gly Thr 1025 1030 1035

    Leu Asn Leu Pro Phe Thr Asp Lys Asp Gly Asn Gln Arg Ser Ile 1040 1045 1050

    Lys Lys Glu Lys Tyr Phe Tyr Asn Lys Gln Glu Asp Lys Trp Glu 1055 1060 1065

    Ala Lys Glu Val Asp Cys Trp Asn Tyr Asn Asp Leu Leu Asp Ala 1070 1075 1080

    Met Ala Ser Asn Arg Asp Met Ala Arg Lys Asn Trp Gln Arg Ile 1085 1090 1095

    Gly Thr Ile Lys Glu Ala Lys Asn Gly Tyr Val Ser Leu Val Ile 1100 1105 1110

    Arg Lys Ile Ala Asp Leu Ala Val Asn Asn Glu Arg Pro Ala Phe 1115 1120 1125

    Ile Val Leu Glu Asp Leu Asn Thr Gly Phe Lys Arg Ser Arg Gln 1130 1135 1140

    Lys Ile Asp Lys Ser Val Tyr Gln Lys Phe Glu Leu Ala Leu Ala 1145 1150 1155

    Lys Lys Leu Asn Phe Leu Val Asp Lys Asn Ala Lys Arg Asp Glu 1160 1165 1170

    Ile Gly Ser Pro Thr Lys Ala Leu Gln Leu Thr Pro Pro Val Asn 1175 1180 1185

    Asn Tyr Gly Asp Ile Glu Asn Lys Lys Gln Ala Gly Ile Met Leu 1190 1195 1200

    Tyr Thr Arg Ala Asn Tyr Thr Ser Gln Thr Asp Pro Ala Thr Gly 1205 1210 1215

    Trp Arg Lys Thr Ile Tyr Leu Lys Ala Gly Pro Glu Glu Thr Thr 1220 1225 1230

    Tyr Lys Lys Asp Gly Lys Ile Lys Asn Lys Ser Val Lys Asp Gln 1235 1240 1245

    Ile Ile Glu Thr Phe Thr Asp Ile Gly Phe Asp Gly Lys Asp Tyr 1250 1255 1260

    Tyr Phe Glu Tyr Asp Lys Gly Glu Phe Val Asp Glu Lys Thr Gly 1265 1270 1275

    Glu Ile Lys Pro Lys Lys Trp Arg Leu Tyr Ser Gly Glu Asn Gly 1280 1285 1290

    Lys Ser Leu Asp Arg Phe Arg Gly Glu Arg Glu Lys Asp Lys Tyr 1295 1300 1305

    Glu Trp Lys Ile Asp Lys Ile Asp Ile Val Lys Ile Leu Asp Asp 1310 1315 1320

    Leu Phe Val Asn Phe Asp Lys Asn Ile Ser Leu Leu Lys Gln Leu 1325 1330 1335

    Lys Glu Gly Val Glu Leu Thr Arg Asn Asn Glu His Gly Thr Gly 1340 1345 1350

    Glu Ser Leu Arg Phe Ala Ile Asn Leu Ile Gln Gln Ile Arg Asn 1355 1360 1365

    Thr Gly Asn Asn Glu Arg Asp Asn Asp Phe Ile Leu Ser Pro Val 1370 1375 1380

    Arg Asp Glu Asn Gly Lys His Phe Asp Ser Arg Glu Tyr Trp Asp 1385 1390 1395

    Lys Glu Thr Lys Gly Glu Lys Ile Ser Met Pro Ser Ser Gly Asp 1400 1405 1410

    Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Ile Ile Met Asn 1415 1420 1425

    Ala His Ile Leu Ala Asn Ser Asp Ser Lys Asp Leu Ser Leu Phe 1430 1435 1440

    Val Ser Asp Glu Glu Trp Asp Leu His Leu Asn Asn Lys Thr Glu 1445 1450 1455

    Trp Lys Lys Gln Leu Asn Ile Phe Ser Ser Arg Lys Ala Met Ala 1460 1465 1470

    Lys Arg Lys Lys 1475 <210> 1112 <211> 1477 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <400> 1112

    Met Ser Asn Phe Phe Lys Asn Phe Thr Asn Leu Tyr Glu Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Asp Thr Leu Thr Asn Met 20 25 30

    Lys Asp His Leu Glu Tyr Asp Glu Lys Leu Gln Thr Phe Leu Lys Asp 35 40 45

    Gln Asn Ile Asp Asp Ala Tyr Gln Ala Leu Lys Pro Gln Phe Asp Glu 50 55 60

    Ile His Glu Glu Phe Ile Thr Asp Ser Leu Glu Ser Lys Lys Ala Lys 65 70 75 80

    Glu Ile Asp Phe Ser Glu Tyr Leu Asp Leu Phe Gln Glu Lys Lys Glu 85 90 95

    Leu Asn Asp Ser Glu Lys Lys Leu Arg Asn Lys Ile Gly Glu Thr Phe 100 105 110

    Asn Lys Ala Gly Glu Lys Trp Lys Lys Glu Lys Tyr Pro Gln Tyr Glu 115 120 125

    Trp Lys Lys Gly Ser Lys Ile Ala Asn Gly Ala Asp Ile Leu Ser Cys 130 135 140

    Gln Asp Met Leu Gln Phe Ile Lys Tyr Lys Asn Pro Glu Asp Glu Lys 145 150 155 160

    Ile Lys Asn Tyr Ile Asp Asp Thr Leu Lys Gly Phe Phe Thr Tyr Phe 165 170 175

    Gly Gly Phe Asn Gln Asn Arg Ala Asn Tyr Tyr Glu Thr Lys Lys Glu 180 185 190

    Ala Ser Thr Ala Val Ala Thr Arg Ile Val His Glu Asn Leu Pro Lys 195 200 205

    Phe Cys Asp Asn Val Ile Gln Phe Lys His Ile Ile Lys Arg Lys Lys 210 215 220

    Asp Gly Thr Val Glu Lys Thr Glu Arg Lys Thr Glu Tyr Leu Asn Ala 225 230 235 240

    Tyr Gln Tyr Leu Lys Asn Asn Asn Lys Ile Thr Gln Ile Lys Asp Ala 245 250 255

    Glu Thr Glu Lys Met Ile Glu Ser Thr Pro Ile Ala Glu Lys Ile Phe 260 265 270

    Asp Val Tyr Tyr Phe Ser Ser Cys Leu Ser Gln Lys Gln Ile Glu Glu 275 280 285

    Tyr Asn Arg Ile Ile Gly His Tyr Asn Leu Leu Ile Asn Leu Tyr Asn 290 295 300

    Gln Ala Lys Arg Ser Glu Gly Lys His Leu Ser Ala Asn Glu Lys Lys 305 310 315 320

    Tyr Lys Asp Leu Pro Lys Phe Lys Thr Leu Tyr Lys Gln Ile Gly Cys 325 330 335

    Gly Lys Lys Lys Asp Leu Phe Tyr Thr Ile Lys Cys Asp Thr Glu Glu 340 345 350

    Glu Ala Asn Lys Ser Arg Asn Glu Gly Lys Glu Ser His Ser Val Glu 355 360 365

    Glu Ile Ile Asn Lys Ala Gln Glu Ala Ile Asn Lys Tyr Phe Lys Ser 370 375 380

    Asn Asn Asp Cys Glu Asn Ile Asn Thr Val Pro Asp Phe Ile Asn Tyr 385 390 395 400

    Ile Leu Thr Lys Glu Asn Tyr Glu Gly Val Tyr Trp Ser Lys Ala Ala 405 410 415

    Met Asn Thr Ile Ser Asp Lys Tyr Phe Ala Asn Tyr His Asp Leu Gln

    420

    425

    430

    Asp Arg Leu Lys Glu Ala Lys Val Phe Gln Lys Ala Asp Lys Lys Ser 435 440 445

    Glu Asp Asp Ile Lys Ile Pro Glu Ala Ile Glu Leu Ser Gly Leu Phe 450 455 460

    Gly Val Leu Asp Ser Leu Ala Asp Trp Gln Thr Thr Leu Phe Lys Ser 465 470 475 480

    Ser Ile Leu Ser Asn Glu Asp Lys Leu Lys Ile Ile Thr Asp Ser Gln 485 490 495

    Thr Pro Ser Glu Ala Leu Leu Lys Met Ile Phe Asn Asp Ile Glu Lys 500 505 510

    Asn Met Glu Ser Phe Leu Lys Glu Thr Asn Asp Ile Ile Thr Leu Lys 515 520 525

    Lys Tyr Lys Gly Asn Lys Glu Gly Thr Glu Lys Ile Lys Gln Trp Phe 530 535 540

    Asp Tyr Thr Leu Ala Ile Asn Arg Met Leu Lys Tyr Phe Leu Val Lys 545 550 555 560

    Glu Asn Lys Ile Lys Gly Asn Ser Leu Asp Thr Asn Ile Ser Glu Ala 565 570 575

    Leu Lys Thr Leu Ile Tyr Ser Asp Asp Ala Glu Trp Phe Lys Trp Tyr 580 585 590

    Asp Ala Leu Arg Asn Tyr Leu Thr Gln Lys Pro Gln Asp Glu Ala Lys 595 600 605

    Glu Asn Lys Leu Lys Leu Asn Phe Asp Asn Pro Ser Leu Ala Gly Gly 610 615 620

    Trp Asp Val Asn Lys Glu Cys Ser Asn Phe Cys Val Ile Leu Lys Asp 625 630 635 640

    Lys Asn Glu Lys Lys Tyr Leu Ala Ile Met Lys Lys Gly Glu Asn Thr 645 650 655

    Leu Phe Gln Lys Glu Trp Thr Glu Gly Arg Gly Lys Asn Leu Thr Lys 660 665 670

    Lys Ser Asn Pro Leu Phe Glu Ile Asn Asn Cys Glu Ile Leu Ser Lys 675 680 685

    Met Glu Tyr Asp Phe Trp Ala Asp Val Ser Lys Met Ile Pro Lys Cys 690 695 700

    Ser Thr Gln Leu Lys Ala Val Val Asn His Phe Lys Gln Ser Asp Asn 705 710 715 720

    Glu Phe Ile Phe Pro Ile Gly Tyr Lys Val Thr Ser Gly Glu Lys Phe 725 730 735

    Arg Glu Glu Cys Lys Ile Ser Lys Gln Asp Phe Glu Leu Asn Asn Lys 740 745 750

    Val Phe Asn Lys Asn Glu Leu Ser Val Thr Ala Met Arg Tyr Asp Leu 755 760 765

    Ser Ser Thr Gln Glu Lys Gln Tyr Ile Lys Ala Phe Gln Lys Glu Tyr 770 775 780

    Trp Glu Leu Leu Phe Lys Gln Glu Lys Arg Asp Thr Lys Leu Thr Asn 785 790 795 800

    Asn Glu Ile Phe Asn Glu Trp Ile Asn Phe Cys Asn Lys Lys Tyr Ser 805 810 815

    Glu Leu Leu Ser Trp Glu Arg Lys Tyr Lys Asp Ala Leu Thr Asn Trp 820 825 830

    Ile Asn Phe Cys Lys Tyr Phe Leu Ser Lys Tyr Pro Lys Thr Thr Leu 835 840 845

    Phe Asn Tyr Ser Phe Lys Glu Ser Glu Asn Tyr Asn Ser Leu Asp Glu 850 855 860

    Phe Tyr Arg Asp Val Asp Ile Cys Ser Tyr Lys Leu Asn Ile Asn Thr 865 870 875 880

    Thr Ile Asn Lys Ser Ile Leu Asp Arg Leu Val Glu Glu Gly Lys Leu 885 890 895

    Tyr Leu Phe Glu Ile Lys Asn Gln Asp Ser Asn Asp Gly Lys Ser Ile 900 905 910

    Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp Asn Ala Ile Phe Glu 915 920 925

    Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr 930 935 940

    Arg Lys Ala Ile Ser Lys Asp Lys Leu Gly Ile Val Lys Gly Lys Lys 945 950 955 960

    Thr Lys Asn Gly Thr Glu Ile Ile Lys Asn Tyr Arg Phe Ser Lys Glu 965 970 975

    Lys Phe Ile Leu His Val Pro Ile Thr Leu Asn Phe Cys Ser Asn Asn 980 985 990

    Glu Tyr Val Asn Asp Ile Val Asn Thr Lys Phe Tyr Asn Phe Ser Asn 995 1000 1005

    Leu His Phe Leu Gly Ile Asp Arg Gly Glu Lys His Leu Ala Tyr 1010 1015 1020

    Tyr Ser Leu Val Asn Lys Asn Gly Glu Ile Val Asp Gln Gly Thr 1025 1030 1035

    Leu Asn Leu Pro Phe Thr Asp Lys Asp Gly Asn Gln Arg Ser Ile 1040 1045 1050

    Lys Lys Glu Lys Tyr Phe Tyr Asn Lys Gln Glu Asp Lys Trp Glu 1055 1060 1065

    Ala Lys Glu Val Asp Cys Trp Asn Tyr Asn Asp Leu Leu Asp Ala 1070 1075 1080

    Met Ala Ser Asn Arg Asp Met Ala Arg Lys Asn Trp Gln Arg Ile 1085 1090 1095

    Gly Thr Ile Lys Glu Ala Lys Asn Gly Tyr Val Ser Leu Val Ile 1100 1105 1110

    Arg Lys Ile Ala Asp Leu Ala Val Asn Asn Glu Arg Pro Ala Phe 1115 1120 1125

    Ile Val Leu Glu Asp Leu Asn Thr Gly Phe Lys Arg Ser Arg Gln

    1130

    1135

    1140

    Lys Ile Asp Lys Ser Val Tyr Gln Lys Phe Glu Leu Ala Leu Ala 1145 1150 1155

    Lys Lys Leu Asn Phe Leu Val Asp Lys Asn Ala Lys Arg Asp Glu 1160 1165 1170

    Ile Gly Ser Pro Thr Lys Ala Leu Gln Leu Thr Pro Pro Val Asn 1175 1180 1185

    Asn Tyr Gly Asp Ile Glu Asn Lys Lys Gln Ala Gly Ile Met Leu 1190 1195 1200

    Tyr Thr Arg Ala Asn Tyr Thr Ser Gln Thr Asp Pro Ala Thr Gly 1205 1210 1215

    Trp Arg Lys Thr Ile Tyr Leu Lys Ala Gly Pro Glu Glu Thr Thr 1220 1225 1230 Tyr Lys Lys Asp Gly Lys Ile Lys Asn Lys Ser Val Lys Asp Gln 1235 1240 1245 Ile Ile Glu Thr Phe Thr Asp Ile Gly Phe Asp Gly Lys Asp Tyr 1250 1255 1260

    Tyr Phe Glu Tyr Asp Lys Gly Glu Phe Val Asp Glu Lys Thr Gly 1265 1270 1275

    Glu Ile Lys Pro Lys Lys Trp Arg Leu Tyr Ser Gly Glu Asn Gly 1280 1285 1290

    Lys Ser Leu Asp Arg Phe Arg Gly Glu Arg Glu Lys Asp Lys Tyr 1295 1300 1305

    Glu Trp Lys Ile Asp Lys Ile Asp Ile Val Lys Ile Leu Asp Asp 1310 1315 1320

    Leu Phe Val Asn Phe Asp Lys Asn Ile Ser Leu Leu Lys Gln Leu 1325 1330 1335

    Lys Glu Gly Val Glu Leu Thr Arg Asn Asn Glu His Gly Thr Gly 1340 1345 1350

    Glu Ser Leu Arg Phe Ala Ile Asn Leu Ile Gln Gln Ile Arg Asn 1355 1360 1365

    Thr Gly Asn Asn Glu Arg Asp Asn Asp Phe Ile Leu Ser Pro Val 1370 1375 1380

    Arg Asp Glu Asn Gly Lys His Phe Asp Ser Arg Glu Tyr Trp Asp 1385 1390 1395

    Lys Glu Thr Lys Gly Glu Lys Ile Ser Met Pro Ser Ser Gly Asp 1400 1405 1410

    Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Ile Ile Met Asn 1415 1420 1425

    Ala His Ile Leu Ala Asn Ser Asp Ser Lys Asp Leu Ser Leu Phe 1430 1435 1440

    Val Ser Asp Glu Glu Trp Asp Leu His Leu Asn Asn Lys Thr Glu 1445 1450 1455

    Trp Lys Lys Gln Leu Asn Ile Phe Ser Ser Arg Lys Ala Met Ala 1460 1465 1470

    Lys Arg Lys Lys 1475 <210> 1113 <211> 1477 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <400> 1113

    Met Ser Asn Phe Phe Lys Asn Phe Thr Asn Leu Tyr Glu Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Asp Thr Leu Thr Asn Met 20 25 30

    Lys Asp His Leu Glu Tyr Asp Glu Lys Leu Gln Thr Phe Leu Lys Asp 35 40 45

    Gln Asn Ile Asp Asp Ala Tyr Gln Ala Leu Lys Pro Gln Phe Asp Glu 50 55 60

    Ile His Glu Glu Phe Ile Thr Asp Ser Leu Glu Ser Lys Lys Ala Lys 65 70 75 80

    Glu Ile Asp Phe Ser Glu Tyr Leu Asp Leu Phe Gln Glu Lys Lys Glu 85 90 95

    Leu Asn Asp Ser Glu Lys Lys Leu Arg Asn Lys Ile Gly Glu Thr Phe 100 105 110

    Asn Lys Ala Gly Glu Lys Trp Lys Lys Glu Lys Tyr Pro Gln Tyr Glu 115 120 125

    Trp Lys Lys Gly Ser Lys Ile Ala Asn Gly Ala Asp Ile Leu Ser Cys 130 135 140

    Gln Asp Met Leu Gln Phe Ile Lys Tyr Lys Asn Pro Glu Asp Glu Lys 145 150 155 160

    Ile Lys Asn Tyr Ile Asp Asp Thr Leu Lys Gly Phe Phe Thr Tyr Phe 165 170 175

    Gly Gly Phe Asn Gln Asn Arg Ala Asn Tyr Tyr Glu Thr Lys Lys Glu 180 185 190

    Ala Ser Thr Ala Val Ala Thr Arg Ile Val His Glu Asn Leu Pro Lys 195 200 205

    Phe Cys Asp Asn Val Ile Gln Phe Lys His Ile Ile Lys Arg Lys Lys 210 215 220

    Asp Gly Thr Val Glu Lys Thr Glu Arg Lys Thr Glu Tyr Leu Asn Ala 225 230 235 240

    Tyr Gln Tyr Leu Lys Asn Asn Asn Lys Ile Thr Gln Ile Lys Asp Ala 245 250 255

    Glu Thr Glu Lys Met Ile Glu Ser Thr Pro Ile Ala Glu Lys Ile Phe 260 265 270

    Asp Val Tyr Tyr Phe Ser Ser Cys Leu Ser Gln Lys Gln Ile Glu Glu 275 280 285

    Tyr Asn Arg Ile Ile Gly His Tyr Asn Leu Leu Ile Asn Leu Tyr Asn 290 295 300

    Gln Ala Lys Arg Ser Glu Gly Lys His Leu Ser Ala Asn Glu Lys Lys 305 310 315 320

    Tyr Lys Asp Leu Pro Lys Phe Lys Thr Leu Tyr Lys Gln Ile Gly Cys 325 330 335

    Gly Lys Lys Lys Asp Leu Phe Tyr Thr Ile Lys Cys Asp Thr Glu Glu 340 345 350

    Glu Ala Asn Lys Ser Arg Asn Glu Gly Lys Glu Ser His Ser Val Glu 355 360 365

    Glu Ile Ile Asn Lys Ala Gln Glu Ala Ile Asn Lys Tyr Phe Lys Ser 370 375 380

    Asn Asn Asp Cys Glu Asn Ile Asn Thr Val Pro Asp Phe Ile Asn Tyr 385 390 395 400

    Ile Leu Thr Lys Glu Asn Tyr Glu Gly Val Tyr Trp Ser Lys Ala Ala 405 410 415

    Met Asn Thr Ile Ser Asp Lys Tyr Phe Ala Asn Tyr His Asp Leu Gln 420 425 430

    Asp Arg Leu Lys Glu Ala Lys Val Phe Gln Lys Ala Asp Lys Lys Ser 435 440 445

    Glu Asp Asp Ile Lys Ile Pro Glu Ala Ile Glu Leu Ser Gly Leu Phe 450 455 460

    Gly Val Leu Asp Ser Leu Ala Asp Trp Gln Thr Thr Leu Phe Lys Ser 465 470 475 480

    Ser Ile Leu Ser Asn Glu Asp Lys Leu Lys Ile Ile Thr Asp Ser Gln 485 490 495

    Thr Pro Ser Glu Ala Leu Leu Lys Met Ile Phe Asn Asp Ile Glu Lys 500 505 510

    Asn Met Glu Ser Phe Leu Lys Glu Thr Asn Asp Ile Ile Thr Leu Lys 515 520 525

    Lys Tyr Lys Gly Asn Lys Glu Gly Thr Glu Lys Ile Lys Gln Trp Phe 530 535 540

    Asp Tyr Thr Leu Ala Ile Asn Arg Met Leu Lys Tyr Phe Leu Val Lys 545 550 555 560

    Glu Asn Lys Ile Lys Gly Asn Ser Leu Asp Thr Asn Ile Ser Glu Ala 565 570 575

    Leu Lys Thr Leu Ile Tyr Ser Asp Asp Ala Glu Trp Phe Lys Trp Tyr 580 585 590

    Asp Ala Leu Arg Asn Tyr Leu Thr Gln Lys Pro Gln Asp Glu Ala Lys 595 600 605

    Glu Asn Lys Leu Lys Leu Asn Phe Asp Asn Pro Ser Leu Ala Gly Gly 610 615 620

    Trp Asp Val Asn Lys Glu Cys Ser Asn Phe Cys Val Ile Leu Lys Asp 625 630 635 640

    Lys Asn Glu Lys Lys Tyr Leu Ala Ile Met Lys Lys Gly Glu Asn Thr 645 650 655

    Leu Phe Gln Lys Glu Trp Thr Glu Gly Arg Gly Lys Asn Leu Thr Lys

    660

    665

    670

    Lys Ser Asn Pro Leu Phe Glu Ile Asn Asn Cys Glu Ile Leu Ser Lys 675 680 685

    Met Glu Tyr Asp Phe Trp Ala Asp Val Ser Lys Met Ile Pro Lys Cys 690 695 700

    Ser Thr Gln Leu Lys Ala Val Val Asn His Phe Lys Gln Ser Asp Asn 705 710 715 720

    Glu Phe Ile Phe Pro Ile Gly Tyr Lys Val Thr Ser Gly Glu Lys Phe 725 730 735

    Arg Glu Glu Cys Lys Ile Ser Lys Gln Asp Phe Glu Leu Asn Asn Lys 740 745 750

    Val Phe Asn Lys Asn Glu Leu Ser Val Thr Ala Met Arg Tyr Asp Leu 755 760 765

    Ser Ser Thr Gln Glu Lys Gln Tyr Ile Lys Ala Phe Gln Lys Glu Tyr 770 775 780

    Trp Glu Leu Leu Phe Lys Gln Glu Lys Arg Asp Thr Lys Leu Thr Asn 785 790 795 800

    Asn Glu Ile Phe Asn Glu Trp Ile Asn Phe Cys Asn Lys Lys Tyr Ser 805 810 815

    Glu Leu Leu Ser Trp Glu Arg Lys Tyr Lys Asp Ala Leu Thr Asn Trp 820 825 830

    Ile Asn Phe Cys Lys Tyr Phe Leu Ser Lys Tyr Pro Lys Thr Thr Leu 835 840 845

    Phe Asn Tyr Ser Phe Lys Glu Ser Glu Asn Tyr Asn Ser Leu Asp Glu 850 855 860

    Phe Tyr Arg Asp Val Asp Ile Cys Ser Tyr Lys Leu Asn Ile Asn Thr 865 870 875 880

    Thr Ile Asn Lys Ser Ile Leu Asp Arg Leu Val Glu Glu Gly Lys Leu 885 890 895

    Tyr Leu Phe Glu Ile Lys Asn Gln Asp Ser Asn Asp Gly Lys Ser Ile 900 905 910

    Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp Asn Ala Ile Phe Glu 915 920 925

    Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr 930 935 940

    Arg Lys Ala Ile Ser Lys Asp Lys Leu Gly Ile Val Lys Gly Lys Lys 945 950 955 960

    Thr Lys Asn Gly Thr Glu Ile Ile Lys Asn Tyr Arg Phe Ser Lys Glu 965 970 975

    Lys Phe Ile Leu His Val Pro Ile Thr Leu Asn Phe Cys Ser Asn Asn 980 985 990

    Glu Tyr Val Asn Asp Ile Val Asn Thr Lys Phe Tyr Asn Phe Ser Asn 995 1000 1005

    Leu His Phe Leu Gly Ile Asp Arg Gly Glu Lys His Leu Ala Tyr 1010 1015 1020

    Tyr Ser Leu Val Asn Lys Asn Gly Glu Ile Val Asp Gln Gly Thr 1025 1030 1035

    Leu Asn Leu Pro Phe Thr Asp Lys Asp Gly Asn Gln Arg Ser Ile 1040 1045 1050

    Lys Lys Glu Lys Tyr Phe Tyr Asn Lys Gln Glu Asp Lys Trp Glu 1055 1060 1065

    Ala Lys Glu Val Asp Cys Trp Asn Tyr Asn Asp Leu Leu Asp Ala 1070 1075 1080

    Met Ala Ser Asn Arg Asp Met Ala Arg Lys Asn Trp Gln Arg Ile 1085 1090 1095

    Gly Thr Ile Lys Glu Ala Lys Asn Gly Tyr Val Ser Leu Val Ile 1100 1105 1110

    Arg Lys Ile Ala Asp Leu Ala Val Asn Asn Glu Arg Pro Ala Phe 1115 1120 1125

    Ile Val Leu Glu Asp Leu Asn Thr Gly Phe Lys Arg Ser Arg Gln 1130 1135 1140

    Lys Ile Asp Lys Ser Val Tyr Gln Lys Phe Glu Leu Ala Leu Ala 1145 1150 1155

    Lys Lys Leu Asn Phe Leu Val Asp Lys Asn Ala Lys Arg Asp Glu 1160 1165 1170

    Ile Gly Ser Pro Thr Lys Ala Leu Gln Leu Thr Pro Pro Val Asn 1175 1180 1185

    Asn Tyr Gly Asp Ile Glu Asn Lys Lys Gln Ala Gly Ile Met Leu 1190 1195 1200

    Tyr Thr Arg Ala Asn Tyr Thr Ser Gln Thr Asp Pro Ala Thr Gly 1205 1210 1215

    Trp Arg Lys Thr Ile Tyr Leu Lys Ala Gly Pro Glu Glu Thr Thr 1220 1225 1230 Tyr Lys Lys Asp Gly Lys Ile Lys Asn Lys Ser Val Lys Asp Gln 1235 1240 1245 Ile Ile Glu Thr Phe Thr Asp Ile Gly Phe Asp Gly Lys Asp Tyr 1250 1255 1260

    Tyr Phe Glu Tyr Asp Lys Gly Glu Phe Val Asp Glu Lys Thr Gly 1265 1270 1275

    Glu Ile Lys Pro Lys Lys Trp Arg Leu Tyr Ser Gly Glu Asn Gly 1280 1285 1290

    Lys Ser Leu Asp Arg Phe Arg Gly Glu Arg Glu Lys Asp Lys Tyr 1295 1300 1305

    Glu Trp Lys Ile Asp Lys Ile Asp Ile Val Lys Ile Leu Asp Asp 1310 1315 1320

    Leu Phe Val Asn Phe Asp Lys Asn Ile Ser Leu Leu Lys Gln Leu 1325 1330 1335

    Lys Glu Gly Val Glu Leu Thr Arg Asn Asn Glu His Gly Thr Gly 1340 1345 1350

    Glu Ser Leu Arg Phe Ala Ile Asn Leu Ile Gln Gln Ile Arg Asn

    1355

    1360

    1365

    Thr Gly Asn Asn Glu Arg Asp Asn Asp Phe Ile Leu Ser Pro Val 1370 1375 1380

    Arg Asp Glu Asn Gly Lys His Phe Asp Ser Arg Glu Tyr Trp Asp 1385 1390 1395

    Lys Glu Thr Lys Gly Glu Lys Ile Ser Met Pro Ser Ser Gly Asp 1400 1405 1410

    Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Ile Ile Met Asn 1415 1420 1425

    Ala His Ile Leu Ala Asn Ser Asp Ser Lys Asp Leu Ser Leu Phe 1430 1435 1440

    Val Ser Asp Glu Glu Trp Asp Leu His Leu Asn Asn Lys Thr Glu 1445 1450 1455

    Trp Lys Lys Gln Leu Asn Ile Phe Ser Ser Arg Lys Ala Met Ala 1460 1465 1470

    Lys Arg Lys Lys 1475 <210> 1114 <211> 1403 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Falkowbacteria bacterium sequence <400> 1114

    Met Leu Phe Phe Met Ser Thr Asp Ile Thr Asn Lys Pro Arg Glu Lys 1 5 10 15

    Gly Val Phe Asp Asn Phe Thr Asn Leu Tyr Glu Phe Ser Lys Thr Leu 20 25 30

    Thr Phe Gly Leu Ile Pro Leu Lys Trp Asp Asp Asn Lys Lys Met Ile 35 40 45

    Val Glu Asp Glu Asp Phe Ser Val Leu Arg Lys Tyr Gly Val Ile Glu 50 55 60

    Glu Asp Lys Arg Ile Ala Glu Ser Ile Lys Ile Ala Lys Phe Tyr Leu 65 70 75 80

    Asn Ile Leu His Arg Glu Leu Ile Gly Lys Val Leu Gly Ser Leu Lys 85 90 95

    Phe Glu Lys Lys Asn Leu Glu Asn Tyr Asp Arg Leu Leu Gly Glu Ile 100 105 110

    Glu Lys Asn Asn Lys Asn Glu Asn Ile Ser Glu Asp Lys Lys Lys Glu 115 120 125

    Ile Arg Lys Asn Phe Lys Lys Glu Leu Ser Ile Ala Gln Asp Ile Leu 130 135 140

    Leu Lys Lys Val Gly Glu Val Phe Glu Ser Asn Gly Ser Gly Ile Leu 145 150 155 160

    Ser Ser Lys Asn Cys Leu Asp Glu Leu Thr Lys Arg Phe Thr Arg Gln 165 170 175

    Glu Val Asp Lys Leu Arg Arg Glu Asn Lys Asp Ile Gly Val Glu Tyr

    180

    185

    190

    Pro Asp Val Ala Tyr Arg Glu Lys Asp Gly Lys Glu Glu Thr Lys Ser 195 200 205

    Phe Phe Ala Met Asp Val Gly Tyr Leu Asp Asp Phe His Lys Asn Arg 210 215 220

    Lys Gln Leu Tyr Ser Val Lys Gly Lys Lys Asn Ser Leu Gly Arg Arg 225 230 235 240

    Ile Leu Asp Asn Phe Glu Ile Phe Cys Lys Asn Lys Lys Leu Tyr Glu 245 250 255

    Lys Tyr Lys Asn Leu Asp Ile Asp Phe Ser Glu Ile Glu Arg Asn Phe 260 265 270

    Asn Leu Thr Leu Glu Lys Val Phe Asp Phe Asp Asn Tyr Asn Glu Arg 275 280 285

    Leu Thr Gln Glu Gly Leu Asp Glu Tyr Ala Lys Ile Leu Gly Gly Glu 290 295 300

    Ser Asn Lys Gln Glu Arg Thr Ala Asn Ile His Gly Leu Asn Gln Ile 305 310 315 320

    Ile Asn Leu Tyr Ile Gln Lys Lys Gln Ser Glu Gln Lys Ala Glu Gln 325 330 335

    Lys Glu Thr Gly Lys Lys Lys Ile Lys Phe Asn Lys Lys Asp Tyr Pro 340 345 350

    Thr Phe Thr Cys Leu Gln Lys Gln Ile Leu Ser Gln Val Phe Arg Lys 355 360 365

    Glu Ile Ile Ile Glu Ser Asp Arg Asp Leu Ile Arg Glu Leu Lys Phe 370 375 380

    Phe Val Glu Glu Ser Lys Glu Lys Val Asp Lys Ala Arg Gly Ile Ile 385 390 395 400

    Glu Phe Leu Leu Asn His Glu Glu Asn Asp Ile Asp Leu Ala Met Val 405 410 415

    Tyr Leu Pro Lys Ser Lys Ile Asn Ser Phe Val Tyr Lys Val Phe Lys 420 425 430

    Glu Pro Gln Asp Phe Leu Ser Val Phe Gln Asp Gly Ala Ser Asn Leu 435 440 445

    Asp Phe Val Ser Phe Asp Lys Ile Lys Thr His Leu Glu Asn Asn Lys 450 455 460

    Leu Thr Tyr Lys Ile Phe Phe Lys Thr Leu Ile Lys Glu Asn His Asp 465 470 475 480

    Phe Glu Ser Phe Leu Ile Leu Leu Gln Gln Glu Ile Asp Leu Leu Ile 485 490 495

    Asp Gly Gly Glu Thr Val Thr Leu Gly Gly Lys Lys Glu Ser Ile Thr 500 505 510

    Ser Leu Asp Glu Lys Lys Asn Arg Leu Lys Glu Lys Leu Gly Trp Phe 515 520 525

    Glu Gly Lys Val Arg Glu Asn Glu Lys Met Lys Asp Glu Glu Glu Gly 530 535 540

    Glu Phe Cys Ser Thr Val Leu Ala Tyr Ser Gln Ala Val Leu Asn Ile 545 550 555 560

    Thr Lys Arg Ala Glu Ile Phe Trp Leu Asn Glu Lys Gln Asp Ala Lys 565 570 575

    Val Gly Glu Asp Asn Lys Asp Met Ile Phe Tyr Lys Lys Phe Asp Glu 580 585 590

    Phe Ala Asp Asp Gly Phe Ala Pro Phe Phe Tyr Phe Asp Lys Phe Gly 595 600 605

    Asn Tyr Leu Lys Arg Arg Ser Arg Asn Thr Thr Lys Glu Ile Lys Leu 610 615 620

    His Phe Gly Asn Asp Asp Leu Leu Glu Gly Trp Asp Met Asn Lys Glu 625 630 635 640

    Pro Glu Tyr Trp Ser Phe Ile Leu Arg Asp Arg Asn Gln Tyr Tyr Leu 645 650 655

    Gly Ile Gly Lys Lys Asp Gly Glu Ile Phe His Lys Lys Leu Gly Asn 660 665 670

    Ser Val Glu Ala Val Lys Glu Ala Tyr Glu Leu Glu Asn Glu Ala Asp 675 680 685

    Phe Tyr Glu Lys Ile Asp Tyr Lys Gln Leu Asn Ile Asp Arg Phe Glu 690 695 700

    Gly Ile Ala Phe Pro Lys Lys Thr Lys Thr Glu Glu Ala Phe Arg Gln 705 710 715 720

    Val Cys Lys Lys Arg Ala Asp Glu Phe Leu Gly Gly Asp Thr Tyr Glu 725 730 735

    Phe Lys Ile Leu Leu Ala Ile Lys Lys Glu Tyr Asp Asp Phe Lys Ala 740 745 750

    Arg Arg Gln Lys Glu Lys Asp Trp Asp Ser Lys Phe Ser Lys Glu Lys 755 760 765

    Met Ser Lys Leu Ile Glu Tyr Tyr Ile Thr Cys Leu Gly Lys Arg Asp 770 775 780

    Asp Trp Lys Arg Phe Asn Leu Asn Phe Arg Gln Pro Lys Glu Tyr Glu 785 790 795 800

    Asp Arg Ser Asp Phe Val Arg His Ile Gln Arg Gln Ala Tyr Trp Ile 805 810 815

    Asp Pro Arg Lys Val Ser Lys Asp Tyr Val Asp Lys Lys Val Ala Glu 820 825 830

    Gly Glu Met Phe Leu Phe Lys Val His Asn Lys Asp Phe Tyr Asp Phe 835 840 845

    Glu Arg Lys Ser Glu Asp Lys Lys Asn His Thr Ala Asn Leu Phe Thr 850 855 860

    Gln Tyr Leu Leu Glu Leu Phe Ser Cys Glu Asn Ile Lys Asn Ile Lys 865 870 875 880

    Ser Lys Asp Leu Ile Glu Ser Ile Phe Glu Leu Asp Gly Lys Ala Glu 885 890 895

    Ile Arg Phe Arg Pro Lys Thr Asp Asp Val Lys Leu Lys Ile Tyr Gln

    900

    905

    910

    Lys Lys Gly Lys Asp Val Thr Tyr Ala Asp Lys Arg Asp Gly Asn Lys 915 920 925

    Glu Lys Glu Val Ile Gln His Arg Arg Phe Ala Lys Asp Ala Leu Thr 930 935 940

    Leu His Leu Lys Ile Arg Leu Asn Phe Gly Lys His Val Asn Leu Phe 945 950 955 960

    Asp Phe Asn Lys Leu Val Asn Thr Glu Leu Phe Ala Lys Val Pro Val 965 970 975

    Lys Ile Leu Gly Met Asp Arg Gly Glu Asn Asn Leu Ile Tyr Tyr Cys 980 985 990

    Phe Leu Asp Glu His Gly Glu Ile Glu Asn Gly Lys Cys Gly Ser Leu 995 1000 1005

    Asn Arg Val Gly Glu Gln Ile Ile Thr Leu Glu Asp Asp Lys Lys 1010 1015 1020

    Val Lys Glu Pro Val Asp Tyr Phe Gln Leu Leu Val Asp Arg Glu 1025 1030 1035

    Gly Gln Arg Asp Trp Glu Gln Lys Asn Trp Gln Lys Met Thr Arg 1040 1045 1050

    Ile Lys Asp Leu Lys Lys Ala Tyr Leu Gly Asn Val Val Ser Trp 1055 1060 1065

    Ile Ser Lys Glu Met Leu Ser Gly Ile Lys Glu Gly Val Val Thr 1070 1075 1080

    Ile Gly Val Leu Glu Asp Leu Asn Ser Asn Phe Lys Arg Thr Arg 1085 1090 1095

    Phe Phe Arg Glu Arg Gln Val Tyr Gln Gly Phe Glu Lys Ala Leu 1100 1105 1110

    Val Asn Lys Leu Gly Tyr Leu Val Asp Lys Lys Tyr Asp Asn Tyr 1115 1120 1125

    Arg Asn Val Tyr Gln Phe Ala Pro Ile Val Asp Ser Val Glu Glu 1130 1135 1140

    Met Glu Lys Asn Lys Gln Ile Gly Thr Leu Val Tyr Val Pro Ala 1145 1150 1155

    Ser Tyr Thr Ser Lys Ile Cys Pro His Pro Lys Cys Gly Trp Arg 1160 1165 1170

    Glu Arg Leu Tyr Met Lys Asn Ser Ala Ser Lys Glu Lys Ile Val 1175 1180 1185

    Gly Leu Leu Lys Ser Asp Gly Ile Lys Ile Ser Tyr Asp Gln Lys 1190 1195 1200

    Asn Asp Arg Phe Tyr Phe Glu Tyr Gln Trp Glu Gln Glu His Lys 1205 1210 1215

    Ser Asp Gly Lys Lys Lys Lys Tyr Ser Gly Val Asp Lys Val Phe 1220 1225 1230

    Ser Asn Val Ser Arg Met Arg Trp Asp Val Glu Gln Lys Lys Ser 1235 1240 1245

    Ile Asp Phe Val Asp Gly Thr Asp Gly Ser Ile Thr Asn Lys Leu 1250 1255 1260

    Lys Ser Leu Leu Lys Gly Lys Gly Ile Glu Leu Asp Asn Ile Asn 1265 1270 1275

    Gln Gln Ile Val Asn Gln Gln Lys Glu Leu Gly Val Glu Phe Phe 1280 1285 1290

    Gln Ser Ile Ile Phe Tyr Phe Asn Leu Ile Met Gln Ile Arg Asn 1295 1300 1305

    Tyr Asp Lys Glu Lys Ser Gly Ser Glu Ala Asp Tyr Ile Gln Cys 1310 1315 1320

    Pro Ser Cys Leu Phe Asp Ser Arg Lys Pro Glu Met Asn Gly Lys 1325 1330 1335

    Leu Ser Ala Ile Thr Asn Gly Asp Ala Asn Gly Ala Tyr Asn Ile 1340 1345 1350

    Ala Arg Lys Gly Phe Met Gln Leu Cys Arg Ile Arg Glu Asn Pro 1355 1360 1365

    Gln Glu Pro Met Lys Leu Ile Thr Asn Arg Glu Trp Asp Glu Ala 1370 1375 1380

    Val Arg Glu Trp Asp Ile Tyr Ser Ala Ala Gln Lys Ile Pro Val 1385 1390 1395

    Leu Ser Glu Glu Asn

    1400 <210> 1115 <211> 1403 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Falkowbacteria bacterium sequence <400> 1115

    Met Leu Phe Phe Met Ser Thr Asp Ile Thr Asn Lys Pro Arg Glu Lys 1 5 10 15

    Gly Val Phe Asp Asn Phe Thr Asn Leu Tyr Glu Phe Ser Lys Thr Leu 20 25 30

    Thr Phe Gly Leu Ile Pro Leu Lys Trp Asp Asp Asn Lys Lys Met Ile 35 40 45

    Val Glu Asp Glu Asp Phe Ser Val Leu Arg Lys Tyr Gly Val Ile Glu 50 55 60

    Glu Asp Lys Arg Ile Ala Glu Ser Ile Lys Ile Ala Lys Phe Tyr Leu 65 70 75 80

    Asn Ile Leu His Arg Glu Leu Ile Gly Lys Val Leu Gly Ser Leu Lys 85 90 95

    Phe Glu Lys Lys Asn Leu Glu Asn Tyr Asp Arg Leu Leu Gly Glu Ile 100 105 110

    Glu Lys Asn Asn Lys Asn Glu Asn Ile Ser Glu Asp Lys Lys Lys Glu 115 120 125

    Ile Arg Lys Asn Phe Lys Lys Glu Leu Ser Ile Ala Gln Asp Ile Leu 130 135 140

    Leu Lys Lys Val Gly Glu Val Phe Glu Ser Asn Gly Ser Gly Ile Leu 145 150 155 160

    Ser Ser Lys Asn Cys Leu Asp Glu Leu Thr Lys Arg Phe Thr Arg Gln 165 170 175

    Glu Val Asp Lys Leu Arg Arg Glu Asn Lys Asp Ile Gly Val Glu Tyr 180 185 190

    Pro Asp Val Ala Tyr Arg Glu Lys Asp Gly Lys Glu Glu Thr Lys Ser 195 200 205

    Phe Phe Ala Met Asp Val Gly Tyr Leu Asp Asp Phe His Lys Asn Arg 210 215 220

    Lys Gln Leu Tyr Ser Val Lys Gly Lys Lys Asn Ser Leu Gly Arg Arg 225 230 235 240

    Ile Leu Asp Asn Phe Glu Ile Phe Cys Lys Asn Lys Lys Leu Tyr Glu 245 250 255

    Lys Tyr Lys Asn Leu Asp Ile Asp Phe Ser Glu Ile Glu Arg Asn Phe 260 265 270

    Asn Leu Thr Leu Glu Lys Val Phe Asp Phe Asp Asn Tyr Asn Glu Arg 275 280 285

    Leu Thr Gln Glu Gly Leu Asp Glu Tyr Ala Lys Ile Leu Gly Gly Glu 290 295 300

    Ser Asn Lys Gln Glu Arg Thr Ala Asn Ile His Gly Leu Asn Gln Ile 305 310 315 320

    Ile Asn Leu Tyr Ile Gln Lys Lys Gln Ser Glu Gln Lys Ala Glu Gln 325 330 335

    Lys Glu Thr Gly Lys Lys Lys Ile Lys Phe Asn Lys Lys Asp Tyr Pro 340 345 350

    Thr Phe Thr Cys Leu Gln Lys Gln Ile Leu Ser Gln Val Phe Arg Lys 355 360 365

    Glu Ile Ile Ile Glu Ser Asp Arg Asp Leu Ile Arg Glu Leu Lys Phe 370 375 380

    Phe Val Glu Glu Ser Lys Glu Lys Val Asp Lys Ala Arg Gly Ile Ile 385 390 395 400

    Glu Phe Leu Leu Asn His Glu Glu Asn Asp Ile Asp Leu Ala Met Val 405 410 415

    Tyr Leu Pro Lys Ser Lys Ile Asn Ser Phe Val Tyr Lys Val Phe Lys 420 425 430

    Glu Pro Gln Asp Phe Leu Ser Val Phe Gln Asp Gly Ala Ser Asn Leu 435 440 445

    Asp Phe Val Ser Phe Asp Lys Ile Lys Thr His Leu Glu Asn Asn Lys 450 455 460

    Leu Thr Tyr Lys Ile Phe Phe Lys Thr Leu Ile Lys Glu Asn His Asp 465 470 475 480

    Phe Glu Ser Phe Leu Ile Leu Leu Gln Gln Glu Ile Asp Leu Leu Ile 485 490 495

    Asp Gly Gly Glu Thr Val Thr Leu Gly Gly Lys Lys Glu Ser Ile Thr

    500

    505

    510

    Ser Leu Asp Glu Lys Lys Asn Arg Leu Lys Glu Lys Leu Gly Trp Phe 515 520 525

    Glu Gly Lys Val Arg Glu Asn Glu Lys Met Lys Asp Glu Glu Glu Gly 530 535 540

    Glu Phe Cys Ser Thr Val Leu Ala Tyr Ser Gln Ala Val Leu Asn Ile 545 550 555 560

    Thr Lys Arg Ala Glu Ile Phe Trp Leu Asn Glu Lys Gln Asp Ala Lys 565 570 575

    Val Gly Glu Asp Asn Lys Asp Met Ile Phe Tyr Lys Lys Phe Asp Glu 580 585 590

    Phe Ala Asp Asp Gly Phe Ala Pro Phe Phe Tyr Phe Asp Lys Phe Gly 595 600 605

    Asn Tyr Leu Lys Arg Arg Ser Arg Asn Thr Thr Lys Glu Ile Lys Leu 610 615 620

    His Phe Gly Asn Asp Asp Leu Leu Glu Gly Trp Asp Met Asn Lys Glu 625 630 635 640

    Pro Glu Tyr Trp Ser Phe Ile Leu Arg Asp Arg Asn Gln Tyr Tyr Leu 645 650 655

    Gly Ile Gly Lys Lys Asp Gly Glu Ile Phe His Lys Lys Leu Gly Asn 660 665 670

    Ser Val Glu Ala Val Lys Glu Ala Tyr Glu Leu Glu Asn Glu Ala Asp 675 680 685

    Phe Tyr Glu Lys Ile Asp Tyr Lys Gln Leu Asn Ile Asp Arg Phe Glu 690 695 700

    Gly Ile Ala Phe Pro Lys Lys Thr Lys Thr Glu Glu Ala Phe Arg Gln 705 710 715 720

    Val Cys Lys Lys Arg Ala Asp Glu Phe Leu Gly Gly Asp Thr Tyr Glu 725 730 735

    Phe Lys Ile Leu Leu Ala Ile Lys Lys Glu Tyr Asp Asp Phe Lys Ala 740 745 750

    Arg Arg Gln Lys Glu Lys Asp Trp Asp Ser Lys Phe Ser Lys Glu Lys 755 760 765

    Met Ser Lys Leu Ile Glu Tyr Tyr Ile Thr Cys Leu Gly Lys Arg Asp 770 775 780

    Asp Trp Lys Arg Phe Asn Leu Asn Phe Arg Gln Pro Lys Glu Tyr Glu 785 790 795 800

    Asp Arg Ser Asp Phe Val Arg His Ile Gln Arg Gln Ala Tyr Trp Ile 805 810 815

    Asp Pro Arg Lys Val Ser Lys Asp Tyr Val Asp Lys Lys Val Ala Glu 820 825 830

    Gly Glu Met Phe Leu Phe Lys Val His Asn Lys Asp Phe Tyr Asp Phe 835 840 845

    Glu Arg Lys Ser Glu Asp Lys Lys Asn His Thr Ala Asn Leu Phe Thr 850 855 860

    Gln Tyr Leu Leu Glu Leu Phe Ser Cys Glu Asn Ile Lys Asn Ile Lys 865 870 875 880

    Ser Lys Asp Leu Ile Glu Ser Ile Phe Glu Leu Asp Gly Lys Ala Glu 885 890 895

    Ile Arg Phe Arg Pro Lys Thr Asp Asp Val Lys Leu Lys Ile Tyr Gln 900 905 910

    Lys Lys Gly Lys Asp Val Thr Tyr Ala Asp Lys Arg Asp Gly Asn Lys 915 920 925

    Glu Lys Glu Val Ile Gln His Arg Arg Phe Ala Lys Asp Ala Leu Thr 930 935 940

    Leu His Leu Lys Ile Arg Leu Asn Phe Gly Lys His Val Asn Leu Phe 945 950 955 960

    Asp Phe Asn Lys Leu Val Asn Thr Glu Leu Phe Ala Lys Val Pro Val 965 970 975

    Lys Ile Leu Gly Met Asp Arg Gly Glu Asn Asn Leu Ile Tyr Tyr Cys 980 985 990

    Phe Leu Asp Glu His Gly Glu Ile Glu Asn Gly Lys Cys Gly Ser Leu 995 1000 1005

    Asn Arg Val Gly Glu Gln Ile Ile Thr Leu Glu Asp Asp Lys Lys 1010 1015 1020

    Val Lys Glu Pro Val Asp Tyr Phe Gln Leu Leu Val Asp Arg Glu 1025 1030 1035

    Gly Gln Arg Asp Trp Glu Gln Lys Asn Trp Gln Lys Met Thr Arg 1040 1045 1050

    Ile Lys Asp Leu Lys Lys Ala Tyr Leu Gly Asn Val Val Ser Trp 1055 1060 1065

    Ile Ser Lys Glu Met Leu Ser Gly Ile Lys Glu Gly Val Val Thr 1070 1075 1080

    Ile Gly Val Leu Glu Asp Leu Asn Ser Asn Phe Lys Arg Thr Arg 1085 1090 1095

    Phe Phe Arg Glu Arg Gln Val Tyr Gln Gly Phe Glu Lys Ala Leu 1100 1105 1110

    Val Asn Lys Leu Gly Tyr Leu Val Asp Lys Lys Tyr Asp Asn Tyr 1115 1120 1125

    Arg Asn Val Tyr Gln Phe Ala Pro Ile Val Asp Ser Val Glu Glu 1130 1135 1140

    Met Glu Lys Asn Lys Gln Ile Gly Thr Leu Val Tyr Val Pro Ala 1145 1150 1155

    Ser Tyr Thr Ser Lys Ile Cys Pro His Pro Lys Cys Gly Trp Arg 1160 1165 1170

    Glu Arg Leu Tyr Met Lys Asn Ser Ala Ser Lys Glu Lys Ile Val 1175 1180 1185

    Gly Leu Leu Lys Ser Asp Gly Ile Lys Ile Ser Tyr Asp Gln Lys 1190 1195 1200

    Asn Asp Arg Phe Tyr Phe Glu Tyr Gln Trp Glu Gln Glu His Lys

    1205 1210 1215

    Ser Asp Gly Lys Lys Lys Lys Tyr Ser Gly Val Asp Lys Val Phe 1220 1225 1230

    Ser Asn Val Ser Arg Met Arg Trp Asp Val Glu Gln Lys Lys Ser 1235 1240 1245

    Ile Asp Phe Val Asp Gly Thr Asp Gly Ser Ile Thr Asn Lys Leu 1250 1255 1260

    Lys Ser Leu Leu Lys Gly Lys Gly Ile Glu Leu Asp Asn Ile Asn 1265 1270 1275

    Gln Gln Ile Val Asn Gln Gln Lys Glu Leu Gly Val Glu Phe Phe 1280 1285 1290

    Gln Ser Ile Ile Phe Tyr Phe Asn Leu Ile Met Gln Ile Arg Asn 1295 1300 1305

    Tyr Asp Lys Glu Lys Ser Gly Ser Glu Ala Asp Tyr Ile Gln Cys 1310 1315 1320

    Pro Ser Cys Leu Phe Asp Ser Arg Lys Pro Glu Met Asn Gly Lys 1325 1330 1335

    Leu Ser Ala Ile Thr Asn Gly Asp Ala Asn Gly Ala Tyr Asn Ile 1340 1345 1350

    Ala Arg Lys Gly Phe Met Gln Leu Cys Arg Ile Arg Glu Asn Pro 1355 1360 1365

    Gln Glu Pro Met Lys Leu Ile Thr Asn Arg Glu Trp Asp Glu Ala 1370 1375 1380

    Val Arg Glu Trp Asp Ile Tyr Ser Ala Ala Gln Lys Ile Pro Val 1385 1390 1395

    Leu Ser Glu Glu Asn 1400 <210> 1116 <211> 1352 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Parcubacteria group bacterium sequence <400> 1116

    Met Glu Asn Ile Phe Asp Gln Phe Ile Gly Lys Tyr Ser Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Glu Asp Phe Leu 20 25 30

    Lys Ile Asn Lys Val Phe Glu Lys Asp Gln Thr Ile Asp Asp Ser Tyr 35 40 45

    Asn Gln Ala Lys Phe Tyr Phe Asp Ser Leu His Gln Lys Phe Ile Asp 50 55 60

    Ala Ala Leu Ala Ser Asp Lys Thr Ser Glu Leu Ser Phe Gln Asn Phe 65 70 75 80

    Ala Asp Val Leu Glu Lys Gln Asn Lys Ile Ile Leu Asp Lys Lys Arg 85 90 95

    Glu Met Gly Ala Leu Arg Lys Arg Asp Lys Asn Ala Val Gly Ile Asp

    100

    105

    110

    Arg Leu Gln Lys Glu Ile Asn Asp Ala Glu Asp Ile Ile Gln Lys Glu 115 120 125

    Lys Glu Lys Ile Tyr Lys Asp Val Arg Thr Leu Phe Asp Asn Glu Ala 130 135 140

    Glu Ser Trp Lys Thr Tyr Tyr Gln Glu Arg Glu Val Asp Gly Lys Lys 145 150 155 160

    Ile Thr Phe Ser Lys Ala Asp Leu Lys Gln Lys Gly Ala Asp Phe Leu 165 170 175

    Thr Ala Ala Gly Ile Leu Lys Val Leu Lys Tyr Glu Phe Pro Glu Glu 180 185 190

    Lys Glu Lys Glu Phe Gln Ala Lys Asn Gln Pro Ser Leu Phe Val Glu 195 200 205

    Glu Lys Glu Asn Pro Gly Gln Lys Arg Tyr Ile Phe Asp Ser Phe Asp 210 215 220

    Lys Phe Ala Gly Tyr Leu Thr Lys Phe Gln Gln Thr Lys Lys Asn Leu 225 230 235 240

    Tyr Ala Ala Asp Gly Thr Ser Thr Ala Val Ala Thr Arg Ile Ala Asp 245 250 255

    Asn Phe Ile Ile Phe His Gln Asn Thr Lys Val Phe Arg Asp Lys Tyr 260 265 270

    Lys Asn Asn His Thr Asp Leu Gly Phe Asp Glu Glu Asn Ile Phe Glu 275 280 285

    Ile Glu Arg Tyr Lys Asn Cys Leu Leu Gln Arg Glu Ile Glu His Ile 290 295 300

    Lys Asn Glu Asn Ser Tyr Asn Lys Ile Ile Gly Arg Ile Asn Lys Lys 305 310 315 320

    Ile Lys Glu Tyr Arg Asp Gln Lys Ala Lys Asp Thr Lys Leu Thr Lys 325 330 335

    Ser Asp Phe Pro Phe Phe Lys Asn Leu Asp Lys Gln Ile Leu Gly Glu 340 345 350

    Val Glu Lys Glu Lys Gln Leu Ile Glu Lys Thr Arg Glu Lys Thr Glu 355 360 365

    Glu Asp Val Leu Ile Glu Arg Phe Lys Glu Phe Ile Glu Asn Asn Glu 370 375 380

    Glu Arg Phe Thr Ala Ala Lys Lys Leu Met Asn Ala Phe Cys Asn Gly 385 390 395 400

    Glu Phe Glu Ser Glu Tyr Glu Gly Ile Tyr Leu Lys Asn Lys Ala Ile 405 410 415

    Asn Thr Ile Ser Arg Arg Trp Phe Val Ser Asp Arg Asp Phe Glu Leu 420 425 430

    Lys Leu Pro Gln Gln Lys Ser Lys Asn Lys Ser Glu Lys Asn Glu Pro 435 440 445

    Lys Val Lys Lys Phe Ile Ser Ile Ala Glu Ile Lys Asn Ala Val Glu 450 455 460

    Glu Leu Asp Gly Asp Ile Phe Lys Ala Val Phe Tyr Asp Lys Lys Ile 465 470 475 480

    Ile Ala Gln Gly Gly Ser Lys Leu Glu Gln Phe Leu Val Ile Trp Lys 485 490 495

    Tyr Glu Phe Glu Tyr Leu Phe Arg Asp Ile Glu Arg Glu Asn Gly Glu 500 505 510

    Lys Leu Leu Gly Tyr Asp Ser Cys Leu Lys Ile Ala Lys Gln Leu Gly 515 520 525

    Ile Phe Pro Gln Glu Lys Glu Ala Arg Glu Lys Ala Thr Ala Val Ile 530 535 540

    Lys Asn Tyr Ala Asp Ala Gly Leu Gly Ile Phe Gln Met Met Lys Tyr 545 550 555 560

    Phe Ser Leu Asp Asp Lys Asp Arg Lys Asn Thr Pro Gly Gln Leu Ser 565 570 575

    Thr Asn Phe Tyr Ala Glu Tyr Asp Gly Tyr Tyr Lys Asp Phe Glu Phe 580 585 590

    Ile Lys Tyr Tyr Asn Glu Phe Arg Asn Phe Ile Thr Lys Lys Pro Phe 595 600 605

    Asp Glu Asp Lys Ile Lys Leu Asn Phe Glu Asn Gly Ala Leu Leu Lys 610 615 620

    Gly Trp Asp Glu Asn Lys Glu Tyr Asp Phe Met Gly Val Ile Leu Lys 625 630 635 640

    Lys Glu Gly Arg Leu Tyr Leu Gly Ile Met His Lys Asn His Arg Lys 645 650 655

    Leu Phe Gln Ser Met Gly Asn Ala Lys Gly Asp Asn Ala Asn Arg Tyr 660 665 670

    Gln Lys Met Ile Tyr Lys Gln Ile Ala Asp Ala Ser Lys Asp Val Pro 675 680 685

    Arg Leu Leu Leu Thr Ser Lys Lys Ala Met Glu Lys Phe Lys Pro Ser 690 695 700

    Gln Glu Ile Leu Arg Ile Lys Lys Glu Lys Thr Phe Lys Arg Glu Ser 705 710 715 720

    Lys Asn Phe Ser Leu Arg Asp Leu His Ala Leu Ile Glu Tyr Tyr Arg 725 730 735

    Asn Cys Ile Pro Gln Tyr Ser Asn Trp Ser Phe Tyr Asp Phe Gln Phe 740 745 750

    Gln Asp Thr Gly Lys Tyr Gln Asn Ile Lys Glu Phe Thr Asp Asp Val 755 760 765

    Gln Lys Tyr Gly Tyr Lys Ile Ser Phe Arg Asp Ile Asp Asp Glu Tyr 770 775 780

    Ile Asn Gln Ala Leu Asn Glu Gly Lys Met Tyr Leu Phe Glu Val Val 785 790 795 800

    Asn Lys Asp Ile Tyr Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr 805 810 815

    Leu Tyr Phe Glu His Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val

    820

    825

    830

    Phe Lys Leu Ser Gly Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val 835 840 845

    Asn Glu Arg Glu Lys Ile Thr Thr Gln Lys Asn Gln Cys Ile Leu Asp 850 855 860

    Lys Gly Asp Arg Ala Tyr Lys Tyr Arg Arg Tyr Thr Glu Lys Lys Ile 865 870 875 880

    Met Phe His Met Ser Leu Val Leu Asn Thr Gly Lys Gly Glu Ile Lys 885 890 895

    Gln Val Gln Phe Asn Lys Ile Ile Asn Gln Arg Ile Ser Ser Ser Asp 900 905 910

    Asn Glu Met Arg Val Asn Val Ile Gly Ile Asp Arg Gly Glu Lys Asn 915 920 925

    Leu Leu Tyr Tyr Ser Val Val Lys Gln Asn Gly Glu Ile Ile Glu Gln 930 935 940

    Ala Ser Leu Asn Glu Ile Asn Gly Val Asn Tyr Arg Asp Lys Leu Ile 945 950 955 960

    Glu Arg Glu Lys Glu Arg Leu Lys Asn Arg Gln Ser Trp Lys Pro Val 965 970 975

    Val Lys Ile Lys Asp Leu Lys Lys Gly Tyr Ile Ser His Val Ile His 980 985 990

    Lys Ile Cys Gln Leu Ile Glu Lys Tyr Ser Ala Ile Val Val Leu Glu 995 1000 1005

    Asp Leu Asn Met Arg Phe Lys Gln Ile Arg Gly Gly Ile Glu Arg 1010 1015 1020

    Ser Val Tyr Gln Gln Phe Glu Lys Ala Leu Ile Asp Lys Leu Gly 1025 1030 1035

    Tyr Leu Val Phe Lys Asp Asn Arg Asp Leu Arg Ala Pro Gly Gly 1040 1045 1050

    Val Leu Asn Gly Tyr Gln Leu Ser Ala Pro Phe Val Ser Phe Glu 1055 1060 1065

    Lys Met Arg Lys Gln Thr Gly Ile Leu Phe Tyr Thr Gln Ala Glu 1070 1075 1080

    Tyr Thr Ser Lys Thr Asp Pro Ile Thr Gly Phe Arg Lys Asn Val 1085 1090 1095

    Tyr Ile Ser Asn Ser Ala Ser Leu Asp Lys Ile Lys Glu Ala Val 1100 1105 1110

    Lys Lys Phe Asp Ala Ile Gly Trp Asp Gly Lys Glu Gln Ser Tyr 1115 1120 1125

    Phe Phe Lys Tyr Asn Pro Tyr Asn Leu Ala Asp Glu Lys Tyr Lys 1130 1135 1140

    Asn Ser Thr Val Ser Lys Glu Trp Ala Ile Phe Ala Ser Ala Pro 1145 1150 1155

    Arg Ile Arg Arg Gln Lys Gly Glu Asp Gly Tyr Trp Lys Tyr Asp 1160 1165 1170

    Arg Val Lys Val Asn Glu Glu Phe Glu Lys Leu Leu Lys Val Trp 1175 1180 1185

    Asn Phe Val Asn Pro Lys Ala Thr Asp Ile Lys Gln Glu Ile Ile 1190 1195 1200

    Lys Lys Glu Lys Ala Gly Asp Leu Gln Gly Glu Lys Glu Leu Asp 1205 1210 1215

    Gly Arg Leu Arg Asn Phe Trp His Ser Phe Ile Tyr Leu Phe Asn 1220 1225 1230

    Leu Val Leu Glu Leu Arg Asn Ser Phe Ser Leu Gln Ile Lys Ile 1235 1240 1245

    Lys Ala Gly Glu Val Ile Ala Val Asp Glu Gly Val Asp Phe Ile 1250 1255 1260

    Ala Ser Pro Val Lys Pro Phe Phe Thr Thr Pro Asn Pro Tyr Ile 1265 1270 1275

    Pro Ser Asn Leu Cys Trp Leu Ala Val Glu Asn Ala Asp Ala Asn 1280 1285 1290

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Val Met Ile Leu Lys Lys 1295 1300 1305

    Ile Arg Glu His Ala Lys Lys Asp Pro Glu Phe Lys Lys Leu Pro 1310 1315 1320

    Asn Leu Phe Ile Ser Asn Ala Glu Trp Asp Glu Ala Ala Arg Asp 1325 1330 1335

    Trp Gly Lys Tyr Ala Gly Thr Thr Ala Leu Asn Leu Asp His 1340 1345 1350 <210> 1117 <211> 1331 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Parcubacteria group bacterium sequence <400> 1117

    Met Lys Pro Val Gly Lys Thr Glu Asp Phe Leu Lys Ile Asn Lys Val 1 5 10 15

    Phe Glu Lys Asp Gln Thr Ile Asp Asp Ser Tyr Asn Gln Ala Lys Phe 20 25 30

    Tyr Phe Asp Ser Leu His Gln Lys Phe Ile Asp Ala Ala Leu Ala Ser 35 40 45

    Asp Lys Thr Ser Glu Leu Ser Phe Gln Asn Phe Ala Asp Val Leu Glu 50 55 60

    Lys Gln Asn Lys Ile Ile Leu Asp Lys Lys Arg Glu Met Gly Ala Leu 65 70 75 80

    Arg Lys Arg Asp Lys Asn Ala Val Gly Ile Asp Arg Leu Gln Lys Glu 85 90 95

    Ile Asn Asp Ala Glu Asp Ile Ile Gln Lys Glu Lys Glu Lys Ile Tyr 100 105 110

    Lys Asp Val Arg Thr Leu Phe Asp Asn Glu Ala Glu Ser Trp Lys Thr 115 120 125

    Tyr Tyr Gln Glu Arg Glu Val Asp Gly Lys Lys Ile Thr Phe Ser Lys 130 135 140

    Ala Asp Leu Lys Gln Lys Gly Ala Asp Phe Leu Thr Ala Ala Gly Ile 145 150 155 160

    Leu Lys Val Leu Lys Tyr Glu Phe Pro Glu Glu Lys Glu Lys Glu Phe 165 170 175

    Gln Ala Lys Asn Gln Pro Ser Leu Phe Val Glu Glu Lys Glu Asn Pro 180 185 190

    Gly Gln Lys Arg Tyr Ile Phe Asp Ser Phe Asp Lys Phe Ala Gly Tyr 195 200 205

    Leu Thr Lys Phe Gln Gln Thr Lys Lys Asn Leu Tyr Ala Ala Asp Gly 210 215 220

    Thr Ser Thr Ala Val Ala Thr Arg Ile Ala Asp Asn Phe Ile Ile Phe 225 230 235 240

    His Gln Asn Thr Lys Val Phe Arg Asp Lys Tyr Lys Asn Asn His Thr 245 250 255

    Asp Leu Gly Phe Asp Glu Glu Asn Ile Phe Glu Ile Glu Arg Tyr Lys 260 265 270

    Asn Cys Leu Leu Gln Arg Glu Ile Glu His Ile Lys Asn Glu Asn Ser 275 280 285

    Tyr Asn Lys Ile Ile Gly Arg Ile Asn Lys Lys Ile Lys Glu Tyr Arg 290 295 300

    Asp Gln Lys Ala Lys Asp Thr Lys Leu Thr Lys Ser Asp Phe Pro Phe 305 310 315 320

    Phe Lys Asn Leu Asp Lys Gln Ile Leu Gly Glu Val Glu Lys Glu Lys 325 330 335

    Gln Leu Ile Glu Lys Thr Arg Glu Lys Thr Glu Glu Asp Val Leu Ile 340 345 350

    Glu Arg Phe Lys Glu Phe Ile Glu Asn Asn Glu Glu Arg Phe Thr Ala 355 360 365

    Ala Lys Lys Leu Met Asn Ala Phe Cys Asn Gly Glu Phe Glu Ser Glu 370 375 380

    Tyr Glu Gly Ile Tyr Leu Lys Asn Lys Ala Ile Asn Thr Ile Ser Arg 385 390 395 400

    Arg Trp Phe Val Ser Asp Arg Asp Phe Glu Leu Lys Leu Pro Gln Gln 405 410 415

    Lys Ser Lys Asn Lys Ser Glu Lys Asn Glu Pro Lys Val Lys Lys Phe 420 425 430

    Ile Ser Ile Ala Glu Ile Lys Asn Ala Val Glu Glu Leu Asp Gly Asp 435 440 445

    Ile Phe Lys Ala Val Phe Tyr Asp Lys Lys Ile Ile Ala Gln Gly Gly 450 455 460

    Ser Lys Leu Glu Gln Phe Leu Val Ile Trp Lys Tyr Glu Phe Glu Tyr 465 470 475 480

    Leu Phe Arg Asp Ile Glu Arg Glu Asn Gly Glu Lys Leu Leu Gly Tyr

    485

    490

    495

    Asp Ser Cys Leu Lys Ile Ala Lys Gln Leu Gly Ile Phe Pro Gln Glu 500 505 510

    Lys Glu Ala Arg Glu Lys Ala Thr Ala Val Ile Lys Asn Tyr Ala Asp 515 520 525

    Ala Gly Leu Gly Ile Phe Gln Met Met Lys Tyr Phe Ser Leu Asp Asp 530 535 540

    Lys Asp Arg Lys Asn Thr Pro Gly Gln Leu Ser Thr Asn Phe Tyr Ala 545 550 555 560

    Glu Tyr Asp Gly Tyr Tyr Lys Asp Phe Glu Phe Ile Lys Tyr Tyr Asn 565 570 575

    Glu Phe Arg Asn Phe Ile Thr Lys Lys Pro Phe Asp Glu Asp Lys Ile 580 585 590

    Lys Leu Asn Phe Glu Asn Gly Ala Leu Leu Lys Gly Trp Asp Glu Asn 595 600 605

    Lys Glu Tyr Asp Phe Met Gly Val Ile Leu Lys Lys Glu Gly Arg Leu 610 615 620

    Tyr Leu Gly Ile Met His Lys Asn His Arg Lys Leu Phe Gln Ser Met 625 630 635 640

    Gly Asn Ala Lys Gly Asp Asn Ala Asn Arg Tyr Gln Lys Met Ile Tyr 645 650 655

    Lys Gln Ile Ala Asp Ala Ser Lys Asp Val Pro Arg Leu Leu Leu Thr 660 665 670

    Ser Lys Lys Ala Met Glu Lys Phe Lys Pro Ser Gln Glu Ile Leu Arg 675 680 685

    Ile Lys Lys Glu Lys Thr Phe Lys Arg Glu Ser Lys Asn Phe Ser Leu 690 695 700

    Arg Asp Leu His Ala Leu Ile Glu Tyr Tyr Arg Asn Cys Ile Pro Gln 705 710 715 720

    Tyr Ser Asn Trp Ser Phe Tyr Asp Phe Gln Phe Gln Asp Thr Gly Lys 725 730 735

    Tyr Gln Asn Ile Lys Glu Phe Thr Asp Asp Val Gln Lys Tyr Gly Tyr 740 745 750

    Lys Ile Ser Phe Arg Asp Ile Asp Asp Glu Tyr Ile Asn Gln Ala Leu 755 760 765

    Asn Glu Gly Lys Met Tyr Leu Phe Glu Val Val Asn Lys Asp Ile Tyr 770 775 780

    Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr Leu Tyr Phe Glu His 785 790 795 800

    Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val Phe Lys Leu Ser Gly 805 810 815

    Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val Asn Glu Arg Glu Lys 820 825 830

    Ile Thr Thr Gln Lys Asn Gln Cys Ile Leu Asp Lys Gly Asp Arg Ala 835 840 845

    Tyr Lys Tyr Arg Arg Tyr Thr Glu Lys Lys Ile Met Phe His Met Ser 850 855 860

    Leu Val Leu Asn Thr Gly Lys Gly Glu Ile Lys Gln Val Gln Phe Asn 865 870 875 880

    Lys Ile Ile Asn Gln Arg Ile Ser Ser Ser Asp Asn Glu Met Arg Val 885 890 895

    Asn Val Ile Gly Ile Asp Arg Gly Glu Lys Asn Leu Leu Tyr Tyr Ser 900 905 910

    Val Val Lys Gln Asn Gly Glu Ile Ile Glu Gln Ala Ser Leu Asn Glu 915 920 925

    Ile Asn Gly Val Asn Tyr Arg Asp Lys Leu Ile Glu Arg Glu Lys Glu 930 935 940

    Arg Leu Lys Asn Arg Gln Ser Trp Lys Pro Val Val Lys Ile Lys Asp 945 950 955 960

    Leu Lys Lys Gly Tyr Ile Ser His Val Ile His Lys Ile Cys Gln Leu 965 970 975

    Ile Glu Lys Tyr Ser Ala Ile Val Val Leu Glu Asp Leu Asn Met Arg 980 985 990

    Phe Lys Gln Ile Arg Gly Gly Ile Glu Arg Ser Val Tyr Gln Gln Phe 995 1000 1005

    Glu Lys Ala Leu Ile Asp Lys Leu Gly Tyr Leu Val Phe Lys Asp 1010 1015 1020

    Asn Arg Asp Leu Arg Ala Pro Gly Gly Val Leu Asn Gly Tyr Gln 1025 1030 1035

    Leu Ser Ala Pro Phe Val Ser Phe Glu Lys Met Arg Lys Gln Thr 1040 1045 1050

    Gly Ile Leu Phe Tyr Thr Gln Ala Glu Tyr Thr Ser Lys Thr Asp 1055 1060 1065

    Pro Ile Thr Gly Phe Arg Lys Asn Val Tyr Ile Ser Asn Ser Ala 1070 1075 1080

    Ser Leu Asp Lys Ile Lys Glu Ala Val Lys Lys Phe Asp Ala Ile 1085 1090 1095

    Gly Trp Asp Gly Lys Glu Gln Ser Tyr Phe Phe Lys Tyr Asn Pro 1100 1105 1110

    Tyr Asn Leu Ala Asp Glu Lys Tyr Lys Asn Ser Thr Val Ser Lys 1115 1120 1125

    Glu Trp Ala Ile Phe Ala Ser Ala Pro Arg Ile Arg Arg Gln Lys 1130 1135 1140

    Gly Glu Asp Gly Tyr Trp Lys Tyr Asp Arg Val Lys Val Asn Glu 1145 1150 1155

    Glu Phe Glu Lys Leu Leu Lys Val Trp Asn Phe Val Asn Pro Lys 1160 1165 1170

    Ala Thr Asp Ile Lys Gln Glu Ile Ile Lys Lys Glu Lys Ala Gly 1175 1180 1185

    Asp Leu Gln Gly Glu Lys Glu Leu Asp Gly Arg Leu Arg Asn Phe

    1190 1195 1200

    Trp His Ser Phe Ile Tyr Leu Phe Asn Leu Val Leu Glu Leu Arg 1205 1210 1215

    Asn Ser Phe Ser Leu Gln Ile Lys Ile Lys Ala Gly Glu Val Ile 1220 1225 1230

    Ala Val Asp Glu Gly Val Asp Phe Ile Ala Ser Pro Val Lys Pro 1235 1240 1245

    Phe Phe Thr Thr Pro Asn Pro Tyr Ile Pro Ser Asn Leu Cys Trp 1250 1255 1260

    Leu Ala Val Glu Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala 1265 1270 1275

    Arg Lys Gly Val Met Ile Leu Lys Lys Ile Arg Glu His Ala Lys 1280 1285 1290

    Lys Asp Pro Glu Phe Lys Lys Leu Pro Asn Leu Phe Ile Ser Asn 1295 1300 1305

    Ala Glu Trp Asp Glu Ala Ala Arg Asp Trp Gly Lys Tyr Ala Gly 1310 1315 1320

    Thr Thr Ala Leu Asn Leu Asp His 1325 1330 <210> 1118 <211> 1285 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Roizmanbacteria bacterium sequence <400> 1118

    Met Lys Ser Phe Asp Ser Phe Thr Asn Leu Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Lys Phe Glu Met Arg Pro Val Gly Asn Thr Gln Lys Met Leu Asp 20 25 30

    Asn Ala Gly Val Phe Glu Lys Asp Lys Leu Ile Gln Lys Lys Tyr Gly 35 40 45

    Lys Thr Lys Pro Tyr Phe Asp Arg Leu His Arg Glu Phe Ile Glu Glu 50 55 60

    Ala Leu Thr Gly Val Glu Leu Ile Gly Leu Asp Glu Asn Phe Arg Thr 65 70 75 80

    Leu Val Asp Trp Gln Lys Asp Lys Lys Asn Asn Val Ala Met Lys Ala 85 90 95

    Tyr Glu Asn Ser Leu Gln Arg Leu Arg Thr Glu Ile Gly Lys Ile Phe 100 105 110

    Asn Leu Lys Ala Glu Asp Trp Val Lys Asn Lys Tyr Pro Ile Leu Gly 115 120 125

    Leu Lys Asn Lys Asn Thr Asp Ile Leu Phe Glu Glu Ala Val Phe Gly 130 135 140

    Ile Leu Lys Ala Arg Tyr Gly Glu Glu Lys Asp Thr Phe Ile Glu Val 145 150 155 160

    Glu Glu Ile Asp Lys Thr Gly Lys Ser Lys Ile Asn Gln Ile Ser Ile

    165

    170

    175

    Phe Asp Ser Trp Lys Gly Phe Thr Gly Tyr Phe Lys Lys Phe Phe Glu 180 185 190

    Thr Arg Lys Asn Phe Tyr Lys Asn Asp Gly Thr Ser Thr Ala Ile Ala 195 200 205

    Thr Arg Ile Ile Asp Gln Asn Leu Lys Arg Phe Ile Asp Asn Leu Ser 210 215 220

    Ile Val Glu Ser Val Arg Gln Lys Val Asp Leu Ala Glu Thr Glu Lys 225 230 235 240

    Ser Phe Ser Ile Ser Leu Ser Gln Phe Phe Ser Ile Asp Phe Tyr Asn 245 250 255

    Lys Cys Leu Leu Gln Asp Gly Ile Asp Tyr Tyr Asn Lys Ile Ile Gly 260 265 270

    Gly Glu Thr Leu Lys Asn Gly Glu Lys Leu Ile Gly Leu Asn Glu Leu 275 280 285

    Ile Asn Gln Tyr Arg Gln Asn Asn Lys Asp Gln Lys Ile Pro Phe Phe 290 295 300

    Lys Leu Leu Asp Lys Gln Ile Leu Ser Glu Lys Ile Leu Phe Leu Asp 305 310 315 320

    Glu Ile Lys Asn Asp Thr Glu Leu Ile Glu Ala Leu Ser Gln Phe Ala 325 330 335

    Lys Thr Ala Glu Glu Lys Thr Lys Ile Val Lys Lys Leu Phe Ala Asp 340 345 350

    Phe Val Glu Asn Asn Ser Lys Tyr Asp Leu Ala Gln Ile Tyr Ile Ser 355 360 365

    Gln Glu Ala Phe Asn Thr Ile Ser Asn Lys Trp Thr Ser Glu Thr Glu 370 375 380

    Thr Phe Ala Lys Tyr Leu Phe Glu Ala Met Lys Ser Gly Lys Leu Ala 385 390 395 400

    Lys Tyr Glu Lys Lys Asp Asn Ser Tyr Lys Phe Pro Asp Phe Ile Ala 405 410 415

    Leu Ser Gln Met Lys Ser Ala Leu Leu Ser Ile Ser Leu Glu Gly His 420 425 430

    Phe Trp Lys Glu Lys Tyr Tyr Lys Ile Ser Lys Phe Gln Glu Lys Thr 435 440 445

    Asn Trp Glu Gln Phe Leu Ala Ile Phe Leu Tyr Glu Phe Asn Ser Leu 450 455 460

    Phe Ser Asp Lys Ile Asn Thr Lys Asp Gly Glu Thr Lys Gln Val Gly 465 470 475 480

    Tyr Tyr Leu Phe Ala Lys Asp Leu His Asn Leu Ile Leu Ser Glu Gln 485 490 495

    Ile Asp Ile Pro Lys Asp Ser Lys Val Thr Ile Lys Asp Phe Ala Asp 500 505 510

    Ser Val Leu Thr Ile Tyr Gln Met Ala Lys Tyr Phe Ala Val Glu Lys 515 520 525

    Lys Arg Ala Trp Leu Ala Glu Tyr Glu Leu Asp Ser Phe Tyr Thr Gln 530 535 540

    Pro Asp Thr Gly Tyr Leu Gln Phe Tyr Asp Asn Ala Tyr Glu Asp Ile 545 550 555 560

    Val Gln Val Tyr Asn Lys Leu Arg Asn Tyr Leu Thr Lys Lys Pro Tyr 565 570 575

    Ser Glu Glu Lys Trp Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn 580 585 590

    Gly Trp Asp Lys Asn Lys Glu Ser Asp Asn Ser Ala Val Ile Leu Gln 595 600 605

    Lys Gly Gly Lys Tyr Tyr Leu Gly Leu Ile Thr Lys Gly His Asn Lys 610 615 620

    Ile Phe Asp Asp Arg Phe Gln Glu Lys Phe Ile Val Gly Ile Glu Gly 625 630 635 640

    Gly Lys Tyr Glu Lys Ile Val Tyr Lys Phe Phe Pro Asp Gln Ala Lys 645 650 655

    Met Phe Pro Lys Val Cys Phe Ser Ala Lys Gly Leu Glu Phe Phe Arg 660 665 670

    Pro Ser Glu Glu Ile Leu Arg Ile Tyr Asn Asn Ala Glu Phe Lys Lys 675 680 685

    Gly Glu Thr Tyr Ser Ile Asp Ser Met Gln Lys Leu Ile Asp Phe Tyr 690 695 700

    Lys Asp Cys Leu Thr Lys Tyr Glu Gly Trp Ala Cys Tyr Thr Phe Arg 705 710 715 720

    His Leu Lys Pro Thr Glu Glu Tyr Gln Asn Asn Ile Gly Glu Phe Phe 725 730 735

    Arg Asp Val Ala Glu Asp Gly Tyr Arg Ile Asp Phe Gln Gly Ile Ser 740 745 750

    Asp Gln Tyr Ile His Glu Lys Asn Glu Lys Gly Glu Leu His Leu Phe 755 760 765

    Glu Ile His Asn Lys Asp Trp Asn Leu Asp Lys Ala Arg Asp Gly Lys 770 775 780

    Ser Lys Thr Thr Gln Lys Asn Leu His Thr Leu Tyr Phe Glu Ser Leu 785 790 795 800

    Phe Ser Asn Asp Asn Val Val Gln Asn Phe Pro Ile Lys Leu Asn Gly 805 810 815

    Gln Ala Glu Ile Phe Tyr Arg Pro Lys Thr Glu Lys Asp Lys Leu Glu 820 825 830

    Ser Lys Lys Asp Lys Lys Gly Asn Lys Val Ile Asp His Lys Arg Tyr 835 840 845

    Ser Glu Asn Lys Ile Phe Phe His Val Pro Leu Thr Leu Asn Arg Thr 850 855 860

    Lys Asn Asp Ser Tyr Arg Phe Asn Ala Gln Ile Asn Asn Phe Leu Ala 865 870 875 880

    Asn Asn Lys Asp Ile Asn Ile Ile Gly Val Asp Arg Gly Glu Lys His

    885

    890

    895

    Leu Val Tyr Tyr Ser Val Ile Thr Gln Ala Ser Asp Ile Leu Glu Ser 900 905 910

    Gly Ser Leu Asn Glu Leu Asn Gly Val Asn Tyr Ala Glu Lys Leu Gly 915 920 925

    Lys Lys Ala Glu Asn Arg Glu Gln Ala Arg Arg Asp Trp Gln Asp Val 930 935 940

    Gln Gly Ile Lys Asp Leu Lys Lys Gly Tyr Ile Ser Gln Val Val Arg 945 950 955 960

    Lys Leu Ala Asp Leu Ala Ile Lys His Asn Ala Ile Ile Ile Leu Glu 965 970 975

    Asp Leu Asn Met Arg Phe Lys Gln Val Arg Gly Gly Ile Glu Lys Ser 980 985 990

    Ile Tyr Gln Gln Leu Glu Lys Ala Leu Ile Asp Lys Leu Ser Phe Leu 995 1000 1005

    Val Asp Lys Gly Glu Lys Asn Pro Glu Gln Ala Gly His Leu Leu 1010 1015 1020

    Lys Ala Tyr Gln Leu Ser Ala Pro Phe Glu Thr Phe Gln Lys Met 1025 1030 1035

    Gly Lys Gln Thr Gly Ile Ile Phe Tyr Thr Gln Ala Ser Tyr Thr 1040 1045 1050

    Ser Lys Ser Asp Pro Val Thr Gly Trp Arg Pro His Leu Tyr Leu 1055 1060 1065

    Lys Tyr Phe Ser Ala Lys Lys Ala Lys Asp Asp Ile Ala Lys Phe 1070 1075 1080

    Thr Lys Ile Glu Phe Val Asn Asp Arg Phe Glu Leu Thr Tyr Asp 1085 1090 1095

    Ile Lys Asp Phe Gln Gln Ala Lys Glu Tyr Pro Asn Lys Thr Val 1100 1105 1110

    Trp Lys Val Cys Ser Asn Val Glu Arg Phe Arg Trp Asp Lys Asn 1115 1120 1125

    Leu Asn Gln Asn Lys Gly Gly Tyr Thr His Tyr Thr Asn Ile Thr 1130 1135 1140

    Glu Asn Ile Gln Glu Leu Phe Thr Lys Tyr Gly Ile Asp Ile Thr 1145 1150 1155

    Lys Asp Leu Leu Thr Gln Ile Ser Thr Ile Asp Glu Lys Gln Asn 1160 1165 1170

    Thr Ser Phe Phe Arg Asp Phe Ile Phe Tyr Phe Asn Leu Ile Cys 1175 1180 1185

    Gln Ile Arg Asn Thr Asp Asp Ser Glu Ile Ala Lys Lys Asn Gly 1190 1195 1200

    Lys Asp Asp Phe Ile Leu Ser Pro Val Glu Pro Phe Phe Asp Ser 1205 1210 1215

    Arg Lys Asp Asn Gly Asn Lys Leu Pro Glu Asn Gly Asp Asp Asn 1220 1225 1230

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Ile Val Ile Leu Asn Lys 1235 1240 1245

    Ile Ser Gln Tyr Ser Glu Lys Asn Glu Asn Cys Glu Lys Met Lys 1250 1255 1260

    Trp Gly Asp Leu Tyr Val Ser Asn Ile Asp Trp Asp Asn Phe Val 1265 1270 1275

    Thr Gln Ala Asn Ala Arg His 1280 1285 <210> 1119 <211> 1247 <212> PRT <213> Unknown <220>

    <223> Description of Unknown: uncultured bacterium sequence <400> 1119

    Met Phe Lys Gly Asp Ala Phe Thr Gly Leu Tyr Glu Val Gln Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Val Pro Ile Gly Leu Thr Gln Ser Tyr Leu Glu 20 25 30

    Asn Asp Trp Val Ile Gln Lys Asp Lys Glu Val Glu Glu Asn Tyr Gly 35 40 45

    Lys Ile Lys Ala Tyr Phe Asp Leu Ile His Lys Glu Phe Val Arg Gln 50 55 60

    Ser Leu Glu Asn Ala Trp Leu Cys Gln Leu Asp Asp Phe Tyr Glu Lys 65 70 75 80

    Tyr Ile Glu Leu His Asn Ser Leu Glu Thr Arg Lys Asp Lys Asn Leu 85 90 95

    Ala Lys Gln Phe Glu Lys Val Met Lys Ser Leu Lys Lys Glu Phe Val 100 105 110

    Ser Phe Phe Asp Ala Lys Trp Asn Glu Trp Lys Gln Lys Phe Ser Phe 115 120 125

    Leu Lys Lys Trp Trp Ile Asp Val Leu Asn Glu Lys Glu Val Leu Asp 130 135 140

    Leu Met Ala Glu Phe Tyr Pro Asp Glu Lys Glu Leu Phe Asp Lys Phe 145 150 155 160

    Asp Lys Phe Phe Thr Tyr Phe Ser Asn Phe Lys Glu Ser Arg Lys Asn 165 170 175

    Phe Tyr Ala Asp Asp Gly Arg Ala Trp Ala Ile Ala Thr Arg Ala Ile 180 185 190

    Asp Glu Asn Leu Ile Thr Phe Ile Lys Asn Ile Glu Asp Phe Lys Lys 195 200 205

    Leu Asn Ser Ser Phe Arg Glu Phe Val Asn Asp Asn Phe Ser Glu Glu 210 215 220

    Asp Lys Gln Ile Phe Glu Ile Asp Phe Tyr Asn Asn Cys Leu Leu Gln 225 230 235 240

    Pro Trp Ile Asp Lys Tyr Asn Lys Ile Val Trp Trp Tyr Ser Leu Glu 245 250 255

    Asn Trp Glu Lys Val Gln Trp Leu Asn Glu Lys Ile Asn Asn Phe Lys 260 265 270

    Gln Asn Gln Asn Lys Ser Asn Ser Lys Asp Leu Lys Phe Pro Arg Met 275 280 285

    Lys Leu Leu Tyr Lys Gln Ile Leu Gly Asp Lys Glu Lys Lys Val Tyr 290 295 300

    Ile Asp Glu Ile Arg Asp Asp Lys Asn Leu Ile Asp Leu Ile Asp Asn 305 310 315 320

    Ser Lys Arg Arg Asn Gln Ile Lys Ile Asp Asn Ala Asn Asp Ile Ile 325 330 335

    Asn Asp Phe Ile Asn Asn Asn Ala Lys Phe Glu Leu Asp Lys Ile Tyr 340 345 350

    Leu Thr Arg Gln Ser Ile Asn Thr Ile Ser Ser Lys Tyr Phe Ser Ser 355 360 365

    Trp Asp Tyr Ile Arg Trp Tyr Phe Trp Thr Gly Glu Leu Gln Glu Phe 370 375 380

    Val Ser Phe Tyr Asp Leu Lys Glu Thr Phe Trp Lys Ile Glu Tyr Glu 385 390 395 400

    Thr Leu Glu Asn Ile Phe Lys Asp Cys Tyr Val Lys Gly Ile Asn Thr 405 410 415

    Glu Ser Gln Asn Asn Ile Val Phe Glu Thr Gln Gly Ile Tyr Glu Asn 420 425 430

    Phe Leu Asn Ile Phe Lys Phe Glu Phe Asn Gln Asn Ile Ser Gln Ile 435 440 445

    Ser Leu Leu Glu Trp Glu Leu Asp Lys Ile Gln Asn Glu Asp Ile Lys 450 455 460

    Lys Asn Glu Lys Gln Val Glu Val Ile Lys Asn Tyr Phe Asp Ser Val 465 470 475 480

    Met Ser Val Tyr Lys Met Thr Lys Tyr Phe Ser Leu Glu Lys Trp Lys 485 490 495

    Lys Arg Val Glu Leu Asp Thr Asp Asn Asn Phe Tyr Asn Asp Phe Asn 500 505 510

    Glu Tyr Leu Glu Gly Phe Glu Ile Trp Lys Asp Tyr Asn Leu Val Arg 515 520 525

    Asn Tyr Ile Thr Lys Lys Gln Val Asn Thr Asp Lys Ile Lys Leu Asn 530 535 540

    Phe Asp Asn Ser Gln Phe Leu Thr Trp Trp Asp Lys Asp Lys Glu Asn 545 550 555 560

    Glu Arg Leu Gly Ile Ile Leu Arg Arg Glu Trp Lys Tyr Tyr Leu Trp 565 570 575

    Ile Leu Lys Lys Trp Asn Thr Leu Asn Phe Gly Asp Tyr Leu Gln Lys 580 585 590

    Glu Trp Glu Ile Phe Tyr Glu Lys Met Asn Tyr Lys Gln Leu Asn Asn 595 600 605

    Val Tyr Arg Gln Leu Pro Arg Leu Leu Phe Pro Leu Thr Lys Lys Leu

    610

    615

    620

    Asn Glu Leu Lys Trp Asp Glu Leu Lys Lys Tyr Leu Ser Lys Tyr Ile 625 630 635 640

    Gln Asn Phe Trp Tyr Asn Glu Glu Ile Ala Gln Ile Lys Ile Glu Phe 645 650 655

    Asp Ile Phe Gln Glu Ser Lys Glu Lys Trp Glu Lys Phe Asp Ile Asp 660 665 670

    Lys Leu Arg Lys Leu Ile Glu Tyr Tyr Lys Lys Trp Val Leu Ala Leu 675 680 685

    Tyr Ser Asp Leu Tyr Asp Leu Glu Phe Ile Lys Tyr Lys Asn Tyr Asp 690 695 700

    Asp Leu Ser Ile Phe Tyr Ser Asp Val Glu Lys Lys Met Tyr Asn Leu 705 710 715 720

    Asn Phe Thr Lys Ile Asp Lys Ser Leu Ile Asp Gly Lys Val Lys Ser 725 730 735

    Trp Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Glu Ser 740 745 750

    Lys Lys Glu Trp Ser Thr Glu Asn Ile His Thr Lys Tyr Phe Lys Leu 755 760 765

    Leu Phe Asn Glu Lys Asn Leu Gln Asn Leu Val Val Lys Leu Ser Trp 770 775 780

    Trp Ala Asp Ile Phe Phe Arg Asp Lys Thr Glu Asn Leu Lys Phe Lys 785 790 795 800

    Lys Asp Lys Asn Gly Gln Glu Ile Leu Asp His Arg Arg Phe Ser Gln 805 810 815

    Asp Lys Ile Met Phe His Ile Ser Ile Thr Leu Asn Ala Asn Cys Trp 820 825 830

    Asp Lys Tyr Trp Phe Asn Gln Tyr Val Asn Glu Tyr Met Asn Lys Glu 835 840 845

    Arg Asp Ile Lys Ile Ile Trp Ile Asp Arg Trp Glu Lys His Leu Ala 850 855 860

    Tyr Tyr Cys Val Ile Asp Lys Ser Trp Lys Ile Phe Asn Asn Glu Ile 865 870 875 880

    Trp Thr Leu Asn Glu Leu Asn Trp Val Asn Tyr Leu Glu Lys Leu Glu 885 890 895

    Lys Ile Glu Ser Ser Arg Lys Asp Ser Arg Ile Ser Trp Trp Glu Ile 900 905 910

    Glu Asn Ile Lys Glu Leu Lys Asn Gly Tyr Ile Ser Gln Val Ile Asn 915 920 925

    Lys Leu Thr Glu Leu Ile Val Lys Tyr Asn Ala Ile Ile Val Phe Glu 930 935 940

    Asp Leu Asn Ile Trp Phe Lys Arg Trp Arg Gln Lys Ile Glu Lys Gln 945 950 955 960

    Ile Tyr Gln Lys Leu Glu Leu Ala Leu Ala Lys Lys Leu Asn Tyr Leu 965 970 975

    Thr Gln Lys Asp Lys Lys Asp Asp Glu Ile Leu Trp Asn Leu Lys Ala 980 985 990

    Leu Gln Leu Val Pro Lys Val Asn Asp Tyr Gln Asp Ile Trp Asn Tyr 995 1000 1005

    Lys Gln Ser Trp Ile Met Phe Tyr Val Arg Ala Asn Tyr Thr Ser 1010 1015 1020

    Val Thr Cys Pro Asn Cys Trp Leu Arg Lys Asn Leu Tyr Ile Ser 1025 1030 1035

    Asn Ser Ala Thr Lys Glu Asn Gln Lys Lys Ser Leu Asn Ser Ile 1040 1045 1050

    Ala Ile Lys Tyr Asn Asp Trp Lys Phe Ser Phe Ser Tyr Glu Ile 1055 1060 1065

    Asp Asp Lys Ser Trp Lys Gln Lys Gln Ser Leu Asn Lys Lys Lys 1070 1075 1080

    Phe Ile Val Tyr Ser Asp Ile Glu Arg Phe Val Tyr Ser Pro Leu 1085 1090 1095

    Glu Lys Leu Thr Lys Val Ile Asp Val Asn Lys Lys Leu Leu Glu 1100 1105 1110

    Leu Phe Arg Asp Phe Asn Leu Ser Leu Asp Ile Asn Lys Gln Ile 1115 1120 1125

    Gln Glu Lys Asp Leu Asp Ser Val Phe Phe Lys Ser Leu Thr His 1130 1135 1140

    Leu Phe Asn Leu Ile Leu Gln Leu Arg Asn Ser Asp Ser Lys Asp 1145 1150 1155

    Asn Lys Asp Tyr Ile Ser Cys Pro Ser Cys Tyr Tyr His Ser Asn 1160 1165 1170

    Asn Trp Leu Gln Trp Phe Glu Phe Asn Trp Asp Ala Asn Trp Ala 1175 1180 1185

    Tyr Asn Ile Ala Arg Lys Gly Ile Ile Leu Leu Asp Arg Ile Arg 1190 1195 1200

    Lys Asn Gln Glu Lys Pro Asp Leu Tyr Val Ser Asp Ile Asp Trp 1205 1210 1215

    Asp Asn Phe Val Gln Ser Asn Gln Phe Pro Asn Thr Ile Ile Pro 1220 1225 1230

    Ile Gln Asn Ile Glu Lys Gln Val Pro Leu Asn Ile Lys Ile 1235 1240 1245 <210> 1120 <211> 1219 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    candidate division WS6 bacterium sequence <400> 1120

    Met Lys Asn Val Phe Gly Gly Phe Thr Asn Leu Tyr Ser Leu Thr Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Thr Ser Lys Thr Gln Lys Leu Met 20 25 30

    Lys Arg Asn Asn Val Ile Gln Thr Asp Glu Glu Ile Asp Lys Leu Tyr 35 40 45

    His Asp Glu Met Lys Pro Ile Leu Asp Glu Ile His Arg Arg Phe Ile 50 55 60

    Asn Asp Ala Leu Ala Gln Lys Ile Phe Ile Ser Ala Ser Leu Asp Asn 65 70 75 80

    Phe Leu Lys Val Val Lys Asn Tyr Lys Val Glu Ser Ala Lys Lys Asn 85 90 95

    Ile Lys Gln Asn Gln Val Lys Leu Leu Gln Lys Glu Ile Thr Ile Lys 100 105 110

    Thr Leu Gly Leu Arg Arg Glu Val Val Ser Gly Phe Ile Thr Val Ser 115 120 125

    Lys Lys Trp Lys Asp Lys Tyr Val Gly Leu Gly Ile Lys Leu Lys Gly 130 135 140

    Asp Gly Tyr Lys Val Leu Thr Glu Gln Ala Val Leu Asp Ile Leu Lys 145 150 155 160

    Ile Glu Phe Pro Asn Lys Ala Lys Tyr Ile Asp Lys Phe Arg Gly Phe 165 170 175

    Trp Thr Tyr Phe Ser Gly Phe Asn Glu Asn Arg Lys Asn Tyr Tyr Ser 180 185 190

    Glu Glu Asp Lys Ala Thr Ser Ile Ala Asn Arg Ile Val Asn Glu Asn 195 200 205

    Leu Ser Arg Tyr Ile Asp Asn Ile Ile Ala Phe Glu Glu Ile Leu Gln 210 215 220

    Lys Ile Pro Asn Leu Lys Lys Phe Lys Gln Asp Leu Asp Ile Thr Ser 225 230 235 240

    Tyr Asn Tyr Tyr Leu Asn Gln Ala Gly Ile Asp Lys Tyr Asn Lys Ile 245 250 255

    Ile Gly Gly Tyr Ile Val Asp Lys Asp Lys Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Lys Val Asn Leu Tyr Thr Gln Gln Thr Lys Lys Lys Leu Pro Lys 275 280 285

    Leu Lys Phe Leu Phe Lys Gln Ile Gly Ser Glu Arg Lys Gly Phe Gly 290 295 300

    Ile Phe Glu Ile Lys Glu Gly Lys Glu Trp Glu Gln Leu Gly Asp Leu 305 310 315 320

    Phe Lys Leu Gln Arg Thr Lys Ile Asn Ser Asn Gly Arg Glu Lys Gly 325 330 335

    Leu Phe Asp Ser Leu Arg Thr Met Tyr Arg Glu Phe Phe Asp Glu Ile 340 345 350

    Lys Arg Asp Ser Asn Ser Gln Ala Arg Tyr Ser Leu Asp Lys Ile Tyr 355 360 365

    Phe Asn Lys Ala Ser Val Asn Thr Ile Ser Asn Ser Trp Phe Thr Asn 370 375 380

    Trp Asn Lys Phe Ala Glu Leu Leu Asn Ile Lys Glu Asp Lys Lys Asn

    385

    390

    395

    400

    Gly Glu Lys Lys Ile Pro Glu Gln Ile Ser Ile Glu Asp Ile Lys Asp 405 410 415

    Ser Leu Ser Ile Ile Pro Lys Glu Asn Leu Glu Glu Leu Phe Lys Leu 420 425 430

    Thr Asn Arg Glu Lys His Asp Arg Thr Arg Phe Phe Gly Ser Asn Ala 435 440 445

    Trp Val Thr Phe Leu Asn Ile Trp Gln Asn Glu Ile Glu Glu Ser Phe 450 455 460

    Asn Lys Leu Glu Glu Lys Glu Lys Asp Phe Lys Lys Asn Ala Ala Ile 465 470 475 480

    Lys Phe Gln Lys Asn Asn Leu Val Gln Lys Asn Tyr Ile Lys Glu Val 485 490 495

    Cys Asp Arg Met Leu Ala Ile Glu Arg Met Ala Lys Tyr His Leu Pro 500 505 510

    Lys Asp Ser Asn Leu Ser Arg Glu Glu Asp Phe Tyr Trp Ile Ile Asp 515 520 525

    Asn Leu Ser Glu Gln Arg Glu Ile Tyr Lys Tyr Tyr Asn Ala Phe Arg 530 535 540

    Asn Tyr Ile Ser Lys Lys Pro Tyr Asn Lys Ser Lys Met Lys Leu Asn 545 550 555 560

    Phe Glu Asn Gly Asn Leu Leu Gly Gly Trp Ser Asp Gly Gln Glu Arg 565 570 575

    Asn Lys Ala Gly Val Ile Leu Arg Asn Gly Asn Lys Tyr Tyr Leu Gly 580 585 590

    Val Leu Ile Asn Arg Gly Ile Phe Arg Thr Asp Lys Ile Asn Asn Glu 595 600 605

    Ile Tyr Arg Thr Gly Ser Ser Lys Trp Glu Arg Leu Ile Leu Ser Asn 610 615 620

    Leu Lys Phe Gln Thr Leu Ala Gly Lys Gly Phe Leu Gly Lys His Gly 625 630 635 640

    Val Ser Tyr Gly Asn Met Asn Pro Glu Lys Ser Val Pro Ser Leu Gln 645 650 655

    Lys Phe Ile Arg Glu Asn Tyr Leu Lys Lys Tyr Pro Gln Leu Thr Glu 660 665 670

    Val Ser Asn Thr Lys Phe Leu Ser Lys Lys Asp Phe Asp Ala Ala Ile 675 680 685

    Lys Glu Ala Leu Lys Glu Cys Phe Thr Met Asn Phe Ile Asn Ile Ala 690 695 700

    Glu Asn Lys Leu Leu Glu Ala Glu Asp Lys Gly Asp Leu Tyr Leu Phe 705 710 715 720

    Glu Ile Thr Asn Lys Asp Phe Ser Gly Lys Lys Ser Lys Gly Tyr Glu 725 730 735

    Lys Gly Lys Asp Asn Ile His Thr Ile Tyr Trp Lys Tyr Leu Phe Ser 740 745 750

    Glu Ser Asn Cys Lys Ser Pro Ile Ile Gly Leu Asn Gly Gly Ala Glu 755 760 765

    Ile Phe Phe Arg Glu Gly Gln Lys Asp Lys Leu His Thr Lys Leu Asp 770 775 780

    Lys Lys Gly Lys Lys Val Phe Asp Ala Lys Arg Tyr Ser Glu Asp Lys 785 790 795 800

    Leu Phe Phe His Val Ser Ile Thr Ile Asn Tyr Gly Lys Pro Lys Asn 805 810 815

    Ile Lys Phe Arg Asp Ile Ile Asn Gln Leu Ile Thr Ser Met Asn Val 820 825 830

    Asn Ile Ile Gly Ile Asp Arg Gly Glu Lys His Leu Leu Tyr Tyr Ser 835 840 845

    Val Ile Asp Ser Asn Gly Ile Ile Leu Lys Gln Gly Ser Leu Asn Lys 850 855 860

    Ile Arg Val Gly Asp Lys Glu Val Asp Phe Asn Lys Lys Leu Thr Glu 865 870 875 880

    Arg Ala Asn Glu Met Lys Lys Ala Arg Gln Ser Trp Glu Gln Ile Gly 885 890 895

    Asn Ile Lys Asn Phe Lys Glu Gly Tyr Leu Ser Gln Ala Ile His Glu 900 905 910

    Ile Tyr Gln Leu Met Ile Lys Tyr Asn Ala Ile Ile Val Leu Glu Asp 915 920 925

    Leu Asn Thr Glu Phe Lys Ala Lys Arg Leu Ser Lys Val Glu Lys Ser 930 935 940

    Val Tyr Lys Lys Phe Glu Leu Lys Leu Ala Arg Lys Leu Asn His Leu 945 950 955 960

    Ile Leu Lys Asp Arg Asn Thr Asn Glu Ile Gly Gly Val Leu Lys Ala 965 970 975

    Tyr Gln Leu Thr Pro Thr Ile Gly Gly Gly Asp Val Ser Lys Phe Glu 980 985 990

    Lys Ala Lys Gln Trp Gly Met Met Phe Tyr Val Arg Ala Asn Tyr Thr 995 1000 1005

    Ser Thr Thr Asp Pro Val Thr Gly Trp Arg Lys His Leu Tyr Ile 1010 1015 1020

    Ser Asn Phe Ser Asn Asn Ser Val Ile Lys Ser Phe Phe Asp Pro 1025 1030 1035

    Thr Asn Arg Asp Thr Gly Ile Glu Ile Phe Tyr Ser Gly Lys Tyr 1040 1045 1050

    Arg Ser Trp Gly Phe Arg Tyr Val Gln Lys Glu Thr Gly Lys Lys 1055 1060 1065

    Trp Glu Leu Phe Ala Thr Lys Glu Leu Glu Arg Phe Lys Tyr Asn 1070 1075 1080

    Gln Thr Thr Lys Leu Cys Glu Lys Ile Asn Leu Tyr Asp Lys Phe 1085 1090 1095

    Glu Glu Leu Phe Lys Gly Ile Asp Lys Ser Ala Asp Ile Tyr Ser

    1100 1105 1110

    Gln Leu Cys Asn Val Leu Asp Phe Arg Trp Lys Ser Leu Val Tyr 1115 1120 1125

    Leu Trp Asn Leu Leu Asn Gln Ile Arg Asn Val Asp Lys Asn Ala 1130 1135 1140

    Glu Gly Asn Lys Asn Asp Phe Ile Gln Ser Pro Val Tyr Pro Phe 1145 1150 1155

    Phe Asp Ser Arg Lys Thr Asp Gly Lys Thr Glu Pro Ile Asn Gly 1160 1165 1170

    Asp Ala Asn Gly Ala Leu Asn Ile Ala Arg Lys Gly Leu Met Leu 1175 1180 1185

    Val Glu Arg Ile Lys Asn Asn Pro Glu Lys Tyr Glu Gln Leu Ile 1190 1195 1200

    Arg Asp Thr Glu Trp Asp Ala Trp Ile Gln Asn Phe Asn Lys Val 1205 1210 1215

    Asn <210> 1121 <211> 1295 <212> PRT <213> Francisella tularensis <400> 1121

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr

    1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu

    195

    200

    205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Val Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Asp Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Arg Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Asn Pro Gln 690 695 700

    Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe Ile Asp Phe Tyr Lys 705 710 715 720

    Glu Ser Ile Ser Lys His Pro Glu Trp Lys Asp Phe Gly Phe Arg Phe 725 730 735

    Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu Val 740 745 750

    Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn Ile Ser Glu Ser Tyr 755 760 765

    Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr 770 775 780

    Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr 785 790 795 800

    Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val 805 810 815

    Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr Arg Lys Lys Ser Ile 820 825 830

    Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala Ile Ala Asn Lys Asn 835 840 845

    Lys Asp Asn Pro Lys Lys Glu Ser Phe Phe Glu Tyr Asp Leu Ile Lys 850 855 860

    Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr 865 870 875 880

    Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe Asn Asp Glu Ile Asn 885 890 895

    Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His Ile Leu Ser Ile Asp 900 905 910

    Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu Val Asp Gly Lys Gly

    915

    920

    925

    Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile Gly Asn Asp Arg Met 930 935 940

    Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile Glu Lys Asp Arg Asp 945 950 955 960

    Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys 965 970 975

    Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile Ala Lys Leu Val Ile 980 985 990

    Glu His Asn Ala Ile Val Val Phe Glu Asp Leu Asn Phe Gly Phe Lys 995 1000 1005

    Arg Gly Arg Phe Lys Val Glu Lys Gln Val Tyr Gln Lys Leu Glu 1010 1015 1020

    Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu Val Phe Lys Asp Asn 1025 1030 1035

    Glu Phe Asp Lys Thr Gly Gly Val Leu Arg Ala Tyr Gln Leu Thr 1040 1045 1050

    Ala Pro Phe Glu Thr Phe Lys Lys Met Gly Lys Gln Thr Gly Ile 1055 1060 1065

    Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser Lys Ile Cys Pro Val 1070 1075 1080

    Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys Tyr Glu Ser Val Ser 1085 1090 1095

    Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp Lys Ile Cys Tyr Asn 1100 1105 1110

    Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe Asp Tyr Lys Asn Phe 1115 1120 1125

    Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser Phe Gly 1130 1135 1140

    Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp Lys Asn His Asn Trp 1145 1150 1155

    Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu Leu Glu Lys Leu Leu 1160 1165 1170

    Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala 1175 1180 1185

    Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe Phe Ala Lys Leu Thr 1190 1195 1200

    Ser Ile Leu Asn Thr Ile Leu Gln Met Arg Asn Ser Lys Thr Gly 1205 1210 1215

    Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val Ala Asp Val Asn Gly 1220 1225 1230

    Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp 1235 1240 1245

    Ala Asp Ala Asn Gly Ala Tyr His Ile Gly Leu Lys Gly Leu Met 1250 1255 1260

    Leu Leu Asp Arg Ile Lys Asn Asn Gln Glu Gly Lys Lys Leu Asn 1265 1270 1275

    Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu Phe Val Gln Asn Arg 1280 1285 1290

    Asn Asn 1295 <210> 1122 <211> 1300 <212> PRT <213> Francisella tularensis <400> 1122

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asp Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Val Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Asp Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Leu Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Glu Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Arg Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys

    645

    650

    655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Asn Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Glu Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu His Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Asp Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 1123 <211> 1300 <212> PRT <213> Francisella tularensis <400> 1123

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr

    1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln

    370

    375

    380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 945 950 955 960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys

    1085

    1090

    1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 1124 <211> 1307 <212> PRT <213> Francisella tularensis <400> 1124

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Lys Tyr

    100

    105

    110

    Ile Asn Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu 225 230 235 240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Val Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Asp Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ser 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Glu Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Arg Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Ser Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Ser Ala Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Ile Met Asp Lys Lys His Asn Lys Ile 625 630 635 640

    Phe Ser Asp Lys Ala Ile Glu Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Gln Ile Ala Asp Ala Ser Lys Asp Ile Gln Asn Leu 660 665 670

    Met Ile Ile Asp Gly Lys Thr Val Cys Lys Lys Gly Arg Lys Asp Arg 675 680 685

    Asn Gly Val Asn Arg Gln Leu Leu Ser Leu Lys Arg Lys His Leu Pro 690 695 700

    Glu Asn Ile Tyr Arg Ile Lys Glu Thr Lys Ser Tyr Leu Lys Asn Glu 705 710 715 720

    Ala Arg Phe Ser Arg Lys Asp Leu Tyr Asp Phe Ile Asp Tyr Tyr Lys 725 730 735

    Asp Arg Leu Asp Tyr Tyr Asp Phe Glu Phe Glu Leu Lys Pro Ser Asn 740 745 750

    Glu Tyr Ser Asp Phe Asn Asp Phe Thr Asn His Ile Gly Ser Gln Gly 755 760 765

    Tyr Lys Leu Thr Phe Glu Asn Ile Ser Gln Asp Tyr Ile Asn Ser Leu 770 775 780

    Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Ser Lys Asp Phe 785 790 795 800

    Ser Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys 805 810 815

    Ala Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn

    820

    825

    830

    Gly Glu Ala Glu Leu Phe Tyr Arg Lys Gln Ser Ile Pro Lys Lys Ile 835 840 845

    Thr His Pro Ala Lys Glu Thr Ile Ala Asn Lys Asn Lys Asp Asn Pro 850 855 860

    Lys Lys Glu Ser Val Phe Glu Tyr Asp Leu Ile Lys Asp Lys Arg Phe 865 870 875 880

    Thr Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys 885 890 895

    Ser Ser Gly Ala Asn Lys Phe Asn Asp Glu Ile Asn Leu Leu Leu Lys 900 905 910

    Glu Lys Ala Asn Asp Val His Ile Leu Ser Ile Asp Arg Gly Glu Arg 915 920 925

    His Leu Ala Tyr Tyr Thr Leu Val Asp Gly Lys Gly Asn Ile Ile Lys 930 935 940

    Gln Asp Asn Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr 945 950 955 960

    His Asp Lys Leu Ala Ala Ile Glu Lys Asp Arg Asp Ser Ala Arg Lys 965 970 975

    Asp Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu 980 985 990

    Ser Gln Val Val His Glu Ile Ala Lys Leu Val Ile Glu Tyr Asn Ala 995 1000 1005

    Ile Val Val Phe Glu Asp Leu Asn Phe Gly Phe Lys Arg Gly Arg 1010 1015 1020

    Phe Lys Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu 1025 1030 1035

    Ile Glu Lys Leu Asn Tyr Leu Val Phe Lys Asp Asn Glu Phe Asp 1040 1045 1050

    Lys Thr Gly Gly Val Leu Arg Ala Tyr Gln Leu Thr Ala Pro Phe 1055 1060 1065

    Glu Thr Phe Lys Lys Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr 1070 1075 1080

    Val Pro Ala Gly Phe Thr Ser Lys Ile Cys Pro Val Thr Gly Phe 1085 1090 1095

    Val Asn Gln Leu Tyr Pro Lys Tyr Glu Ser Val Ser Lys Ser Gln 1100 1105 1110

    Glu Phe Phe Ser Lys Phe Asp Lys Ile Cys Tyr Asn Leu Asp Lys 1115 1120 1125

    Gly Tyr Phe Glu Phe Ser Phe Asp Tyr Lys Asn Phe Gly Asp Lys 1130 1135 1140

    Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser Phe Gly Ser Arg Leu 1145 1150 1155

    Ile Asn Phe Arg Asn Ser Asp Lys Asn His Asn Trp Asp Thr Arg 1160 1165 1170

    Glu Val Tyr Pro Thr Lys Glu Leu Glu Lys Leu Leu Lys Asp Tyr 1175 1180 1185

    Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala Ile Cys 1190 1195 1200

    Gly Glu Ser Asp Lys Lys Phe Phe Ala Lys Leu Thr Ser Val Leu 1205 1210 1215

    Asn Thr Ile Leu Gln Met Arg Asn Ser Lys Thr Gly Thr Glu Leu 1220 1225 1230

    Asp Tyr Leu Ile Ser Pro Val Ala Asp Val Asn Gly Asn Phe Phe 1235 1240 1245

    Asp Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala 1250 1255 1260

    Asn Gly Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Asp 1265 1270 1275

    Arg Ile Lys Asn Asn Gln Glu Gly Lys Lys Leu Asn Leu Val Ile 1280 1285 1290

    Lys Asn Glu Glu Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn 1295 1300 1305 <210> 1125 <211> 1323 <212> PRT <213> Prevotella disiens <400> 1125

    Met Glu Asn Tyr Gln Glu Phe Thr Asn Leu Phe Gln Leu Asn Lys Thr

    1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Cys Glu Leu Leu Glu 20 25 30

    Glu Gly Lys Ile Phe Ala Ser Gly Ser Phe Leu Glu Lys Asp Lys Val 35 40 45

    Arg Ala Asp Asn Val Ser Tyr Val Lys Lys Glu Ile Asp Lys Lys His 50 55 60

    Lys Ile Phe Ile Glu Glu Thr Leu Ser Ser Phe Ser Ile Ser Asn Asp 65 70 75 80

    Leu Leu Lys Gln Tyr Phe Asp Cys Tyr Asn Glu Leu Lys Ala Phe Lys 85 90 95

    Lys Asp Cys Lys Ser Asp Glu Glu Glu Val Lys Lys Thr Ala Leu Arg 100 105 110

    Asn Lys Cys Thr Ser Ile Gln Arg Ala Met Arg Glu Ala Ile Ser Gln 115 120 125

    Ala Phe Leu Lys Ser Pro Gln Lys Lys Leu Leu Ala Ile Lys Asn Leu 130 135 140

    Ile Glu Asn Val Phe Lys Ala Asp Glu Asn Val Gln His Phe Ser Glu 145 150 155 160

    Phe Thr Ser Tyr Phe Ser Gly Phe Glu Thr Asn Arg Glu Asn Phe Tyr 165 170 175

    Ser Asp Glu Glu Lys Ser Thr Ser Ile Ala Tyr Arg Leu Val His Asp 180 185 190

    Asn Leu Pro Ile Phe Ile Lys Asn Ile Tyr Ile Phe Glu Lys Leu Lys 195 200 205

    Glu Gln Phe Asp Ala Lys Thr Leu Ser Glu Ile Phe Glu Asn Tyr Lys 210 215 220

    Leu Tyr Val Ala Gly Ser Ser Leu Asp Glu Val Phe Ser Leu Glu Tyr 225 230 235 240

    Phe Asn Asn Thr Leu Thr Gln Lys Gly Ile Asp Asn Tyr Asn Ala Val 245 250 255

    Ile Gly Lys Ile Val Lys Glu Asp Lys Gln Glu Ile Gln Gly Leu Asn 260 265 270

    Glu His Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Arg Arg Leu Pro 275 280 285

    Phe Phe Ile Ser Leu Lys Lys Gln Ile Leu Ser Asp Arg Glu Ala Leu 290 295 300

    Ser Trp Leu Pro Asp Met Phe Lys Asn Asp Ser Glu Val Ile Lys Ala 305 310 315 320

    Leu Lys Gly Phe Tyr Ile Glu Asp Gly Phe Glu Asn Asn Val Leu Thr 325 330 335

    Pro Leu Ala Thr Leu Leu Ser Ser Leu Asp Lys Tyr Asn Leu Asn Gly 340 345 350

    Ile Phe Ile Arg Asn Asn Glu Ala Leu Ser Ser Leu Ser Gln Asn Val 355 360 365

    Tyr Arg Asn Phe Ser Ile Asp Glu Ala Ile Asp Ala Asn Ala Glu Leu 370 375 380

    Gln Thr Phe Asn Asn Tyr Glu Leu Ile Ala Asn Ala Leu Arg Ala Lys 385 390 395 400

    Ile Lys Lys Glu Thr Lys Gln Gly Arg Lys Ser Phe Glu Lys Tyr Glu 405 410 415

    Glu Tyr Ile Asp Lys Lys Val Lys Ala Ile Asp Ser Leu Ser Ile Gln 420 425 430

    Glu Ile Asn Glu Leu Val Glu Asn Tyr Val Ser Glu Phe Asn Ser Asn 435 440 445

    Ser Gly Asn Met Pro Arg Lys Val Glu Asp Tyr Phe Ser Leu Met Arg 450 455 460

    Lys Gly Asp Phe Gly Ser Asn Asp Leu Ile Glu Asn Ile Lys Thr Lys 465 470 475 480

    Leu Ser Ala Ala Glu Lys Leu Leu Gly Thr Lys Tyr Gln Glu Thr Ala 485 490 495

    Lys Asp Ile Phe Lys Lys Asp Glu Asn Ser Lys Leu Ile Lys Glu Leu 500 505 510

    Leu Asp Ala Thr Lys Gln Phe Gln His Phe Ile Lys Pro Leu Leu Gly 515 520 525

    Thr Gly Glu Glu Ala Asp Arg Asp Leu Val Phe Tyr Gly Asp Phe Leu 530 535 540

    Pro Leu Tyr Glu Lys Phe Glu Glu Leu Thr Leu Leu Tyr Asn Lys Val

    545

    550

    555

    560

    Arg Asn Arg Leu Thr Gln Lys Pro Tyr Ser Lys Asp Lys Ile Arg Leu 565 570 575

    Cys Phe Asn Lys Pro Lys Leu Met Thr Gly Trp Val Asp Ser Lys Thr 580 585 590

    Glu Lys Ser Asp Asn Gly Thr Gln Tyr Gly Gly Tyr Leu Phe Arg Lys 595 600 605

    Lys Asn Glu Ile Gly Glu Tyr Asp Tyr Phe Leu Gly Ile Ser Ser Lys 610 615 620

    Ala Gln Leu Phe Arg Lys Asn Glu Ala Val Ile Gly Asp Tyr Glu Arg 625 630 635 640

    Leu Asp Tyr Tyr Gln Pro Lys Ala Asn Thr Ile Tyr Gly Ser Ala Tyr 645 650 655

    Glu Gly Glu Asn Ser Tyr Lys Glu Asp Lys Lys Arg Leu Asn Lys Val 660 665 670

    Ile Ile Ala Tyr Ile Glu Gln Ile Lys Gln Thr Asn Ile Lys Lys Ser 675 680 685

    Ile Ile Glu Ser Ile Ser Lys Tyr Pro Asn Ile Ser Asp Asp Asp Lys 690 695 700

    Val Thr Pro Ser Ser Leu Leu Glu Lys Ile Lys Lys Val Ser Ile Asp 705 710 715 720

    Ser Tyr Asn Gly Ile Leu Ser Phe Lys Ser Phe Gln Ser Val Asn Lys 725 730 735

    Glu Val Ile Asp Asn Leu Leu Lys Thr Ile Ser Pro Leu Lys Asn Lys 740 745 750

    Ala Glu Phe Leu Asp Leu Ile Asn Lys Asp Tyr Gln Ile Phe Thr Glu 755 760 765

    Val Gln Ala Val Ile Asp Glu Ile Cys Lys Gln Lys Thr Phe Ile Tyr 770 775 780

    Phe Pro Ile Ser Asn Val Glu Leu Glu Lys Glu Met Gly Asp Lys Asp 785 790 795 800

    Lys Pro Leu Cys Leu Phe Gln Ile Ser Asn Lys Asp Leu Ser Phe Ala 805 810 815

    Lys Thr Phe Ser Ala Asn Leu Arg Lys Lys Arg Gly Ala Glu Asn Leu 820 825 830

    His Thr Met Leu Phe Lys Ala Leu Met Glu Gly Asn Gln Asp Asn Leu 835 840 845

    Asp Leu Gly Ser Gly Ala Ile Phe Tyr Arg Ala Lys Ser Leu Asp Gly 850 855 860

    Asn Lys Pro Thr His Pro Ala Asn Glu Ala Ile Lys Cys Arg Asn Val 865 870 875 880

    Ala Asn Lys Asp Lys Val Ser Leu Phe Thr Tyr Asp Ile Tyr Lys Asn 885 890 895

    Arg Arg Tyr Met Glu Asn Lys Phe Leu Phe His Leu Ser Ile Val Gln 900 905 910

    Asn Tyr Lys Ala Ala Asn Asp Ser Ala Gln Leu Asn Ser Ser Ala Thr 915 920 925

    Glu Tyr Ile Arg Lys Ala Asp Asp Leu His Ile Ile Gly Ile Asp Arg 930 935 940

    Gly Glu Arg Asn Leu Leu Tyr Tyr Ser Val Ile Asp Met Lys Gly Asn 945 950 955 960

    Ile Val Glu Gln Asp Ser Leu Asn Ile Ile Arg Asn Asn Asp Leu Glu 965 970 975

    Thr Asp Tyr His Asp Leu Leu Asp Lys Arg Glu Lys Glu Arg Lys Ala 980 985 990

    Asn Arg Gln Asn Trp Glu Ala Val Glu Gly Ile Lys Asp Leu Lys Lys 995 1000 1005

    Gly Tyr Leu Ser Gln Ala Val His Gln Ile Ala Gln Leu Met Leu 1010 1015 1020

    Lys Tyr Asn Ala Ile Ile Ala Leu Glu Asp Leu Gly Gln Met Phe 1025 1030 1035

    Val Thr Arg Gly Gln Lys Ile Glu Lys Ala Val Tyr Gln Gln Phe 1040 1045 1050

    Glu Lys Ser Leu Val Asp Lys Leu Ser Tyr Leu Val Asp Lys Lys 1055 1060 1065

    Arg Pro Tyr Asn Glu Leu Gly Gly Ile Leu Lys Ala Tyr Gln Leu 1070 1075 1080

    Ala Ser Ser Ile Thr Lys Asn Asn Ser Asp Lys Gln Asn Gly Phe 1085 1090 1095

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val 1100 1105 1110

    Thr Gly Phe Thr Asp Leu Leu Arg Pro Lys Ala Met Thr Ile Lys 1115 1120 1125

    Glu Ala Gln Asp Phe Phe Gly Ala Phe Asp Asn Ile Ser Tyr Asn 1130 1135 1140

    Asp Lys Gly Tyr Phe Glu Phe Glu Thr Asn Tyr Asp Lys Phe Lys 1145 1150 1155

    Ile Arg Met Lys Ser Ala Gln Thr Arg Trp Thr Ile Cys Thr Phe 1160 1165 1170

    Gly Asn Arg Ile Lys Arg Lys Lys Asp Lys Asn Tyr Trp Asn Tyr 1175 1180 1185

    Glu Glu Val Glu Leu Thr Glu Glu Phe Lys Lys Leu Phe Lys Asp 1190 1195 1200

    Ser Asn Ile Asp Tyr Glu Asn Cys Asn Leu Lys Glu Glu Ile Gln 1205 1210 1215

    Asn Lys Asp Asn Arg Lys Phe Phe Asp Asp Leu Ile Lys Leu Leu 1220 1225 1230

    Gln Leu Thr Leu Gln Met Arg Asn Ser Asp Asp Lys Gly Asn Asp 1235 1240 1245

    Tyr Ile Ile Ser Pro Val Ala Asn Ala Glu Gly Gln Phe Phe Asp

    1250

    1255

    1260

    Ser Arg Asn Gly Asp Lys Lys Leu Pro Leu Asp Ala Asp Ala Asn 1265 1270 1275

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Asn Ile Arg Gln 1280 1285 1290

    Ile Lys Gln Thr Lys Asn Asp Lys Lys Leu Asn Leu Ser Ile Ser 1295 1300 1305

    Ser Thr Glu Trp Leu Asp Phe Val Arg Glu Lys Pro Tyr Leu Lys 1310 1315 1320 <210> 1126 <211> 1323 <212> PRT <213> Prevotella disiens <400> 1126

    Met Glu Asn Tyr Gln Glu Phe Thr Asn Leu Phe Gln Leu Asn Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Cys Glu Leu Leu Glu 20 25 30

    Glu Gly Lys Ile Phe Ala Ser Gly Ser Phe Leu Glu Lys Asp Lys Val 35 40 45

    Arg Ala Asp Asn Val Ser Tyr Val Lys Lys Glu Ile Asp Lys Lys His 50 55 60

    Lys Ile Phe Ile Glu Glu Thr Leu Ser Ser Phe Ser Ile Ser Asn Asp 65 70 75 80

    Leu Leu Lys Gln Tyr Phe Asp Cys Tyr Asn Glu Leu Lys Ala Phe Lys 85 90 95

    Lys Asp Cys Lys Ser Asp Glu Glu Glu Val Lys Lys Thr Ala Leu Arg 100 105 110

    Asn Lys Cys Thr Ser Ile Gln Arg Ala Met Arg Glu Ala Ile Ser Gln 115 120 125

    Ala Phe Leu Lys Ser Pro Gln Lys Lys Leu Leu Ala Ile Lys Asn Leu 130 135 140

    Ile Glu Asn Val Phe Lys Ala Asp Glu Asn Val Gln His Phe Ser Glu 145 150 155 160

    Phe Thr Ser Tyr Phe Ser Gly Phe Glu Thr Asn Arg Glu Asn Phe Tyr 165 170 175

    Ser Asp Glu Glu Lys Ser Thr Ser Ile Ala Tyr Arg Leu Val His Asp 180 185 190

    Asn Leu Pro Ile Phe Ile Lys Asn Ile Tyr Ile Phe Glu Lys Leu Lys 195 200 205

    Glu Gln Phe Asp Ala Lys Thr Leu Ser Glu Ile Phe Glu Asn Tyr Lys 210 215 220

    Leu Tyr Val Ala Gly Ser Ser Leu Asp Glu Val Phe Ser Leu Glu Tyr 225 230 235 240

    Phe Asn Asn Thr Leu Thr Gln Lys Gly Ile Asp Asn Tyr Asn Ala Val 245 250 255

    Ile Gly Lys Ile Val Lys Glu Asp Lys Gln Glu Ile Gln Gly Leu Asn

    260

    265

    270

    Glu His Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Arg Arg Leu Pro 275 280 285

    Phe Phe Ile Ser Leu Lys Lys Gln Ile Leu Ser Asp Arg Glu Ala Leu 290 295 300

    Ser Trp Leu Pro Asp Met Phe Lys Asn Asp Ser Glu Val Ile Lys Ala 305 310 315 320

    Leu Lys Gly Phe Tyr Ile Glu Asp Gly Phe Glu Asn Asn Val Leu Thr 325 330 335

    Pro Leu Ala Thr Leu Leu Ser Ser Leu Asp Lys Tyr Asn Leu Asn Gly 340 345 350

    Ile Phe Ile Arg Asn Asn Glu Ala Leu Ser Ser Leu Ser Gln Asn Val 355 360 365

    Tyr Arg Asn Phe Ser Ile Asp Glu Ala Ile Asp Ala Asn Ala Glu Leu 370 375 380

    Gln Thr Phe Asn Asn Tyr Glu Leu Ile Ala Asn Ala Leu Arg Ala Lys 385 390 395 400

    Ile Lys Lys Glu Thr Lys Gln Gly Arg Lys Ser Phe Glu Lys Tyr Glu 405 410 415

    Glu Tyr Ile Asp Lys Lys Val Lys Ala Ile Asp Ser Leu Ser Ile Gln 420 425 430

    Glu Ile Asn Glu Leu Val Glu Asn Tyr Val Ser Glu Phe Asn Ser Asn 435 440 445

    Ser Gly Asn Met Pro Arg Lys Val Glu Asp Tyr Phe Ser Leu Met Arg 450 455 460

    Lys Gly Asp Phe Gly Ser Asn Asp Leu Ile Glu Asn Ile Lys Thr Lys 465 470 475 480

    Leu Ser Ala Ala Glu Lys Leu Leu Gly Thr Lys Tyr Gln Glu Thr Ala 485 490 495

    Lys Asp Ile Phe Lys Lys Asp Glu Asn Ser Lys Leu Ile Lys Glu Leu 500 505 510

    Leu Asp Ala Thr Lys Gln Phe Gln His Phe Ile Lys Pro Leu Leu Gly 515 520 525

    Thr Gly Glu Glu Ala Asp Arg Asp Leu Val Phe Tyr Gly Asp Phe Leu 530 535 540

    Pro Leu Tyr Glu Lys Phe Glu Glu Leu Thr Leu Leu Tyr Asn Lys Val 545 550 555 560

    Arg Asn Arg Leu Thr Gln Lys Pro Tyr Ser Lys Asp Lys Ile Arg Leu 565 570 575

    Cys Phe Asn Lys Pro Lys Leu Met Thr Gly Trp Val Asp Ser Lys Thr 580 585 590

    Glu Lys Ser Asp Asn Gly Thr Gln Tyr Gly Gly Tyr Leu Phe Arg Lys 595 600 605

    Lys Asn Glu Ile Gly Glu Tyr Asp Tyr Phe Leu Gly Ile Ser Ser Lys 610 615 620

    Ala Gln Leu Phe Arg Lys Asn Glu Ala Val Ile Gly Asp Tyr Glu Arg 625 630 635 640

    Leu Asp Tyr Tyr Gln Pro Lys Ala Asn Thr Ile Tyr Gly Ser Ala Tyr 645 650 655

    Glu Gly Glu Asn Ser Tyr Lys Glu Asp Lys Lys Arg Leu Asn Lys Val 660 665 670

    Ile Ile Ala Tyr Ile Glu Gln Ile Lys Gln Thr Asn Ile Lys Lys Ser 675 680 685

    Ile Ile Glu Ser Ile Ser Lys Tyr Pro Asn Ile Ser Asp Asp Asp Lys 690 695 700

    Val Thr Pro Ser Ser Leu Leu Glu Lys Ile Lys Lys Val Ser Ile Asp 705 710 715 720

    Ser Tyr Asn Gly Ile Leu Ser Phe Lys Ser Phe Gln Ser Val Asn Lys 725 730 735

    Glu Val Ile Asp Asn Leu Leu Lys Thr Ile Ser Pro Leu Lys Asn Lys 740 745 750

    Ala Glu Phe Leu Asp Leu Ile Asn Lys Asp Tyr Gln Ile Phe Thr Glu 755 760 765

    Val Gln Ala Val Ile Asp Glu Ile Cys Lys Gln Lys Thr Phe Ile Tyr 770 775 780

    Phe Pro Ile Ser Asn Val Glu Leu Glu Lys Glu Met Gly Asp Lys Asp 785 790 795 800

    Lys Pro Leu Cys Leu Phe Gln Ile Ser Asn Lys Asp Leu Ser Phe Ala 805 810 815

    Lys Thr Phe Ser Ala Asn Leu Arg Lys Lys Arg Gly Ala Glu Asn Leu 820 825 830

    His Thr Met Leu Phe Lys Ala Leu Met Glu Gly Asn Gln Asp Asn Leu 835 840 845

    Asp Leu Gly Ser Gly Ala Ile Phe Tyr Arg Ala Lys Ser Leu Asp Gly 850 855 860

    Asn Lys Pro Thr His Pro Ala Asn Glu Ala Ile Lys Cys Arg Asn Val 865 870 875 880

    Ala Asn Lys Asp Lys Val Ser Leu Phe Thr Tyr Asp Ile Tyr Lys Asn 885 890 895

    Arg Arg Tyr Met Glu Asn Lys Phe Leu Phe His Leu Ser Ile Val Gln 900 905 910

    Asn Tyr Lys Ala Ala Asn Asp Ser Ala Gln Leu Asn Ser Ser Ala Thr 915 920 925

    Glu Tyr Ile Arg Lys Ala Asp Asp Leu His Ile Ile Gly Ile Asp Arg 930 935 940

    Gly Glu Arg Asn Leu Leu Tyr Tyr Ser Val Ile Asp Met Lys Gly Asn 945 950 955 960

    Ile Val Glu Gln Asp Ser Leu Asn Ile Ile Arg Asn Asn Asp Leu Glu 965 970 975

    Thr Asp Tyr His Asp Leu Leu Asp Lys Arg Glu Lys Glu Arg Lys Ala

    980

    985

    990

    Asn Arg Gln Asn Trp Glu Ala Val Glu Gly Ile Lys Asp Leu Lys Lys 995 1000 1005

    Gly Tyr Leu Ser Gln Ala Val His Gln Ile Ala Gln Leu Met Leu 1010 1015 1020

    Lys Tyr Asn Ala Ile Ile Ala Leu Glu Asp Leu Gly Gln Met Phe 1025 1030 1035

    Val Thr Arg Gly Gln Lys Ile Glu Lys Ala Val Tyr Gln Gln Phe 1040 1045 1050

    Glu Lys Ser Leu Val Asp Lys Leu Ser Tyr Leu Val Asp Lys Lys 1055 1060 1065

    Arg Pro Tyr Asn Glu Leu Gly Gly Ile Leu Lys Ala Tyr Gln Leu 1070 1075 1080

    Ala Ser Ser Ile Thr Lys Asn Asn Ser Asp Lys Gln Asn Gly Phe 1085 1090 1095

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val 1100 1105 1110

    Thr Gly Phe Thr Asp Leu Leu Arg Pro Lys Ala Met Thr Ile Lys 1115 1120 1125

    Glu Ala Gln Asp Phe Phe Gly Ala Phe Asp Asn Ile Ser Tyr Asn 1130 1135 1140

    Asp Lys Gly Tyr Phe Glu Phe Glu Thr Asn Tyr Asp Lys Phe Lys 1145 1150 1155

    Ile Arg Met Lys Ser Ala Gln Thr Arg Trp Thr Ile Cys Thr Phe 1160 1165 1170

    Gly Asn Arg Ile Lys Arg Lys Lys Asp Lys Asn Tyr Trp Asn Tyr 1175 1180 1185

    Glu Glu Val Glu Leu Thr Glu Glu Phe Lys Lys Leu Phe Lys Asp 1190 1195 1200

    Ser Asn Ile Asp Tyr Glu Asn Cys Asn Leu Lys Glu Glu Ile Gln 1205 1210 1215

    Asn Lys Asp Asn Arg Lys Phe Phe Asp Asp Leu Ile Lys Leu Leu 1220 1225 1230

    Gln Leu Thr Leu Gln Met Arg Asn Ser Asp Asp Lys Gly Asn Asp 1235 1240 1245

    Tyr Ile Ile Ser Pro Val Ala Asn Ala Glu Gly Gln Phe Phe Asp 1250 1255 1260

    Ser Arg Asn Gly Asp Lys Lys Leu Pro Leu Asp Ala Asp Ala Asn 1265 1270 1275

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Asn Ile Arg Gln 1280 1285 1290

    Ile Lys Gln Thr Lys Asn Asp Lys Lys Leu Asn Leu Ser Ile Ser 1295 1300 1305

    Ser Thr Glu Trp Leu Asp Phe Val Arg Glu Lys Pro Tyr Leu Lys 1310 1315 1320 <210> 1127 <211> 1246 <212> PRT <213> Porphyromonas macacae <400> 1127

    Met Lys Thr Gln His Phe Phe Glu Asp Phe Thr Ser Leu Tyr Ser Leu 1 5 10 15

    Ser Lys Thr Ile Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu 20 25 30

    Asn Ile Lys Lys Asn Gly Leu Ile Arg Arg Asp Glu Gln Arg Leu Asp 35 40 45

    Asp Tyr Glu Lys Leu Lys Lys Val Ile Asp Glu Tyr His Glu Asp Phe 50 55 60

    Ile Ala Asn Ile Leu Ser Ser Phe Ser Phe Ser Glu Glu Ile Leu Gln 65 70 75 80

    Ser Tyr Ile Gln Asn Leu Ser Glu Ser Glu Ala Arg Ala Lys Ile Glu 85 90 95

    Lys Thr Met Arg Asp Thr Leu Ala Lys Ala Phe Ser Glu Asp Glu Arg 100 105 110

    Tyr Lys Ser Ile Phe Lys Lys Glu Leu Val Lys Lys Asp Ile Pro Val 115 120 125

    Trp Cys Pro Ala Tyr Lys Ser Leu Cys Lys Lys Phe Asp Asn Phe Thr 130 135 140

    Thr Ser Leu Val Pro Phe His Glu Asn Arg Lys Asn Leu Tyr Thr Ser 145 150 155 160

    Asn Glu Ile Thr Ala Ser Ile Pro Tyr Arg Ile Val His Val Asn Leu 165 170 175

    Pro Lys Phe Ile Gln Asn Ile Glu Ala Leu Cys Glu Leu Gln Lys Lys 180 185 190

    Met Gly Ala Asp Leu Tyr Leu Glu Met Met Glu Asn Leu Arg Asn Val 195 200 205

    Trp Pro Ser Phe Val Lys Thr Pro Asp Asp Leu Cys Asn Leu Lys Thr 210 215 220

    Tyr Asn His Leu Met Val Gln Ser Ser Ile Ser Glu Tyr Asn Arg Phe 225 230 235 240

    Val Gly Gly Tyr Ser Thr Glu Asp Gly Thr Lys His Gln Gly Ile Asn 245 250 255

    Glu Trp Ile Asn Ile Tyr Arg Gln Arg Asn Lys Glu Met Arg Leu Pro 260 265 270

    Gly Leu Val Phe Leu His Lys Gln Ile Leu Ala Lys Val Asp Ser Ser 275 280 285

    Ser Phe Ile Ser Asp Thr Leu Glu Asn Asp Asp Gln Val Phe Cys Val 290 295 300

    Leu Arg Gln Phe Arg Lys Leu Phe Trp Asn Thr Val Ser Ser Lys Glu 305 310 315 320

    Asp Asp Ala Ala Ser Leu Lys Asp Leu Phe Cys Gly Leu Ser Gly Tyr 325 330 335

    Asp Pro Glu Ala Ile Tyr Val Ser Asp Ala His Leu Ala Thr Ile Ser 340 345 350

    Lys Asn Ile Phe Asp Arg Trp Asn Tyr Ile Ser Asp Ala Ile Arg Arg 355 360 365

    Lys Thr Glu Val Leu Met Pro Arg Lys Lys Glu Ser Val Glu Arg Tyr 370 375 380

    Ala Glu Lys Ile Ser Lys Gln Ile Lys Lys Arg Gln Ser Tyr Ser Leu 385 390 395 400

    Ala Glu Leu Asp Asp Leu Leu Ala His Tyr Ser Glu Glu Ser Leu Pro 405 410 415

    Ala Gly Phe Ser Leu Leu Ser Tyr Phe Thr Ser Leu Gly Gly Gln Lys 420 425 430

    Tyr Leu Val Ser Asp Gly Glu Val Ile Leu Tyr Glu Glu Gly Ser Asn 435 440 445

    Ile Trp Asp Glu Val Leu Ile Ala Phe Arg Asp Leu Gln Val Ile Leu 450 455 460

    Asp Lys Asp Phe Thr Glu Lys Lys Leu Gly Lys Asp Glu Glu Ala Val 465 470 475 480

    Ser Val Ile Lys Lys Ala Leu Asp Ser Ala Leu Arg Leu Arg Lys Phe 485 490 495

    Phe Asp Leu Leu Ser Gly Thr Gly Ala Glu Ile Arg Arg Asp Ser Ser 500 505 510

    Phe Tyr Ala Leu Tyr Thr Asp Arg Met Asp Lys Leu Lys Gly Leu Leu 515 520 525

    Lys Met Tyr Asp Lys Val Arg Asn Tyr Leu Thr Lys Lys Pro Tyr Ser 530 535 540

    Ile Glu Lys Phe Lys Leu His Phe Asp Asn Pro Ser Leu Leu Ser Gly 545 550 555 560

    Trp Asp Lys Asn Lys Glu Leu Asn Asn Leu Ser Val Ile Phe Arg Gln 565 570 575

    Asn Gly Tyr Tyr Tyr Leu Gly Ile Met Thr Pro Lys Gly Lys Asn Leu 580 585 590

    Phe Lys Thr Leu Pro Lys Leu Gly Ala Glu Glu Met Phe Tyr Glu Lys 595 600 605

    Met Glu Tyr Lys Gln Ile Ala Glu Pro Met Leu Met Leu Pro Lys Val 610 615 620

    Phe Phe Pro Lys Lys Thr Lys Pro Ala Phe Ala Pro Asp Gln Ser Val 625 630 635 640

    Val Asp Ile Tyr Asn Lys Lys Thr Phe Lys Thr Gly Gln Lys Gly Phe 645 650 655

    Asn Lys Lys Asp Leu Tyr Arg Leu Ile Asp Phe Tyr Lys Glu Ala Leu 660 665 670

    Thr Val His Glu Trp Lys Leu Phe Asn Phe Ser Phe Ser Pro Thr Glu 675 680 685

    Gln Tyr Arg Asn Ile Gly Glu Phe Phe Asp Glu Val Arg Glu Gln Ala

    690

    695

    700

    Tyr Lys Val Ser Met Val Asn Val Pro Ala Ser Tyr Ile Asp Glu Ala 705 710 715 720

    Val Glu Asn Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 725 730 735

    Ser Pro Tyr Ser Lys Gly Ile Pro Asn Leu His Thr Leu Tyr Trp Lys 740 745 750

    Ala Leu Phe Ser Glu Gln Asn Gln Ser Arg Val Tyr Lys Leu Cys Gly 755 760 765

    Gly Gly Glu Leu Phe Tyr Arg Lys Ala Ser Leu His Met Gln Asp Thr 770 775 780

    Thr Val His Pro Lys Gly Ile Ser Ile His Lys Lys Asn Leu Asn Lys 785 790 795 800

    Lys Gly Glu Thr Ser Leu Phe Asn Tyr Asp Leu Val Lys Asp Lys Arg 805 810 815

    Phe Thr Glu Asp Lys Phe Phe Phe His Val Pro Ile Ser Ile Asn Tyr 820 825 830

    Lys Asn Lys Lys Ile Thr Asn Val Asn Gln Met Val Arg Asp Tyr Ile 835 840 845

    Ala Gln Asn Asp Asp Leu Gln Ile Ile Gly Ile Asp Arg Gly Glu Arg 850 855 860

    Asn Leu Leu Tyr Ile Ser Arg Ile Asp Thr Arg Gly Asn Leu Leu Glu 865 870 875 880

    Gln Phe Ser Leu Asn Val Ile Glu Ser Asp Lys Gly Asp Leu Arg Thr 885 890 895

    Asp Tyr Gln Lys Ile Leu Gly Asp Arg Glu Gln Glu Arg Leu Arg Arg 900 905 910

    Arg Gln Glu Trp Lys Ser Ile Glu Ser Ile Lys Asp Leu Lys Asp Gly 915 920 925

    Tyr Met Ser Gln Val Val His Lys Ile Cys Asn Met Val Val Glu His 930 935 940

    Lys Ala Ile Val Val Leu Glu Asn Leu Asn Leu Ser Phe Met Lys Gly 945 950 955 960

    Arg Lys Lys Val Glu Lys Ser Val Tyr Glu Lys Phe Glu Arg Met Leu 965 970 975

    Val Asp Lys Leu Asn Tyr Leu Val Val Asp Lys Lys Asn Leu Ser Asn 980 985 990

    Glu Pro Gly Gly Leu Tyr Ala Ala Tyr Gln Leu Thr Asn Pro Leu Phe 995 1000 1005

    Ser Phe Glu Glu Leu His Arg Tyr Pro Gln Ser Gly Ile Leu Phe 1010 1015 1020

    Phe Val Asp Pro Trp Asn Thr Ser Leu Thr Asp Pro Ser Thr Gly 1025 1030 1035

    Phe Val Asn Leu Leu Gly Arg Ile Asn Tyr Thr Asn Val Gly Asp 1040 1045 1050

    Ala Arg Lys Phe Phe Asp Arg Phe Asn Ala Ile Arg Tyr Asp Gly 1055 1060 1065

    Lys Gly Asn Ile Leu Phe Asp Leu Asp Leu Ser Arg Phe Asp Val

    1070 1075 1080 Arg Val Glu Thr Gln Arg Lys Leu Trp Thr Leu Thr Thr Phe Gly 1085 1090 1095 Ser Arg Ile Ala Lys Ser Lys Lys Ser Gly Lys Trp Met Val Glu 1100 1105 1110 Arg Ile Glu Asn Leu Ser Leu Cys Phe Leu Glu Leu Phe Glu Gln 1115 1120 1125 Phe Asn Ile Gly Tyr Arg Val Glu Lys Asp Leu Lys Lys Ala Ile 1130 1135 1140 Leu Ser Gln Asp Arg Lys Glu Phe Tyr Val Arg Leu Ile Tyr Leu 1145 1150 1155 Phe Asn Leu Met Met Gln Ile Arg Asn Ser Asp Gly Glu Glu Asp 1160 1165 1170

    Tyr Ile Leu Ser Pro Ala Leu Asn Glu Lys Asn Leu Gln Phe Asp 1175 1180 1185

    Ser Arg Leu Ile Glu Ala Lys Asp Leu Pro Val Asp Ala Asp Ala 1190 1195 1200

    Asn Gly Ala Tyr Asn Val Ala Arg Lys Gly Leu Met Val Val Gln 1205 1210 1215

    Arg Ile Lys Arg Gly Asp His Glu Ser Ile His Arg Ile Gly Arg 1220 1225 1230

    Ala Gln Trp Leu Arg Tyr Val Gln Glu Gly Ile Val Glu 1235 1240 1245 <210> 1128 <211> 1257 <212> PRT <213> Prevotella bryantii <400> 1128

    Met Gln Ile Asn Asn Leu Lys Ile Ile Tyr Met Lys Phe Thr Asp Phe 1 5 10 15

    Thr Gly Leu Tyr Ser Leu Ser Lys Thr Leu Arg Phe Glu Leu Lys Pro 20 25 30

    Ile Gly Lys Thr Leu Glu Asn Ile Lys Lys Ala Gly Leu Leu Glu Gln 35 40 45

    Asp Gln His Arg Ala Asp Ser Tyr Lys Lys Val Lys Lys Ile Ile Asp 50 55 60

    Glu Tyr His Lys Ala Phe Ile Glu Lys Ser Leu Ser Asn Phe Glu Leu 65 70 75 80

    Lys Tyr Gln Ser Glu Asp Lys Leu Asp Ser Leu Glu Glu Tyr Leu Met 85 90 95

    Tyr Tyr Ser Met Lys Arg Ile Glu Lys Thr Glu Lys Asp Lys Phe Ala 100 105 110

    Lys Ile Gln Asp Asn Leu Arg Lys Gln Ile Ala Asp His Leu Lys Gly 115 120 125

    Asp Glu Ser Tyr Lys Thr Ile Phe Ser Lys Asp Leu Ile Arg Lys Asn 130 135 140

    Leu Pro Asp Phe Val Lys Ser Asp Glu Glu Arg Thr Leu Ile Lys Glu 145 150 155 160

    Phe Lys Asp Phe Thr Thr Tyr Phe Lys Gly Phe Tyr Glu Asn Arg Glu 165 170 175

    Asn Met Tyr Ser Ala Glu Asp Lys Ser Thr Ala Ile Ser His Arg Ile 180 185 190

    Ile His Glu Asn Leu Pro Lys Phe Val Asp Asn Ile Asn Ala Phe Ser 195 200 205

    Lys Ile Ile Leu Ile Pro Glu Leu Arg Glu Lys Leu Asn Gln Ile Tyr 210 215 220

    Gln Asp Phe Glu Glu Tyr Leu Asn Val Glu Ser Ile Asp Glu Ile Phe 225 230 235 240

    His Leu Asp Tyr Phe Ser Met Val Met Thr Gln Lys Gln Ile Glu Val 245 250 255

    Tyr Asn Ala Ile Ile Gly Gly Lys Ser Thr Asn Asp Lys Lys Ile Gln 260 265 270

    Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Cys 275 280 285

    Lys Leu Pro Lys Leu Lys Leu Leu Phe Lys Gln Ile Leu Ser Asp Arg 290 295 300

    Ile Ala Ile Ser Trp Leu Pro Asp Asn Phe Lys Asp Asp Gln Glu Ala 305 310 315 320

    Leu Asp Ser Ile Asp Thr Cys Tyr Lys Asn Leu Leu Asn Asp Gly Asn 325 330 335

    Val Leu Gly Glu Gly Asn Leu Lys Leu Leu Leu Glu Asn Ile Asp Thr 340 345 350

    Tyr Asn Leu Lys Gly Ile Phe Ile Arg Asn Asp Leu Gln Leu Thr Asp 355 360 365

    Ile Ser Gln Lys Met Tyr Ala Ser Trp Asn Val Ile Gln Asp Ala Val 370 375 380

    Ile Leu Asp Leu Lys Lys Gln Val Ser Arg Lys Lys Lys Glu Ser Ala 385 390 395 400

    Glu Asp Tyr Asn Asp Arg Leu Lys Lys Leu Tyr Thr Ser Gln Glu Ser 405 410 415

    Phe Ser Ile Gln Tyr Leu Asn Asp Cys Leu Arg Ala Tyr Gly Lys Thr 420 425 430

    Glu Asn Ile Gln Asp Tyr Phe Ala Lys Leu Gly Ala Val Asn Asn Glu 435 440 445

    His Glu Gln Thr Ile Asn Leu Phe Ala Gln Val Arg Asn Ala Tyr Thr 450 455 460

    Ser Val Gln Ala Ile Leu Thr Thr Pro Tyr Pro Glu Asn Ala Asn Leu 465 470 475 480

    Ala Gln Asp Lys Glu Thr Val Ala Leu Ile Lys Asn Leu Leu Asp Ser

    485

    490

    495

    Leu Lys Arg Leu Gln Arg Phe Ile Lys Pro Leu Leu Gly Lys Gly Asp 500 505 510

    Glu Ser Asp Lys Asp Glu Arg Phe Tyr Gly Asp Phe Thr Pro Leu Trp 515 520 525

    Glu Thr Leu Asn Gln Ile Thr Pro Leu Tyr Asn Met Val Arg Asn Tyr 530 535 540

    Met Thr Arg Lys Pro Tyr Ser Gln Glu Lys Ile Lys Leu Asn Phe Glu 545 550 555 560

    Asn Ser Thr Leu Leu Gly Gly Trp Asp Leu Asn Lys Glu His Asp Asn 565 570 575

    Thr Ala Ile Ile Leu Arg Lys Asn Gly Leu Tyr Tyr Leu Ala Ile Met 580 585 590

    Lys Lys Ser Ala Asn Lys Ile Phe Asp Lys Asp Lys Leu Asp Asn Ser 595 600 605

    Gly Asp Cys Tyr Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn 610 615 620

    Lys Met Leu Pro Lys Val Phe Phe Ser Lys Ser Arg Ile Asp Glu Phe 625 630 635 640

    Lys Pro Ser Glu Asn Ile Ile Glu Asn Tyr Lys Lys Gly Thr His Lys 645 650 655

    Lys Gly Ala Asn Phe Asn Leu Ala Asp Cys His Asn Leu Ile Asp Phe 660 665 670

    Phe Lys Ser Ser Ile Ser Lys His Glu Asp Trp Ser Lys Phe Asn Phe 675 680 685

    His Phe Ser Asp Thr Ser Ser Tyr Glu Asp Leu Ser Asp Phe Tyr Arg 690 695 700

    Glu Val Glu Gln Gln Gly Tyr Ser Ile Ser Phe Cys Asp Val Ser Val 705 710 715 720

    Glu Tyr Ile Asn Lys Met Val Glu Lys Gly Asp Leu Tyr Leu Phe Gln 725 730 735

    Ile Tyr Asn Lys Asp Phe Ser Glu Phe Ser Lys Gly Thr Pro Asn Met 740 745 750

    His Thr Leu Tyr Trp Asn Ser Leu Phe Ser Lys Glu Asn Leu Asn Asn 755 760 765

    Ile Ile Tyr Lys Leu Asn Gly Gln Ala Glu Ile Phe Phe Arg Lys Lys 770 775 780

    Ser Leu Asn Tyr Lys Arg Pro Thr His Pro Ala His Gln Ala Ile Lys 785 790 795 800

    Asn Lys Asn Lys Cys Asn Glu Lys Lys Glu Ser Ile Phe Asp Tyr Asp 805 810 815

    Leu Val Lys Asp Lys Arg Tyr Thr Val Asp Lys Phe Gln Phe His Val 820 825 830

    Pro Ile Thr Met Asn Phe Lys Ser Thr Gly Asn Thr Asn Ile Asn Gln 835 840 845

    Gln Val Ile Asp Tyr Leu Arg Thr Glu Asp Asp Thr His Ile Ile Gly 850 855 860

    Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Leu Val Val Ile Asp Ser 865 870 875 880

    His Gly Lys Ile Val Glu Gln Phe Thr Leu Asn Glu Ile Val Asn Glu 885 890 895

    Tyr Gly Gly Asn Ile Tyr Arg Thr Asn Tyr His Asp Leu Leu Asp Thr 900 905 910

    Arg Glu Gln Asn Arg Glu Lys Ala Arg Glu Ser Trp Gln Thr Ile Glu 915 920 925

    Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile Ser Gln Val Ile His Lys 930 935 940

    Ile Thr Asp Leu Met Gln Lys Tyr His Ala Val Val Val Leu Glu Asp 945 950 955 960

    Leu Asn Met Gly Phe Met Arg Gly Arg Gln Lys Val Glu Lys Gln Val 965 970 975

    Tyr Gln Lys Phe Glu Glu Met Leu Ile Asn Lys Leu Asn Tyr Leu Val 980 985 990

    Asn Lys Lys Ala Asp Gln Asn Ser Ala Gly Gly Leu Leu His Ala Tyr 995 1000 1005

    Gln Leu Thr Ser Lys Phe Glu Ser Phe Gln Lys Leu Gly Lys Gln 1010 1015 1020

    Ser Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn Thr Ser Lys Ile 1025 1030 1035

    Asp Pro Val Thr Gly Phe Val Asn Leu Phe Asp Thr Arg Tyr Glu 1040 1045 1050

    Ser Ile Asp Lys Ala Lys Ala Phe Phe Gly Lys Phe Asp Ser Ile 1055 1060 1065

    Arg Tyr Asn Ala Asp Lys Asp Trp Phe Glu Phe Ala Phe Asp Tyr 1070 1075 1080

    Asn Asn Phe Thr Thr Lys Ala Glu Gly Thr Arg Thr Asn Trp Thr 1085 1090 1095

    Ile Cys Thr Tyr Gly Ser Arg Ile Arg Thr Phe Arg Asn Gln Ala 1100 1105 1110

    Lys Asn Ser Gln Trp Asp Asn Glu Glu Ile Asp Leu Thr Lys Ala 1115 1120 1125

    Tyr Lys Ala Phe Phe Ala Lys His Gly Ile Asn Ile Tyr Asp Asn 1130 1135 1140

    Ile Lys Glu Ala Ile Ala Met Glu Thr Glu Lys Ser Phe Phe Glu 1145 1150 1155

    Asp Leu Leu His Leu Leu Lys Leu Thr Leu Gln Met Arg Asn Ser 1160 1165 1170

    Ile Thr Gly Thr Thr Thr Asp Tyr Leu Ile Ser Pro Val His Asp 1175 1180 1185

    Ser Lys Gly Asn Phe Tyr Asp Ser Arg Ile Cys Asp Asn Ser Leu

    1190 1195 1200

    Pro Ala Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys 1205 1210 1215

    Gly Leu Met Leu Ile Gln Gln Ile Lys Asp Ser Thr Ser Ser Asn 1220 1225 1230

    Arg Phe Lys Phe Ser Pro Ile Thr Asn Lys Asp Trp Leu Ile Phe 1235 1240 1245

    Ala Gln Glu Lys Pro Tyr Leu Asn Asp 1250 1255 <210> 1129 <211> 1247 <212> PRT <213> Prevotella bryantii <400> 1129

    Met Lys Phe Thr Asp Phe Thr Gly Leu Tyr Ser Leu Ser Lys Thr Leu 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu Asn Ile Lys Lys 20 25 30

    Ala Gly Leu Leu Glu Gln Asp Gln His Arg Ala Asp Ser Tyr Lys Lys 35 40 45

    Val Lys Lys Ile Ile Asp Glu Tyr His Lys Ala Phe Ile Glu Lys Ser 50 55 60

    Leu Ser Asn Phe Glu Leu Lys Tyr Gln Ser Glu Asp Lys Leu Asp Ser 65 70 75 80

    Leu Glu Glu Tyr Leu Met Tyr Tyr Ser Met Lys Arg Ile Glu Lys Thr 85 90 95

    Glu Lys Asp Lys Phe Ala Lys Ile Gln Asp Asn Leu Arg Lys Gln Ile 100 105 110

    Ala Asp His Leu Lys Gly Asp Glu Ser Tyr Lys Thr Ile Phe Ser Lys 115 120 125

    Asp Leu Ile Arg Lys Asn Leu Pro Asp Phe Val Lys Ser Asp Glu Glu 130 135 140

    Arg Thr Leu Ile Lys Glu Phe Lys Asp Phe Thr Thr Tyr Phe Lys Gly 145 150 155 160

    Phe Tyr Glu Asn Arg Glu Asn Met Tyr Ser Ala Glu Asp Lys Ser Thr 165 170 175

    Ala Ile Ser His Arg Ile Ile His Glu Asn Leu Pro Lys Phe Val Asp 180 185 190

    Asn Ile Asn Ala Phe Ser Lys Ile Ile Leu Ile Pro Glu Leu Arg Glu 195 200 205

    Lys Leu Asn Gln Ile Tyr Gln Asp Phe Glu Glu Tyr Leu Asn Val Glu 210 215 220

    Ser Ile Asp Glu Ile Phe His Leu Asp Tyr Phe Ser Met Val Met Thr 225 230 235 240

    Gln Lys Gln Ile Glu Val Tyr Asn Ala Ile Ile Gly Gly Lys Ser Thr 245 250 255

    Asn Asp Lys Lys Ile Gln Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn

    260

    265

    270

    Gln Lys His Lys Asp Cys Lys Leu Pro Lys Leu Lys Leu Leu Phe Lys 275 280 285

    Gln Ile Leu Ser Asp Arg Ile Ala Ile Ser Trp Leu Pro Asp Asn Phe 290 295 300

    Lys Asp Asp Gln Glu Ala Leu Asp Ser Ile Asp Thr Cys Tyr Lys Asn 305 310 315 320

    Leu Leu Asn Asp Gly Asn Val Leu Gly Glu Gly Asn Leu Lys Leu Leu 325 330 335

    Leu Glu Asn Ile Asp Thr Tyr Asn Leu Lys Gly Ile Phe Ile Arg Asn 340 345 350

    Asp Leu Gln Leu Thr Asp Ile Ser Gln Lys Met Tyr Ala Ser Trp Asn 355 360 365

    Val Ile Gln Asp Ala Val Ile Leu Asp Leu Lys Lys Gln Val Ser Arg 370 375 380

    Lys Lys Lys Glu Ser Ala Glu Asp Tyr Asn Asp Arg Leu Lys Lys Leu 385 390 395 400

    Tyr Thr Ser Gln Glu Ser Phe Ser Ile Gln Tyr Leu Asn Asp Cys Leu 405 410 415

    Arg Ala Tyr Gly Lys Thr Glu Asn Ile Gln Asp Tyr Phe Ala Lys Leu 420 425 430

    Gly Ala Val Asn Asn Glu His Glu Gln Thr Ile Asn Leu Phe Ala Gln 435 440 445

    Val Arg Asn Ala Tyr Thr Ser Val Gln Ala Ile Leu Thr Thr Pro Tyr 450 455 460

    Pro Glu Asn Ala Asn Leu Ala Gln Asp Lys Glu Thr Val Ala Leu Ile 465 470 475 480

    Lys Asn Leu Leu Asp Ser Leu Lys Arg Leu Gln Arg Phe Ile Lys Pro 485 490 495

    Leu Leu Gly Lys Gly Asp Glu Ser Asp Lys Asp Glu Arg Phe Tyr Gly 500 505 510

    Asp Phe Thr Pro Leu Trp Glu Thr Leu Asn Gln Ile Thr Pro Leu Tyr 515 520 525

    Asn Met Val Arg Asn Tyr Met Thr Arg Lys Pro Tyr Ser Gln Glu Lys 530 535 540

    Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu Gly Gly Trp Asp Leu 545 550 555 560

    Asn Lys Glu His Asp Asn Thr Ala Ile Ile Leu Arg Lys Asn Gly Leu 565 570 575

    Tyr Tyr Leu Ala Ile Met Lys Lys Ser Ala Asn Lys Ile Phe Asp Lys 580 585 590

    Asp Lys Leu Asp Asn Ser Gly Asp Cys Tyr Glu Lys Met Val Tyr Lys 595 600 605

    Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Phe Ser Lys 610 615 620

    Ser Arg Ile Asp Glu Phe Lys Pro Ser Glu Asn Ile Ile Glu Asn Tyr 625 630 635 640

    Lys Lys Gly Thr His Lys Lys Gly Ala Asn Phe Asn Leu Ala Asp Cys 645 650 655

    His Asn Leu Ile Asp Phe Phe Lys Ser Ser Ile Ser Lys His Glu Asp 660 665 670

    Trp Ser Lys Phe Asn Phe His Phe Ser Asp Thr Ser Ser Tyr Glu Asp 675 680 685

    Leu Ser Asp Phe Tyr Arg Glu Val Glu Gln Gln Gly Tyr Ser Ile Ser 690 695 700

    Phe Cys Asp Val Ser Val Glu Tyr Ile Asn Lys Met Val Glu Lys Gly 705 710 715 720

    Asp Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Glu Phe Ser 725 730 735

    Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Asn Ser Leu Phe Ser 740 745 750

    Lys Glu Asn Leu Asn Asn Ile Ile Tyr Lys Leu Asn Gly Gln Ala Glu 755 760 765

    Ile Phe Phe Arg Lys Lys Ser Leu Asn Tyr Lys Arg Pro Thr His Pro 770 775 780

    Ala His Gln Ala Ile Lys Asn Lys Asn Lys Cys Asn Glu Lys Lys Glu 785 790 795 800

    Ser Ile Phe Asp Tyr Asp Leu Val Lys Asp Lys Arg Tyr Thr Val Asp 805 810 815

    Lys Phe Gln Phe His Val Pro Ile Thr Met Asn Phe Lys Ser Thr Gly 820 825 830

    Asn Thr Asn Ile Asn Gln Gln Val Ile Asp Tyr Leu Arg Thr Glu Asp 835 840 845

    Asp Thr His Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr 850 855 860

    Leu Val Val Ile Asp Ser His Gly Lys Ile Val Glu Gln Phe Thr Leu 865 870 875 880

    Asn Glu Ile Val Asn Glu Tyr Gly Gly Asn Ile Tyr Arg Thr Asn Tyr 885 890 895

    His Asp Leu Leu Asp Thr Arg Glu Gln Asn Arg Glu Lys Ala Arg Glu 900 905 910

    Ser Trp Gln Thr Ile Glu Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 915 920 925

    Ser Gln Val Ile His Lys Ile Thr Asp Leu Met Gln Lys Tyr His Ala 930 935 940

    Val Val Val Leu Glu Asp Leu Asn Met Gly Phe Met Arg Gly Arg Gln 945 950 955 960

    Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Glu Met Leu Ile Asn 965 970 975

    Lys Leu Asn Tyr Leu Val Asn Lys Lys Ala Asp Gln Asn Ser Ala Gly

    980

    985

    990

    Gly Leu Leu His Ala Tyr Gln Leu Thr Ser Lys Phe Glu Ser Phe Gln 995 1000 1005

    Lys Leu Gly Lys Gln Ser Gly Phe Leu Phe Tyr Ile Pro Ala Trp 1010 1015 1020

    Asn Thr Ser Lys Ile Asp Pro Val Thr Gly Phe Val Asn Leu Phe 1025 1030 1035

    Asp Thr Arg Tyr Glu Ser Ile Asp Lys Ala Lys Ala Phe Phe Gly 1040 1045 1050

    Lys Phe Asp Ser Ile Arg Tyr Asn Ala Asp Lys Asp Trp Phe Glu 1055 1060 1065

    Phe Ala Phe Asp Tyr Asn Asn Phe Thr Thr Lys Ala Glu Gly Thr 1070 1075 1080

    Arg Thr Asn Trp Thr Ile Cys Thr Tyr Gly Ser Arg Ile Arg Thr 1085 1090 1095

    Phe Arg Asn Gln Ala Lys Asn Ser Gln Trp Asp Asn Glu Glu Ile 1100 1105 1110

    Asp Leu Thr Lys Ala Tyr Lys Ala Phe Phe Ala Lys His Gly Ile 1115 1120 1125

    Asn Ile Tyr Asp Asn Ile Lys Glu Ala Ile Ala Met Glu Thr Glu 1130 1135 1140

    Lys Ser Phe Phe Glu Asp Leu Leu His Leu Leu Lys Leu Thr Leu 1145 1150 1155

    Gln Met Arg Asn Ser Ile Thr Gly Thr Thr Thr Asp Tyr Leu Ile 1160 1165 1170

    Ser Pro Val His Asp Ser Lys Gly Asn Phe Tyr Asp Ser Arg Ile 1175 1180 1185

    Cys Asp Asn Ser Leu Pro Ala Asn Ala Asp Ala Asn Gly Ala Tyr 1190 1195 1200

    Asn Ile Ala Arg Lys Gly Leu Met Leu Ile Gln Gln Ile Lys Asp 1205 1210 1215

    Ser Thr Ser Ser Asn Arg Phe Lys Phe Ser Pro Ile Thr Asn Lys 1220 1225 1230

    Asp Trp Leu Ile Phe Ala Gln Glu Lys Pro Tyr Leu Asn Asp 1235 1240 1245 <210> 1130 <211> 1253 <212> PRT <213> Prevotella albensis <400> 1130

    Met Asn Ile Lys Asn Phe Thr Gly Leu Tyr Pro Leu Ser Lys Thr Leu 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Lys Glu Asn Ile Glu Lys 20 25 30

    Asn Gly Ile Leu Thr Lys Asp Glu Gln Arg Ala Lys Asp Tyr Leu Ile 35 40 45

    Val Lys Gly Phe Ile Asp Glu Tyr His Lys Gln Phe Ile Lys Asp Arg

    Leu Trp Asp Phe Lys Leu Pro Leu Glu Ser Glu Gly Glu Lys Asn Ser 65 70 75 80

    Leu Glu Glu Tyr Gln Glu Leu Tyr Glu Leu Thr Lys Arg Asn Asp Ala 85 90 95

    Gln Glu Ala Asp Phe Thr Glu Ile Lys Asp Asn Leu Arg Ser Ser Ile 100 105 110

    Thr Glu Gln Leu Thr Lys Ser Gly Ser Ala Tyr Asp Arg Ile Phe Lys 115 120 125

    Lys Glu Phe Ile Arg Glu Asp Leu Val Asn Phe Leu Glu Asp Glu Lys 130 135 140

    Asp Lys Asn Ile Val Lys Gln Phe Glu Asp Phe Thr Thr Tyr Phe Thr 145 150 155 160

    Gly Phe Tyr Glu Asn Arg Lys Asn Met Tyr Ser Ser Glu Glu Lys Ser 165 170 175

    Thr Ala Ile Ala Tyr Arg Leu Ile His Gln Asn Leu Pro Lys Phe Met 180 185 190

    Asp Asn Met Arg Ser Phe Ala Lys Ile Ala Asn Ser Ser Val Ser Glu 195 200 205

    His Phe Ser Asp Ile Tyr Glu Ser Trp Lys Glu Tyr Leu Asn Val Asn 210 215 220

    Ser Ile Glu Glu Ile Phe Gln Leu Asp Tyr Phe Ser Glu Thr Leu Thr 225 230 235 240

    Gln Pro His Ile Glu Val Tyr Asn Tyr Ile Ile Gly Lys Lys Val Leu 245 250 255

    Glu Asp Gly Thr Glu Ile Lys Gly Ile Asn Glu Tyr Val Asn Leu Tyr 260 265 270

    Asn Gln Gln Gln Lys Asp Lys Ser Lys Arg Leu Pro Phe Leu Val Pro 275 280 285

    Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Lys Leu Ser Trp Ile Ala 290 295 300

    Glu Glu Phe Asp Ser Asp Lys Lys Met Leu Ser Ala Ile Thr Glu Ser 305 310 315 320

    Tyr Asn His Leu His Asn Val Leu Met Gly Asn Glu Asn Glu Ser Leu 325 330 335

    Arg Asn Leu Leu Leu Asn Ile Lys Asp Tyr Asn Leu Glu Lys Ile Asn 340 345 350

    Ile Thr Asn Asp Leu Ser Leu Thr Glu Ile Ser Gln Asn Leu Phe Gly 355 360 365

    Arg Tyr Asp Val Phe Thr Asn Gly Ile Lys Asn Lys Leu Arg Val Leu 370 375 380

    Thr Pro Arg Lys Lys Lys Glu Thr Asp Glu Asn Phe Glu Asp Arg Ile 385 390 395 400

    Asn Lys Ile Phe Lys Thr Gln Lys Ser Phe Ser Ile Ala Phe Leu Asn 405 410 415

    Lys Leu Pro Gln Pro Glu Met Glu Asp Gly Lys Pro Arg Asn Ile Glu 420 425 430

    Asp Tyr Phe Ile Thr Gln Gly Ala Ile Asn Thr Lys Ser Ile Gln Lys 435 440 445

    Glu Asp Ile Phe Ala Gln Ile Glu Asn Ala Tyr Glu Asp Ala Gln Val 450 455 460

    Phe Leu Gln Ile Lys Asp Thr Asp Asn Lys Leu Ser Gln Asn Lys Thr 465 470 475 480

    Ala Val Glu Lys Ile Lys Thr Leu Leu Asp Ala Leu Lys Glu Leu Gln 485 490 495

    His Phe Ile Lys Pro Leu Leu Gly Ser Gly Glu Glu Asn Glu Lys Asp 500 505 510

    Glu Leu Phe Tyr Gly Ser Phe Leu Ala Ile Trp Asp Glu Leu Asp Thr 515 520 525

    Ile Thr Pro Leu Tyr Asn Lys Val Arg Asn Trp Leu Thr Arg Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Asp Asn Ala Gln Leu Leu 545 550 555 560

    Gly Gly Trp Asp Val Asn Lys Glu His Asp Cys Ala Gly Ile Leu Leu 565 570 575

    Arg Lys Asn Asp Ser Tyr Tyr Leu Gly Ile Ile Asn Lys Lys Thr Asn 580 585 590

    His Ile Phe Asp Thr Asp Ile Thr Pro Ser Asp Gly Glu Cys Tyr Asp 595 600 605

    Lys Ile Asp Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys 610 615 620

    Val Phe Phe Ser Lys Ser Arg Ile Lys Glu Phe Glu Pro Ser Glu Ala 625 630 635 640

    Ile Ile Asn Cys Tyr Lys Lys Gly Thr His Lys Lys Gly Lys Asn Phe 645 650 655

    Asn Leu Thr Asp Cys His Arg Leu Ile Asn Phe Phe Lys Thr Ser Ile 660 665 670

    Glu Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser Asp Thr 675 680 685

    Glu Thr Tyr Glu Asp Ile Ser Gly Phe Tyr Arg Glu Val Glu Gln Gln 690 695 700

    Gly Tyr Arg Leu Thr Ser His Pro Val Ser Ala Ser Tyr Ile His Ser 705 710 715 720

    Leu Val Lys Glu Gly Lys Leu Tyr Leu Phe Gln Ile Trp Asn Lys Asp 725 730 735

    Phe Ser Gln Phe Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp 740 745 750

    Lys Met Leu Phe Asp Lys Arg Asn Leu Ser Asp Val Val Tyr Lys Leu 755 760 765

    Asn Gly Gln Ala Glu Val Phe Tyr Arg Lys Ser Ser Ile Glu His Gln

    770

    775

    780

    Asn Arg Ile Ile His Pro Ala Gln His Pro Ile Thr Asn Lys Asn Glu 785 790 795 800

    Leu Asn Lys Lys His Thr Ser Thr Phe Lys Tyr Asp Ile Ile Lys Asp 805 810 815

    Arg Arg Tyr Thr Val Asp Lys Phe Gln Phe His Val Pro Ile Thr Ile 820 825 830

    Asn Phe Lys Ala Thr Gly Gln Asn Asn Ile Asn Pro Ile Val Gln Glu 835 840 845

    Val Ile Arg Gln Asn Gly Ile Thr His Ile Ile Gly Ile Asp Arg Gly 850 855 860

    Glu Arg His Leu Leu Tyr Leu Ser Leu Ile Asp Leu Lys Gly Asn Ile 865 870 875 880

    Ile Lys Gln Met Thr Leu Asn Glu Ile Ile Asn Glu Tyr Lys Gly Val 885 890 895

    Thr Tyr Lys Thr Asn Tyr His Asn Leu Leu Glu Lys Arg Glu Lys Glu 900 905 910

    Arg Thr Glu Ala Arg His Ser Trp Ser Ser Ile Glu Ser Ile Lys Glu 915 920 925

    Leu Lys Asp Gly Tyr Met Ser Gln Val Ile His Lys Ile Thr Asp Met 930 935 940

    Met Val Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn Gly Gly 945 950 955 960

    Phe Met Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe 965 970 975

    Glu Lys Lys Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Lys Leu 980 985 990

    Asp Ala Asn Glu Val Gly Gly Val Leu Asn Ala Tyr Gln Leu Thr Asn 995 1000 1005

    Lys Phe Glu Ser Phe Lys Lys Ile Gly Lys Gln Ser Gly Phe Leu 1010 1015 1020

    Phe Tyr Ile Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Ile Thr 1025 1030 1035

    Gly Phe Val Asn Leu Phe Asn Thr Arg Tyr Glu Ser Ile Lys Glu 1040 1045 1050

    Thr Lys Val Phe Trp Ser Lys Phe Asp Ile Ile Arg Tyr Asn Lys 1055 1060 1065

    Glu Lys Asn Trp Phe Glu Phe Val Phe Asp Tyr Asn Thr Phe Thr 1070 1075 1080

    Thr Lys Ala Glu Gly Thr Arg Thr Lys Trp Thr Leu Cys Thr His 1085 1090 1095

    Gly Thr Arg Ile Gln Thr Phe Arg Asn Pro Glu Lys Asn Ala Gln 1100 1105 1110

    Trp Asp Asn Lys Glu Ile Asn Leu Thr Glu Ser Phe Lys Ala Leu 1115 1120 1125

    Phe Glu Lys Tyr Lys Ile Asp Ile Thr Ser Asn Leu Lys Glu Ser 1130 1135 1140

    Ile Met Gln Glu Thr Glu Lys Lys Phe Phe Gln Glu Leu His Asn 1145 1150 1155

    Leu Leu His Leu Thr Leu Gln Met Arg Asn Ser Val Thr Gly Thr 1160 1165 1170

    Asp Ile Asp Tyr Leu Ile Ser Pro Val Ala Asp Glu Asp Gly Asn 1175 1180 1185

    Phe Tyr Asp Ser Arg Ile Asn Gly Lys Asn Phe Pro Glu Asn Ala 1190 1195 1200

    Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Met Leu 1205 1210 1215

    Ile Arg Gln Ile Lys Gln Ala Asp Pro Gln Lys Lys Phe Lys Phe 1220 1225 1230

    Glu Thr Ile Thr Asn Lys Asp Trp Leu Lys Phe Ala Gln Asp Lys 1235 1240 1245

    Pro Tyr Leu Lys Asp 1250 <210> 1131 <211> 1262 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Bacteroidetes oral taxon 274 sequence <400> 1131

    Met Arg Lys Phe Asn Glu Phe Val Gly Leu Tyr Pro Ile Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu His Ile Gln 20 25 30

    Arg Asn Lys Leu Leu Glu His Asp Ala Val Arg Ala Asp Asp Tyr Val 35 40 45

    Lys Val Lys Lys Ile Ile Asp Lys Tyr His Lys Cys Leu Ile Asp Glu 50 55 60

    Ala Leu Ser Gly Phe Thr Phe Asp Thr Glu Ala Asp Gly Arg Ser Asn 65 70 75 80

    Asn Ser Leu Ser Glu Tyr Tyr Leu Tyr Tyr Asn Leu Lys Lys Arg Asn 85 90 95

    Glu Gln Glu Gln Lys Thr Phe Lys Thr Ile Gln Asn Asn Leu Arg Lys 100 105 110

    Gln Ile Val Asn Lys Leu Thr Gln Ser Glu Lys Tyr Lys Arg Ile Asp 115 120 125

    Lys Lys Glu Leu Ile Thr Thr Asp Leu Pro Asp Phe Leu Thr Asn Glu 130 135 140

    Ser Glu Lys Glu Leu Val Glu Lys Phe Lys Asn Phe Thr Thr Tyr Phe 145 150 155 160

    Thr Glu Phe His Lys Asn Arg Lys Asn Met Tyr Ser Lys Glu Glu Lys 165 170 175

    Ser Thr Ala Ile Ala Phe Arg Leu Ile Asn Glu Asn Leu Pro Lys Phe 180 185 190

    Val Asp Asn Ile Ala Ala Phe Glu Lys Val Val Ser Ser Pro Leu Ala 195 200 205

    Glu Lys Ile Asn Ala Leu Tyr Glu Asp Phe Lys Glu Tyr Leu Asn Val 210 215 220

    Glu Glu Ile Ser Arg Val Phe Arg Leu Asp Tyr Tyr Asp Glu Leu Leu 225 230 235 240

    Thr Gln Lys Gln Ile Asp Leu Tyr Asn Ala Ile Val Gly Gly Arg Thr 245 250 255

    Glu Glu Asp Asn Lys Ile Gln Ile Lys Gly Leu Asn Gln Tyr Ile Asn 260 265 270

    Glu Tyr Asn Gln Gln Gln Thr Asp Arg Ser Asn Arg Leu Pro Lys Leu 275 280 285

    Lys Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Ser Val Ser Trp 290 295 300

    Leu Pro Pro Lys Phe Asp Ser Asp Lys Asn Leu Leu Ile Lys Ile Lys 305 310 315 320

    Glu Cys Tyr Asp Ala Leu Ser Glu Lys Glu Lys Val Phe Asp Lys Leu 325 330 335

    Glu Ser Ile Leu Lys Ser Leu Ser Thr Tyr Asp Leu Ser Lys Ile Tyr 340 345 350

    Ile Ser Asn Asp Ser Gln Leu Ser Tyr Ile Ser Gln Lys Met Phe Gly 355 360 365

    Arg Trp Asp Ile Ile Ser Lys Ala Ile Arg Glu Asp Cys Ala Lys Arg 370 375 380

    Asn Pro Gln Lys Ser Arg Glu Ser Leu Glu Lys Phe Ala Glu Arg Ile 385 390 395 400

    Asp Lys Lys Leu Lys Thr Ile Asp Ser Ile Ser Ile Gly Asp Val Asp 405 410 415

    Glu Cys Leu Ala Gln Leu Gly Glu Thr Tyr Val Lys Arg Val Glu Asp 420 425 430

    Tyr Phe Val Ala Met Gly Glu Ser Glu Ile Asp Asp Glu Gln Thr Asp 435 440 445

    Thr Thr Ser Phe Lys Lys Asn Ile Glu Gly Ala Tyr Glu Ser Val Lys 450 455 460

    Glu Leu Leu Asn Asn Ala Asp Asn Ile Thr Asp Asn Asn Leu Met Gln 465 470 475 480

    Asp Lys Gly Asn Val Glu Lys Ile Lys Thr Leu Leu Asp Ala Ile Lys 485 490 495

    Asp Leu Gln Arg Phe Ile Lys Pro Leu Leu Gly Lys Gly Asp Glu Ala 500 505 510

    Asp Lys Asp Gly Val Phe Tyr Gly Glu Phe Thr Ser Leu Trp Thr Lys 515 520 525

    Leu Asp Gln Val Thr Pro Leu Tyr Asn Met Val Arg Asn Tyr Leu Thr

    530

    535

    540

    Ser Lys Pro Tyr Ser Thr Lys Lys Ile Lys Leu Asn Phe Glu Asn Ser 545 550 555 560

    Thr Leu Met Asp Gly Trp Asp Leu Asn Lys Glu Pro Asp Asn Thr Thr 565 570 575

    Val Ile Phe Cys Lys Asp Gly Leu Tyr Tyr Leu Gly Ile Met Gly Lys 580 585 590

    Lys Tyr Asn Arg Val Phe Val Asp Arg Glu Asp Leu Pro His Asp Gly 595 600 605

    Glu Cys Tyr Asp Lys Met Glu Tyr Lys Leu Leu Pro Gly Ala Asn Lys 610 615 620

    Met Leu Pro Lys Val Phe Phe Ser Glu Thr Gly Ile Gln Arg Phe Leu 625 630 635 640

    Pro Ser Glu Glu Leu Leu Gly Lys Tyr Glu Arg Gly Thr His Lys Lys 645 650 655

    Gly Ala Gly Phe Asp Leu Gly Asp Cys Arg Ala Leu Ile Asp Phe Phe 660 665 670

    Lys Lys Ser Ile Glu Arg His Asp Asp Trp Lys Lys Phe Asp Phe Lys 675 680 685

    Phe Ser Asp Thr Ser Thr Tyr Gln Asp Ile Ser Glu Phe Tyr Arg Glu 690 695 700

    Val Glu Gln Gln Gly Tyr Lys Met Ser Phe Arg Lys Val Ser Val Asp 705 710 715 720

    Tyr Ile Lys Ser Leu Val Glu Glu Gly Lys Leu Tyr Leu Phe Gln Ile 725 730 735

    Tyr Asn Lys Asp Phe Ser Ala His Ser Lys Gly Thr Pro Asn Met His 740 745 750

    Thr Leu Tyr Trp Lys Met Leu Phe Asp Glu Glu Asn Leu Lys Asp Val 755 760 765

    Val Tyr Lys Leu Asn Gly Glu Ala Glu Val Phe Phe Arg Lys Ser Ser 770 775 780

    Ile Thr Val Gln Ser Pro Thr His Pro Ala Asn Ser Pro Ile Lys Asn 785 790 795 800

    Lys Asn Lys Asp Asn Gln Lys Lys Glu Ser Lys Phe Glu Tyr Asp Leu 805 810 815

    Ile Lys Asp Arg Arg Tyr Thr Val Asp Lys Phe Leu Phe His Val Pro 820 825 830

    Ile Thr Met Asn Phe Lys Ser Val Gly Gly Ser Asn Ile Asn Gln Leu 835 840 845

    Val Lys Arg His Ile Arg Ser Ala Thr Asp Leu His Ile Ile Gly Ile 850 855 860

    Asp Arg Gly Glu Arg His Leu Leu Tyr Leu Thr Val Ile Asp Ser Arg 865 870 875 880

    Gly Asn Ile Lys Glu Gln Phe Ser Leu Asn Glu Ile Val Asn Glu Tyr 885 890 895

    Asn Gly Asn Thr Tyr Arg Thr Asp Tyr His Glu Leu Leu Asp Thr Arg 900 905 910

    Glu Gly Glu Arg Thr Glu Ala Arg Arg Asn Trp Gln Thr Ile Gln Asn 915 920 925

    Ile Arg Glu Leu Lys Glu Gly Tyr Leu Ser Gln Val Ile His Lys Ile 930 935 940

    Ser Glu Leu Ala Ile Lys Tyr Asn Ala Val Ile Val Leu Glu Asp Leu 945 950 955 960

    Asn Phe Gly Phe Met Arg Ser Arg Gln Lys Val Glu Lys Gln Val Tyr 965 970 975

    Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp 980 985 990

    Lys Lys Lys Pro Val Ala Glu Thr Gly Gly Leu Leu Arg Ala Tyr Gln 995 1000 1005

    Leu Thr Gly Glu Phe Glu Ser Phe Lys Thr Leu Gly Lys Gln Ser 1010 1015 1020

    Gly Ile Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp 1025 1030 1035

    Pro Val Thr Gly Phe Val Asn Leu Phe Asp Thr His Tyr Glu Asn 1040 1045 1050

    Ile Glu Lys Ala Lys Val Phe Phe Asp Lys Phe Lys Ser Ile Arg 1055 1060 1065

    Tyr Asn Ser Asp Lys Asp Trp Phe Glu Phe Val Val Asp Asp Tyr 1070 1075 1080

    Thr Arg Phe Ser Pro Lys Ala Glu Gly Thr Arg Arg Asp Trp Thr 1085 1090 1095

    Ile Cys Thr Gln Gly Lys Arg Ile Gln Ile Cys Arg Asn His Gln 1100 1105 1110

    Arg Asn Asn Glu Trp Glu Gly Gln Glu Ile Asp Leu Thr Lys Ala 1115 1120 1125

    Phe Lys Glu His Phe Glu Ala Tyr Gly Val Asp Ile Ser Lys Asp 1130 1135 1140

    Leu Arg Glu Gln Ile Asn Thr Gln Asn Lys Lys Glu Phe Phe Glu 1145 1150 1155

    Glu Leu Leu Arg Leu Leu Arg Leu Thr Leu Gln Met Arg Asn Ser 1160 1165 1170

    Met Pro Ser Ser Asp Ile Asp Tyr Leu Ile Ser Pro Val Ala Asn 1175 1180 1185

    Asp Thr Gly Cys Phe Phe Asp Ser Arg Lys Gln Ala Glu Leu Lys 1190 1195 1200

    Glu Asn Ala Val Leu Pro Met Asn Ala Asp Ala Asn Gly Ala Tyr 1205 1210 1215

    Asn Ile Ala Arg Lys Gly Leu Leu Ala Ile Arg Lys Met Lys Gln 1220 1225 1230

    Glu Glu Asn Asp Ser Ala Lys Ile Ser Leu Ala Ile Ser Asn Lys

    1235

    1240

    1245

    Glu Trp Leu Lys Phe Ala Gln Thr Lys Pro Tyr Leu Glu Asp 1250 1255 1260 <210> 1132 <211> 1264 <212> PRT <213> Prevotella brevis <400> 1132

    Met Lys Gln Phe Thr Asn Leu Tyr Gln Leu Ser Lys Thr Leu Arg Phe 1 5 10 15

    Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu His Ile Asn Ala Asn Gly 20 25 30

    Phe Ile Asp Asn Asp Ala His Arg Ala Glu Ser Tyr Lys Lys Val Lys 35 40 45

    Lys Leu Ile Asp Asp Tyr His Lys Asp Tyr Ile Glu Asn Val Leu Asn 50 55 60

    Asn Phe Lys Leu Asn Gly Glu Tyr Leu Gln Ala Tyr Phe Asp Leu Tyr 65 70 75 80

    Ser Gln Asp Thr Lys Asp Lys Gln Phe Lys Asp Ile Gln Asp Lys Leu 85 90 95

    Arg Lys Ser Ile Ala Ser Ala Leu Lys Gly Asp Asp Arg Tyr Lys Thr 100 105 110

    Ile Asp Lys Lys Glu Leu Ile Arg Gln Asp Met Lys Thr Phe Leu Lys 115 120 125

    Lys Asp Thr Asp Lys Ala Leu Leu Asp Glu Phe Tyr Glu Phe Thr Thr 130 135 140

    Tyr Phe Thr Gly Tyr His Glu Asn Arg Lys Asn Met Tyr Ser Asp Glu 145 150 155 160

    Ala Lys Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Asp Asn Leu Pro 165 170 175

    Lys Phe Ile Asp Asn Ile Ala Val Phe Lys Lys Ile Ala Asn Thr Ser 180 185 190

    Val Ala Asp Asn Phe Ser Thr Ile Tyr Lys Asn Phe Glu Glu Tyr Leu 195 200 205

    Asn Val Asn Ser Ile Asp Glu Ile Phe Ser Leu Asp Tyr Tyr Asn Ile 210 215 220

    Val Leu Thr Gln Thr Gln Ile Glu Val Tyr Asn Ser Ile Ile Gly Gly 225 230 235 240

    Arg Thr Leu Glu Asp Asp Thr Lys Ile Gln Gly Ile Asn Glu Phe Val 245 250 255

    Asn Leu Tyr Asn Gln Gln Leu Ala Asn Lys Lys Asp Arg Leu Pro Lys 260 265 270

    Leu Lys Pro Leu Phe Lys Gln Ile Leu Ser Asp Arg Val Gln Leu Ser 275 280 285

    Trp Leu Gln Glu Glu Phe Asn Thr Gly Ala Asp Val Leu Asn Ala Val 290 295 300

    Lys Glu Tyr Cys Thr Ser Tyr Phe Asp Asn Val Glu Glu Ser Val Lys

    305

    310

    315

    320

    Val Leu Leu Thr Gly Ile Ser Asp Tyr Asp Leu Ser Lys Ile Tyr Ile 325 330 335

    Thr Asn Asp Leu Ala Leu Thr Asp Val Ser Gln Arg Met Phe Gly Glu 340 345 350

    Trp Ser Ile Ile Pro Asn Ala Ile Glu Gln Arg Leu Arg Ser Asp Asn 355 360 365

    Pro Lys Lys Thr Asn Glu Lys Glu Glu Lys Tyr Ser Asp Arg Ile Ser 370 375 380

    Lys Leu Lys Lys Leu Pro Lys Ser Tyr Ser Leu Gly Tyr Ile Asn Glu 385 390 395 400

    Cys Ile Ser Glu Leu Asn Gly Ile Asp Ile Ala Asp Tyr Tyr Ala Thr 405 410 415

    Leu Gly Ala Ile Asn Thr Glu Ser Lys Gln Glu Pro Ser Ile Pro Thr 420 425 430

    Ser Ile Gln Val His Tyr Asn Ala Leu Lys Pro Ile Leu Asp Thr Asp 435 440 445

    Tyr Pro Arg Glu Lys Asn Leu Ser Gln Asp Lys Leu Thr Val Met Gln 450 455 460

    Leu Lys Asp Leu Leu Asp Asp Phe Lys Ala Leu Gln His Phe Ile Lys 465 470 475 480

    Pro Leu Leu Gly Asn Gly Asp Glu Ala Glu Lys Asp Glu Lys Phe Tyr 485 490 495

    Gly Glu Leu Met Gln Leu Trp Glu Val Ile Asp Ser Ile Thr Pro Leu 500 505 510

    Tyr Asn Lys Val Arg Asn Tyr Cys Thr Arg Lys Pro Phe Ser Thr Glu 515 520 525

    Lys Ile Lys Val Asn Phe Glu Asn Ala Gln Leu Leu Asp Gly Trp Asp 530 535 540

    Glu Asn Lys Glu Ser Thr Asn Ala Ser Ile Ile Leu Arg Lys Asn Gly 545 550 555 560

    Met Tyr Tyr Leu Gly Ile Met Lys Lys Glu Tyr Arg Asn Ile Leu Thr 565 570 575

    Lys Pro Met Pro Ser Asp Gly Asp Cys Tyr Asp Lys Val Val Tyr Lys 580 585 590

    Phe Phe Lys Asp Ile Thr Thr Met Val Pro Lys Cys Thr Thr Gln Met 595 600 605

    Lys Ser Val Lys Glu His Phe Ser Asn Ser Asn Asp Asp Tyr Thr Leu 610 615 620

    Phe Glu Lys Asp Lys Phe Ile Ala Pro Val Val Ile Thr Lys Glu Ile 625 630 635 640

    Phe Asp Leu Asn Asn Val Leu Tyr Asn Gly Val Lys Lys Phe Gln Ile 645 650 655

    Gly Tyr Leu Asn Asn Thr Gly Asp Ser Phe Gly Tyr Asn His Ala Val 660 665 670

    Glu Ile Trp Lys Ser Phe Cys Leu Lys Phe Leu Lys Ala Tyr Lys Ser 675 680 685

    Thr Ser Ile Tyr Asp Phe Ser Ser Ile Glu Lys Asn Ile Gly Cys Tyr 690 695 700

    Asn Asp Leu Asn Ser Phe Tyr Gly Ala Val Asn Leu Leu Leu Tyr Asn 705 710 715 720

    Leu Thr Tyr Arg Lys Val Ser Val Asp Tyr Ile His Gln Leu Val Asp 725 730 735

    Glu Asp Lys Met Tyr Leu Phe Met Ile Tyr Asn Lys Asp Phe Ser Thr 740 745 750

    Tyr Ser Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Lys Met Leu 755 760 765

    Phe Asp Glu Ser Asn Leu Asn Asp Val Val Tyr Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Thr Tyr Gln His Pro Thr 785 790 795 800

    His Pro Ala Asn Lys Pro Ile Asp Asn Lys Asn Val Asn Asn Pro Lys 805 810 815

    Lys Gln Ser Asn Phe Glu Tyr Asp Leu Ile Lys Asp Lys Arg Tyr Thr 820 825 830

    Val Asp Lys Phe Met Phe His Val Pro Ile Thr Leu Asn Phe Lys Gly 835 840 845

    Met Gly Asn Gly Asp Ile Asn Met Gln Val Arg Glu Tyr Ile Lys Thr 850 855 860

    Thr Asp Asp Leu His Phe Ile Gly Ile Asp Arg Gly Glu Arg His Leu 865 870 875 880

    Leu Tyr Ile Cys Val Ile Asn Gly Lys Gly Glu Ile Val Glu Gln Tyr 885 890 895

    Ser Leu Asn Glu Ile Val Asn Asn Tyr Lys Gly Thr Glu Tyr Lys Thr 900 905 910

    Asp Tyr His Thr Leu Leu Ser Glu Arg Asp Lys Lys Arg Lys Glu Glu 915 920 925

    Arg Ser Ser Trp Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Ser Gly 930 935 940

    Tyr Leu Ser Gln Val Ile His Lys Ile Thr Gln Leu Met Ile Lys Tyr 945 950 955 960

    Asn Ala Ile Val Leu Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly 965 970 975

    Arg Gln Lys Val Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Ala Leu 980 985 990

    Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Asp Ala Asn Glu 995 1000 1005

    Ile Gly Gly Leu Leu His Ala Tyr Gln Leu Thr Asn Asp Pro Lys 1010 1015 1020

    Leu Pro Asn Lys Asn Ser Lys Gln Ser Gly Phe Leu Phe Tyr Val

    1025

    1030

    1035

    Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val Thr Gly Phe Val 1040 1045 1050

    Asn Leu Leu Asp Thr Arg Tyr Glu Asn Val Ala Lys Ala Gln Ala 1055 1060 1065

    Phe Phe Lys Lys Phe Asp Ser Ile Arg Tyr Asn Lys Glu Tyr Asp 1070 1075 1080

    Arg Phe Glu Phe Lys Phe Asp Tyr Ser Asn Phe Thr Ala Lys Ala 1085 1090 1095

    Glu Asp Thr Arg Thr Gln Trp Thr Leu Cys Thr Tyr Gly Thr Arg 1100 1105 1110

    Ile Glu Thr Phe Arg Asn Ala Glu Lys Asn Ser Asn Trp Asp Ser 1115 1120 1125

    Arg Glu Ile Asp Leu Thr Thr Glu Trp Lys Thr Leu Phe Thr Gln 1130 1135 1140

    His Asn Ile Pro Leu Asn Ala Asn Leu Lys Glu Ala Ile Leu Leu 1145 1150 1155

    Gln Ala Asn Lys Asn Phe Tyr Thr Asp Ile Leu His Leu Met Lys 1160 1165 1170

    Leu Thr Leu Gln Met Arg Asn Ser Val Thr Gly Thr Asp Ile Asp 1175 1180 1185

    Tyr Met Val Ser Pro Val Ala Asn Glu Cys Gly Glu Phe Phe Asp 1190 1195 1200

    Ser Arg Lys Val Lys Glu Gly Leu Pro Val Asn Ala Asp Ala Asn 1205 1210 1215 Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Leu Ala Gln Gln 1220 1225 1230 Ile Lys Asn Ala Asn Asp Leu Ser Asp Val Lys Leu Ala Ile Thr 1235 1240 1245

    Asn Lys Glu Trp Leu Gln Phe Ala Gln Lys Lys Gln Tyr Leu Lys 1250 1255 1260

    Asp <210> 1133 <211> 1260 <212> PRT <213> Porphyromonas crevioricanis <400> 1133

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Val Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn

    785

    790

    795

    800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg His Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Ala Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 1134 <211> 1260 <212> PRT <213> Porphyromonas crevioricanis <400> 1134

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly

    565

    570

    575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Val Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Ala Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 1135 <211> 1260 <212> PRT <213> Porphyromonas crevioricanis <400> 1135

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg

    340

    345

    350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Met Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro 645 650 655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu His Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050

    Val Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys

    1055

    1060

    1065

    Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 1136 <211> 1262 <212> PRT <213> Porphyromonas crevioricanis <400> 1136

    Met Pro Trp Ile Asp Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser 1 5 10 15

    Lys Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn 20 25 30

    Ile Glu Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser 35 40 45

    Tyr Arg Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile 50 55 60

    Asp Ser Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile 65 70 75 80

    Lys Ala Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg 85 90 95

    Thr Glu Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg 100 105 110

    Gly Leu Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn

    115

    120

    125

    Thr Val Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile 130 135 140

    Lys Glu Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu 145 150 155 160

    Pro Phe Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser 165 170 175

    Phe Thr Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr 180 185 190

    Ser Thr Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu 195 200 205

    Asn Leu Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys 210 215 220

    Glu Pro Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala 225 230 235 240

    Gly Gly Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu 245 250 255

    Asn Tyr Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn 260 265 270

    Ala Leu Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly 275 280 285

    Leu Asn Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp 290 295 300

    Arg Leu Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg 305 310 315 320

    Glu Gln Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu 325 330 335

    Leu Arg Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu 340 345 350

    Gly Arg Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser 355 360 365

    Arg Ile Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys 370 375 380

    Met Leu Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr 385 390 395 400

    Asp His Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp 405 410 415

    Arg Ile Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu 420 425 430

    Asn Ser Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp 435 440 445

    Thr Tyr Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser 450 455 460

    Asn Leu Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu 465 470 475 480

    Leu Ser Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp 485 490 495

    Asn Val Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln 500 505 510

    Arg Phe Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp 515 520 525

    Glu Arg Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln 530 535 540

    Val Ile Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro 545 550 555 560

    Tyr Ser Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu 565 570 575

    Ser Gly Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu 580 585 590

    Arg Lys Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys 595 600 605

    Arg Ser Phe Glu Asn Lys Val Leu Pro Glu Tyr Lys Glu Gly Glu Pro 610 615 620

    Tyr Phe Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met 625 630 635 640

    Leu Pro Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Glu Pro 645 650 655

    Ser Pro Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly 660 665 670

    Asp Thr Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys 675 680 685

    His Ser Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe 690 695 700

    Ser Asp Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val 705 710 715 720

    Glu Asp Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr 725 730 735

    Val Tyr Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr 740 745 750

    Asn Lys Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr 755 760 765

    Leu Tyr Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile 770 775 780

    Tyr Lys Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu 785 790 795 800

    Lys Asn Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys 805 810 815

    Ser Arg Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val 820 825 830

    Lys Asp Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile

    835

    840

    845

    Thr Met Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val 850 855 860

    Asn Ala His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly 885 890 895

    Thr Ile Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr 900 905 910

    His Asp Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu Arg Arg 915 920 925

    Asn Trp Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu 930 935 940

    Ser Gln Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala 945 950 955 960

    Val Val Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln 965 970 975

    Lys Val Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp 980 985 990

    Lys Leu Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly 995 1000 1005

    Gly Leu Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe 1010 1015 1020

    Lys Glu Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala 1025 1030 1035

    Trp Asn Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu 1040 1045 1050

    Phe His Ala Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe 1055 1060 1065

    Gln Lys Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe 1070 1075 1080

    Glu Phe Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly 1085 1090 1095

    Ser Arg Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys 1100 1105 1110

    Asn Phe Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu 1115 1120 1125

    Phe Ala Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu 1130 1135 1140

    Ile Asp Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys 1145 1150 1155

    Gln Lys Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr 1160 1165 1170

    Val Gln Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu 1175 1180 1185

    Ile Ser Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg 1190 1195 1200

    Glu Gly Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala 1205 1210 1215

    Tyr Asn Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg 1220 1225 1230

    Gln Thr Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys 1235 1240 1245

    Glu Trp Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 1137 <211> 1224 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1137

    Met Gly Leu Tyr Asp Gly Phe Val Asn Arg Tyr Ser Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Arg Thr Arg Glu Tyr Ile Glu 20 25 30

    Thr Asn Gly Ile Leu Ser Asp Asp Glu Glu Arg Ala Lys Asp Tyr Lys 35 40 45

    Thr Ile Lys Arg Leu Ile Asp Glu Tyr His Lys Asp Tyr Ile Ser Arg 50 55 60

    Cys Leu Lys Asn Val Asn Ile Ser Cys Leu Glu Glu Tyr Tyr His Leu 65 70 75 80

    Tyr Asn Ser Ser Asn Arg Asp Lys Arg His Glu Glu Leu Asp Ala Leu 85 90 95

    Ser Asp Gln Met Arg Gly Glu Ile Ala Ser Phe Leu Thr Gly Asn Asp 100 105 110

    Glu Tyr Lys Glu Gln Lys Ser Arg Asp Ile Ile Ile Asn Glu Arg Ile 115 120 125

    Ile Asn Phe Ala Ser Thr Asp Glu Glu Leu Ala Ala Val Lys Arg Phe 130 135 140

    Arg Lys Phe Thr Ser Tyr Phe Thr Gly Phe Phe Thr Asn Arg Glu Asn 145 150 155 160

    Met Tyr Ser Ala Glu Lys Lys Ser Thr Ala Ile Ala His Arg Ile Ile 165 170 175

    Asp Val Asn Leu Pro Lys Tyr Val Asp Asn Ile Lys Ala Phe Asn Thr 180 185 190

    Ala Ile Glu Ala Gly Val Phe Asp Ile Ala Glu Phe Glu Ser Asn Phe 195 200 205

    Lys Ala Ile Thr Asp Glu His Glu Val Ser Asp Leu Leu Asp Ile Thr 210 215 220

    Lys Tyr Ser Arg Phe Ile Arg Asn Glu Asp Ile Ile Ile Tyr Asn Thr 225 230 235 240

    Leu Leu Gly Gly Ile Ser Met Lys Asp Glu Lys Ile Gln Gly Leu Asn 245 250 255

    Glu Leu Ile Asn Leu His Asn Gln Lys His Pro Gly Lys Lys Val Pro 260 265 270

    Leu Leu Lys Val Leu Tyr Lys Gln Ile Leu Gly Asp Ser Gln Thr His 275 280 285

    Ser Phe Val Asp Asp Gln Phe Glu Asp Asp Gln Gln Val Ile Asn Ala 290 295 300

    Val Lys Ala Val Thr Asp Thr Phe Ser Glu Thr Leu Leu Gly Ser Leu 305 310 315 320

    Lys Ile Ile Ile Asn Asn Ile Gly His Tyr Asp Leu Asp Arg Ile Tyr 325 330 335

    Ile Lys Ala Gly Gln Asp Ile Thr Thr Leu Ser Lys Arg Ala Leu Asn 340 345 350

    Asp Trp His Ile Ile Thr Glu Cys Leu Glu Ser Glu Tyr Asp Asp Lys 355 360 365

    Phe Pro Lys Asn Lys Lys Ser Asp Thr Tyr Glu Glu Met Arg Asn Arg 370 375 380

    Tyr Val Lys Ser Phe Lys Ser Phe Ser Ile Gly Arg Leu Asn Ser Leu 385 390 395 400

    Val Thr Thr Tyr Thr Glu Gln Ala Cys Phe Leu Glu Asn Tyr Leu Gly 405 410 415

    Ser Phe Gly Gly Asp Thr Asp Lys Asn Cys Leu Thr Asp Phe Thr Asn 420 425 430

    Ser Leu Met Glu Val Glu His Leu Leu Asn Ser Glu Tyr Pro Val Thr 435 440 445

    Asn Arg Leu Ile Thr Asp Tyr Glu Ser Val Arg Ile Leu Lys Arg Leu 450 455 460

    Leu Asp Ser Glu Met Glu Val Ile His Phe Leu Lys Pro Leu Leu Gly 465 470 475 480

    Asn Gly Asn Glu Ser Asp Lys Asp Leu Val Phe Tyr Gly Glu Phe Glu 485 490 495

    Ala Glu Tyr Glu Lys Leu Leu Pro Val Ile Lys Val Tyr Asn Arg Val 500 505 510

    Arg Asn Tyr Leu Thr Arg Lys Pro Phe Ser Thr Glu Lys Ile Lys Leu 515 520 525

    Asn Phe Asn Ser Pro Thr Leu Leu Cys Gly Trp Ser Gln Ser Lys Glu 530 535 540

    Lys Glu Tyr Met Gly Val Ile Leu Arg Lys Asp Gly Gln Tyr Tyr Leu 545 550 555 560

    Gly Ile Met Thr Pro Ser Asn Lys Lys Ile Phe Ser Glu Ala Pro Lys 565 570 575

    Pro Asp Glu Asp Cys Tyr Glu Lys Met Val Leu Arg Tyr Ile Pro His 580 585 590

    Pro Tyr Gln Met Leu Pro Lys Val Phe Phe Ser Lys Ser Asn Ile Ala

    595

    600

    605

    Phe Phe Asn Pro Ser Asp Glu Ile Leu Arg Ile Lys Lys Gln Glu Ser 610 615 620

    Phe Lys Lys Gly Lys Ser Phe Asn Arg Asp Asp Cys His Lys Phe Ile 625 630 635 640

    Asp Phe Tyr Lys Asp Ser Ile Asn Arg His Glu Glu Trp Arg Lys Phe 645 650 655

    Asn Phe Lys Phe Ser Asp Thr Asp Ser Tyr Glu Asp Ile Ser Arg Phe 660 665 670

    Tyr Lys Glu Val Glu Asn Gln Ala Phe Ser Met Ser Phe Thr Lys Ile 675 680 685

    Pro Thr Val Tyr Ile Asp Ser Leu Val Asp Glu Gly Lys Leu Tyr Leu 690 695 700

    Phe Lys Leu His Asn Lys Asp Phe Ser Glu His Ser Lys Gly Lys Pro 705 710 715 720

    Asn Leu His Thr Val Tyr Trp Asn Ala Leu Phe Ser Glu Tyr Asn Leu 725 730 735

    Gln Asn Thr Val Tyr Gln Leu Asn Gly Ser Ala Glu Ile Phe Phe Arg 740 745 750

    Lys Ala Ser Ile Pro Glu Asn Glu Arg Val Ile His Lys Lys Asn Val 755 760 765

    Pro Ile Thr Arg Lys Val Ala Glu Leu Asn Gly Lys Lys Glu Val Ser 770 775 780

    Val Phe Pro Tyr Asp Ile Ile Lys Asn Arg Arg Tyr Thr Val Asp Lys 785 790 795 800

    Phe Gln Phe His Val Pro Leu Lys Met Asn Phe Lys Ala Asp Glu Lys 805 810 815

    Lys Arg Ile Asn Asp Asp Val Ile Glu Ala Ile Arg Ser Asn Lys Gly 820 825 830

    Ile His Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Leu 835 840 845

    Ser Leu Ile Asn Glu Glu Gly Arg Ile Ile Glu Gln Arg Ser Leu Asn 850 855 860

    Ile Ile Asp Ser Gly Glu Gly His Thr Gln Asn Tyr Arg Asp Leu Leu 865 870 875 880

    Asp Ser Arg Glu Lys Asp Arg Glu Lys Ala Arg Glu Asn Trp Gln Glu 885 890 895

    Ile Gln Glu Ile Lys Asp Leu Lys Thr Gly Tyr Leu Ser Gln Ala Ile 900 905 910

    His Thr Ile Thr Lys Trp Met Lys Glu Tyr Asn Ala Ile Ile Val Leu 915 920 925

    Glu Asp Leu Asn Asp Arg Phe Thr Asn Gly Arg Lys Lys Val Glu Lys 930 935 940

    Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr 945 950 955 960

    Tyr Val Asp Lys Asp Glu Glu Phe Asp Arg Met Gly Gly Thr His Arg 965 970 975

    Ala Leu Gln Leu Thr Glu Lys Phe Glu Ser Phe Gln Lys Leu Gly Arg 980 985 990

    Gln Thr Gly Phe Ile Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Leu 995 1000 1005

    Asp Pro Thr Thr Gly Phe Val Asp Leu Leu Tyr Pro Lys Tyr Lys 1010 1015 1020

    Ser Val Asp Ala Thr Lys Asp Phe Ile Lys Lys Phe Asp Phe Ile 1025 1030 1035

    Arg Phe Asn Ser Glu Lys Asn Tyr Phe Glu Phe Gly Leu His Tyr 1040 1045 1050

    Ser Asn Phe Thr Glu Arg Ala 1055 1060

    Ile Gly Cys Arg Asp Glu Trp Ile 1065

    Leu Cys Ser Tyr Gly Asn Arg 1070 1075

    Ile Val Asn Phe Arg Asn Ala Ala 1080

    Lys Asn Asn Ser Trp Asp Tyr 1085 1090

    Lys Glu Ile Asp Ile Thr Lys Gln 1095

    Leu Leu Asp Leu Phe Glu Lys Asn Gly Ile Asp Val Lys Gln Glu 1100 1105 1110

    Asn Leu Ile Asp Ser Ile Cys Glu Met Lys Asp Lys Pro Phe Phe 1115 1120 1125

    Lys Ser Leu Ile Ala Asn Ile Lys Leu Ile Leu Gln Ile Arg Asn 1130 1135 1140

    Ser Ala Ser Gly Thr Asp Ile Asp Tyr Met Ile Ser Pro Ala Met 1145 1150 1155

    Asn Asp Arg Gly Glu Phe Phe Asp Thr Arg Lys Gly Leu Gln Gln 1160 1165 1170

    Leu Pro Leu Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Lys 1175 1180 1185

    Lys Gly Leu Trp Ile Val Asp Gln Ile Arg Asn Thr Thr Gly Asn 1190 1195 1200

    Asn Val Lys Met Ala Met Ser Asn Arg Glu Trp Met His Phe Ala 1205 1210 1215

    Gln Glu Ser Arg Leu Ala 1220 <210> 1138 <211> 1318 <212> PRT <213> Flavobacterium branchiophilum <400> 1138

    Met Thr Asn Lys Phe Thr Asn Gln Tyr Ser Leu Ser Lys Thr Leu Arg 1 5 10 15

    Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Phe Ile Gln Glu Lys 20 25 30

    Gly Leu Leu Ser Gln Asp Lys Gln Arg Ala Glu Ser Tyr Gln Glu Met 35 40 45

    Lys Lys Thr Ile Asp Lys Phe His Lys Tyr Phe Ile Asp Leu Ala Leu 50 55 60

    Ser Asn Ala Lys Leu Thr His Leu Glu Thr Tyr Leu Glu Leu Tyr Asn 65 70 75 80

    Lys Ser Ala Glu Thr Lys Lys Glu Gln Lys Phe Lys Asp Asp Leu Lys 85 90 95

    Lys Val Gln Asp Asn Leu Arg Lys Glu Ile Val Lys Ser Phe Ser Asp 100 105 110

    Gly Asp Ala Lys Ser Ile Phe Ala Ile Leu Asp Lys Lys Glu Leu Ile 115 120 125

    Thr Val Glu Leu Glu Lys Trp Phe Glu Asn Asn Glu Gln Lys Asp Ile 130 135 140

    Tyr Phe Asp Glu Lys Phe Lys Thr Phe Thr Thr Tyr Phe Thr Gly Phe 145 150 155 160

    His Gln Asn Arg Lys Asn Met Tyr Ser Val Glu Pro Asn Ser Thr Ala 165 170 175

    Ile Ala Tyr Arg Leu Ile His Glu Asn Leu Pro Lys Phe Leu Glu Asn 180 185 190

    Ala Lys Ala Phe Glu Lys Ile Lys Gln Val Glu Ser Leu Gln Val Asn 195 200 205

    Phe Arg Glu Leu Met Gly Glu Phe Gly Asp Glu Gly Leu Ile Phe Val 210 215 220

    Asn Glu Leu Glu Glu Met Phe Gln Ile Asn Tyr Tyr Asn Asp Val Leu 225 230 235 240

    Ser Gln Asn Gly Ile Thr Ile Tyr Asn Ser Ile Ile Ser Gly Phe Thr 245 250 255

    Lys Asn Asp Ile Lys Tyr Lys Gly Leu Asn Glu Tyr Ile Asn Asn Tyr 260 265 270

    Asn Gln Thr Lys Asp Lys Lys Asp Arg Leu Pro Lys Leu Lys Gln Leu 275 280 285

    Tyr Lys Gln Ile Leu Ser Asp Arg Ile Ser Leu Ser Phe Leu Pro Asp 290 295 300

    Ala Phe Thr Asp Gly Lys Gln Val Leu Lys Ala Ile Phe Asp Phe Tyr 305 310 315 320

    Lys Ile Asn Leu Leu Ser Tyr Thr Ile Glu Gly Gln Glu Glu Ser Gln 325 330 335

    Asn Leu Leu Leu Leu Ile Arg Gln Thr Ile Glu Asn Leu Ser Ser Phe 340 345 350

    Asp Thr Gln Lys Ile Tyr Leu Lys Asn Asp Thr His Leu Thr Thr Ile 355 360 365

    Ser Gln Gln Val Phe Gly Asp Phe Ser Val Phe Ser Thr Ala Leu Asn 370 375 380

    Tyr Trp Tyr Glu Thr Lys Val Asn Pro Lys Phe Glu Thr Glu Tyr Ser 385 390 395 400

    Lys Ala Asn Glu Lys Lys Arg Glu Ile Leu Asp Lys Ala Lys Ala Val

    405

    410

    415

    Phe Thr Lys Gln Asp Tyr Phe Ser Ile Ala Phe Leu Gln Glu Val Leu 420 425 430

    Ser Glu Tyr Ile Leu Thr Leu Asp His Thr Ser Asp Ile Val Lys Lys 435 440 445

    His Ser Ser Asn Cys Ile Ala Asp Tyr Phe Lys Asn His Phe Val Ala 450 455 460

    Lys Lys Glu Asn Glu Thr Asp Lys Thr Phe Asp Phe Ile Ala Asn Ile 465 470 475 480

    Thr Ala Lys Tyr Gln Cys Ile Gln Gly Ile Leu Glu Asn Ala Asp Gln 485 490 495

    Tyr Glu Asp Glu Leu Lys Gln Asp Gln Lys Leu Ile Asp Asn Leu Lys 500 505 510

    Phe Phe Leu Asp Ala Ile Leu Glu Leu Leu His Phe Ile Lys Pro Leu 515 520 525

    His Leu Lys Ser Glu Ser Ile Thr Glu Lys Asp Thr Ala Phe Tyr Asp 530 535 540

    Val Phe Glu Asn Tyr Tyr Glu Ala Leu Ser Leu Leu Thr Pro Leu Tyr 545 550 555 560

    Asn Met Val Arg Asn Tyr Val Thr Gln Lys Pro Tyr Ser Thr Glu Lys 565 570 575

    Ile Lys Leu Asn Phe Glu Asn Ala Gln Leu Leu Asn Gly Trp Asp Ala 580 585 590

    Asn Lys Glu Gly Asp Tyr Leu Thr Thr Ile Leu Lys Lys Asp Gly Asn 595 600 605

    Tyr Phe Leu Ala Ile Met Asp Lys Lys His Asn Lys Ala Phe Gln Lys 610 615 620

    Phe Pro Glu Gly Lys Glu Asn Tyr Glu Lys Met Val Tyr Lys Leu Leu 625 630 635 640

    Pro Gly Val Asn Lys Met Leu Pro Lys Val Phe Phe Ser Asn Lys Asn 645 650 655

    Ile Ala Tyr Phe Asn Pro Ser Lys Glu Leu Leu Glu Asn Tyr Lys Lys 660 665 670

    Glu Thr His Lys Lys Gly Asp Thr Phe Asn Leu Glu His Cys His Thr 675 680 685

    Leu Ile Asp Phe Phe Lys Asp Ser Leu Asn Lys His Glu Asp Trp Lys 690 695 700

    Tyr Phe Asp Phe Gln Phe Ser Glu Thr Lys Ser Tyr Gln Asp Leu Ser 705 710 715 720

    Gly Phe Tyr Arg Glu Val Glu His Gln Gly Tyr Lys Ile Asn Phe Lys 725 730 735

    Asn Ile Asp Ser Glu Tyr Ile Asp Gly Leu Val Asn Glu Gly Lys Leu 740 745 750

    Phe Leu Phe Gln Ile Tyr Ser Lys Asp Phe Ser Pro Phe Ser Lys Gly 755 760 765

    Lys Pro Asn Met His Thr Leu Tyr Trp Lys Ala Leu Phe Glu Glu Gln 770 775 780

    Asn Leu Gln Asn Val Ile Tyr Lys Leu Asn Gly Gln Ala Glu Ile Phe 785 790 795 800

    Phe Arg Lys Ala Ser Ile Lys Pro Lys Asn Ile Ile Leu His Lys Lys 805 810 815

    Lys Ile Lys Ile Ala Lys Lys His Phe Ile Asp Lys Lys Thr Lys Thr 820 825 830

    Ser Glu Ile Val Pro Val Gln Thr Ile Lys Asn Leu Asn Met Tyr Tyr 835 840 845

    Gln Gly Lys Ile Ser Glu Lys Glu Leu Thr Gln Asp Asp Leu Arg Tyr 850 855 860

    Ile Asp Asn Phe Ser Ile Phe Asn Glu Lys Asn Lys Thr Ile Asp Ile 865 870 875 880

    Ile Lys Asp Lys Arg Phe Thr Val Asp Lys Phe Gln Phe His Val Pro 885 890 895

    Ile Thr Met Asn Phe Lys Ala Thr Gly Gly Ser Tyr Ile Asn Gln Thr 900 905 910

    Val Leu Glu Tyr Leu Gln Asn Asn Pro Glu Val Lys Ile Ile Gly Leu 915 920 925

    Asp Arg Gly Glu Arg His Leu Val Tyr Leu Thr Leu Ile Asp Gln Gln 930 935 940

    Gly Asn Ile Leu Lys Gln Glu Ser Leu Asn Thr Ile Thr Asp Ser Lys 945 950 955 960

    Ile Ser Thr Pro Tyr His Lys Leu Leu Asp Asn Lys Glu Asn Glu Arg 965 970 975

    Asp Leu Ala Arg Lys Asn Trp Gly Thr Val Glu Asn Ile Lys Glu Leu 980 985 990

    Lys Glu Gly Tyr Ile Ser Gln Val Val His Lys Ile Ala Thr Leu Met 995 1000 1005

    Leu Glu Glu Asn Ala Ile Val Val Met Glu Asp Leu Asn Phe Gly 1010 1015 1020

    Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr Gln Lys 1025 1030 1035

    Leu Glu Lys Met Leu Ile Asp 1040 1045

    Lys Leu Asn Tyr Leu Val Leu Lys 1050

    Asp Lys Gln Pro Gln Glu Leu 1055 1060

    Gly Gly Leu Tyr Asn Ala Leu Gln 1065

    Leu Thr Asn Lys Phe Glu Ser 1070 1075

    Phe Gln Lys Met Gly Lys Gln Ser 1080

    Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp 1085 1090 1095

    Pro Thr Thr Gly Phe Val Asn Tyr Phe Tyr Thr Lys Tyr Glu Asn 1100 1105 1110

    Val Asp Lys Ala Lys Ala Phe Phe Glu Lys Phe Glu Ala Ile Arg

    1115

    1120

    1125

    Phe Asn Ala Glu Lys Lys Tyr Phe Glu Phe Glu Val Lys Lys Tyr 1130 1135 1140

    Ser Asp Phe Asn Pro Lys Ala Glu Gly Thr Gln Gln Ala Trp Thr 1145 1150 1155

    Ile Cys Thr Tyr Gly Glu Arg Ile Glu Thr Lys Arg Gln Lys Asp 1160 1165 1170

    Gln Asn Asn Lys Phe Val Ser Thr Pro Ile Asn Leu Thr Glu Lys 1175 1180 1185

    Ile Glu Asp Phe Leu Gly Lys Asn Gln Ile Val Tyr Gly Asp Gly 1190 1195 1200

    Asn Cys Ile Lys Ser Gln Ile Ala Ser Lys Asp Asp Lys Ala Phe 1205 1210 1215

    Phe Glu Thr Leu Leu Tyr Trp Phe Lys Met Thr Leu Gln Met Arg 1220 1225 1230

    Asn Ser Glu Thr Arg Thr Asp Ile Asp Tyr Leu Ile Ser Pro Val 1235 1240 1245

    Met Asn Asp Asn Gly Thr Phe Tyr Asn Ser Arg Asp Tyr Glu Lys 1250 1255 1260

    Leu Glu Asn Pro Thr Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala 1265 1270 1275

    Tyr His Ile Ala Lys Lys Gly Leu Met Leu Leu Asn Lys Ile Asp 1280 1285 1290

    Gln Ala Asp Leu Thr Lys Lys Val Asp Leu Ser Ile Ser Asn Arg 1295 1300 1305

    Asp Trp Leu Gln Phe Val Gln Lys Asn Lys 1310 1315 <210> 1139 <211> 1273 <212> PRT <213> Flavobacterium sp.

    <400> 1139

    Met Lys Asn Phe Ser Asn Leu Tyr Gln Val Ser Lys Thr Val Arg Phe 1 5 10 15

    Glu Leu Lys Pro Ile Gly Asn Thr Leu Glu Asn Ile Lys Asn Lys Ser 20 25 30

    Leu Leu Lys Asn Asp Ser Ile Arg Ala Glu Ser Tyr Gln Lys Met Lys 35 40 45

    Lys Thr Ile Asp Glu Phe His Lys Tyr Phe Ile Asp Leu Ala Leu Asn 50 55 60

    Asn Lys Lys Leu Ser Tyr Leu Asn Glu Tyr Ile Ala Leu Tyr Thr Gln 65 70 75 80

    Ser Ala Glu Ala Lys Lys Glu Asp Lys Phe Lys Ala Asp Phe Lys Lys 85 90 95

    Val Gln Asp Asn Leu Arg Lys Glu Ile Val Ser Ser Phe Thr Glu Gly 100 105 110

    Glu Ala Lys Ala Ile Phe Ser Val Leu Asp Lys Lys Glu Leu Ile Thr

    115

    120

    125

    Ile Glu Leu Glu Lys Trp Lys Asn Glu Asn Asn Leu Ala Val Tyr Leu 130 135 140

    Asp Glu Ser Phe Lys Ser Phe Thr Thr Tyr Phe Thr Gly Phe His Gln 145 150 155 160

    Asn Arg Lys Asn Met Tyr Ser Ala Glu Ala Asn Ser Thr Ala Ile Ala 165 170 175

    Tyr Arg Leu Ile His Glu Asn Leu Pro Lys Phe Ile Glu Asn Ser Lys 180 185 190

    Ala Phe Glu Lys Ser Ser Gln Ile Ala Glu Leu Gln Pro Lys Ile Glu 195 200 205

    Lys Leu Tyr Lys Glu Phe Glu Ala Tyr Leu Asn Val Asn Ser Ile Ser 210 215 220

    Glu Leu Phe Glu Ile Asp Tyr Phe Asn Glu Val Leu Thr Gln Lys Gly 225 230 235 240

    Ile Thr Val Tyr Asn Asn Ile Ile Gly Gly Arg Thr Ala Thr Glu Gly 245 250 255

    Lys Gln Lys Ile Gln Gly Leu Asn Glu Ile Ile Asn Leu Tyr Asn Gln 260 265 270

    Thr Lys Pro Lys Asn Glu Arg Leu Pro Lys Leu Lys Gln Leu Tyr Lys 275 280 285

    Gln Ile Leu Ser Asp Arg Ile Ser Leu Ser Phe Leu Pro Asp Ala Phe 290 295 300

    Thr Glu Gly Lys Gln Val Leu Lys Ala Val Phe Glu Phe Tyr Lys Ile 305 310 315 320

    Asn Leu Leu Ser Tyr Lys Gln Asp Gly Val Glu Glu Ser Gln Asn Leu 325 330 335

    Leu Glu Leu Ile Gln Gln Val Val Lys Asn Leu Gly Asn Gln Asp Val 340 345 350

    Asn Lys Ile Tyr Leu Lys Asn Asp Thr Ser Leu Thr Thr Ile Ala Gln 355 360 365

    Gln Leu Phe Gly Asp Phe Ser Val Phe Ser Ala Ala Leu Gln Tyr Arg 370 375 380

    Tyr Glu Thr Val Val Asn Pro Lys Tyr Thr Ala Glu Tyr Gln Lys Ala 385 390 395 400

    Asn Glu Ala Lys Gln Glu Lys Leu Asp Lys Glu Lys Ile Lys Phe Val 405 410 415

    Lys Gln Asp Tyr Phe Ser Ile Ala Phe Leu Gln Glu Val Val Ala Asp 420 425 430

    Tyr Val Lys Thr Leu Asp Glu Asn Leu Asp Trp Lys Gln Lys Tyr Thr 435 440 445

    Pro Ser Cys Ile Ala Asp Tyr Phe Thr Thr His Phe Ile Ala Lys Lys 450 455 460

    Glu Asn Glu Ala Asp Lys Thr Phe Asn Phe Ile Ala Asn Ile Lys Ala 465 470 475 480

    Lys Tyr Gln Cys Ile Gln Gly Ile Leu Glu Gln Ala Asp Asp Tyr Glu 485 490 495

    Asp Glu Leu Lys Gln Asp Gln Lys Leu Ile Asp Asn Ile Lys Phe Phe 500 505 510

    Leu Asp Ala Ile Leu Glu Val Val His Phe Ile Lys Pro Leu His Leu 515 520 525

    Lys Ser Glu Ser Ile Thr Glu Lys Asp Asn Ala Phe Tyr Asp Val Phe 530 535 540

    Glu Asn Tyr Tyr Glu Ala Leu Asn Val Val Thr Pro Leu Tyr Asn Met 545 550 555 560

    Val Arg Asn Tyr Val Thr Gln Lys Pro Tyr Ser Thr Glu Lys Ile Lys 565 570 575

    Leu Asn Phe Glu Asn Ala Gln Leu Leu Asn Gly Trp Asp Ala Asn Lys 580 585 590

    Glu Lys Asp Tyr Leu Thr Thr Ile Leu Lys Arg Asp Gly Asn Tyr Phe 595 600 605

    Leu Ala Ile Met Asp Lys Lys His Asn Lys Thr Phe Gln Gln Phe Thr 610 615 620

    Glu Asp Asp Glu Asn Tyr Glu Lys Ile Val Tyr Lys Leu Leu Pro Gly 625 630 635 640

    Val Asn Lys Met Leu Pro Lys Val Phe Phe Ser Asn Lys Asn Ile Ala 645 650 655

    Phe Phe Asn Pro Ser Lys Glu Ile Leu Asp Asn Tyr Lys Asn Asn Thr 660 665 670

    His Lys Lys Gly Ala Thr Phe Asn Leu Lys Asp Cys His Ala Leu Ile 675 680 685

    Asp Phe Phe Lys Asp Ser Leu Asn Lys His Glu Asp Trp Lys Tyr Phe 690 695 700

    Asp Phe Gln Phe Ser Glu Thr Lys Thr Tyr Gln Asp Leu Ser Gly Phe 705 710 715 720

    Tyr Lys Glu Val Glu His Gln Gly Tyr Lys Ile Asn Phe Lys Lys Val 725 730 735

    Ser Val Ser Gln Ile Asp Thr Leu Ile Glu Glu Gly Lys Met Tyr Leu 740 745 750

    Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Tyr Ala Lys Gly Lys Pro 755 760 765

    Asn Met His Thr Leu Tyr Trp Lys Ala Leu Phe Glu Thr Gln Asn Leu 770 775 780

    Glu Asn Val Ile Tyr Lys Leu Asn Gly Gln Ala Glu Ile Phe Phe Arg 785 790 795 800

    Lys Ala Ser Ile Lys Lys Lys Asn Ile Ile Thr His Lys Ala His Gln 805 810 815

    Pro Ile Ala Ala Lys Asn Pro Leu Thr Pro Thr Ala Lys Asn Thr Phe 820 825 830

    Ala Tyr Asp Leu Ile Lys Asp Lys Arg Tyr Thr Val Asp Lys Phe Gln

    835

    840

    845

    Phe His Val Pro Ile Thr Met Asn Phe Lys Ala Thr Gly Asn Ser Tyr 850 855 860

    Ile Asn Gln Asp Val Leu Ala Tyr Leu Lys Asp Asn Pro Glu Val Asn 865 870 875 880

    Ile Ile Gly Leu Asp Arg Gly Glu Arg His Leu Val Tyr Leu Thr Leu 885 890 895

    Ile Asp Gln Lys Gly Thr Ile Leu Leu Gln Glu Ser Leu Asn Val Ile 900 905 910

    Gln Asp Glu Lys Thr His Thr Pro Tyr His Thr Leu Leu Asp Asn Lys 915 920 925

    Glu Ile Ala Arg Asp Lys Ala Arg Lys Asn Trp Gly Ser Ile Glu Ser 930 935 940

    Ile Lys Glu Leu Lys Glu Gly Tyr Ile Ser Gln Val Val His Lys Ile 945 950 955 960

    Thr Lys Met Met Ile Glu His Asn Ala Ile Val Val Met Glu Asp Leu 965 970 975

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 980 985 990

    Gln Lys Leu Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Leu 995 1000 1005

    Lys Asp Lys Gln Pro His Glu Leu Gly Gly Leu Tyr Asn Ala Leu 1010 1015 1020

    Gln Leu Thr Asn Lys Phe Glu Ser Phe Gln Lys Met Gly Lys Gln 1025 1030 1035

    Ser Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile 1040 1045 1050

    Asp Pro Thr Thr Gly Phe Val Asn Tyr Phe Tyr Thr Lys Tyr Glu 1055 1060 1065

    Asn Val Glu Lys Ala Lys Thr Phe Phe Ser Lys Phe Asp Ser Ile 1070 1075 1080

    Leu Tyr Asn Lys Thr Lys Gly Tyr Phe Glu Phe Val Val Lys Asn 1085 1090 1095

    Tyr Ser Asp Phe Asn Pro Lys Ala Ala Asp Thr Arg Gln Glu Trp 1100 1105 1110

    Thr Ile Cys Thr His Gly Glu Arg Ile Glu Thr Lys Arg Gln Lys 1115 1120 1125

    Glu Gln Asn Asn Asn Phe Val Ser Thr Thr Ile Gln Leu Thr Glu 1130 1135 1140

    Gln Phe Val Asn Phe Phe Glu Lys Val Gly Leu Asp Leu Ser Lys 1145 1150 1155

    Glu Leu Lys Thr Gln Leu Ile Ala Gln Asn Glu Lys Ser Phe Phe 1160 1165 1170

    Glu Glu Leu Phe His Leu Leu Lys Leu Thr Leu Gln Met Arg Asn 1175 1180 1185

    Ser Glu Ser His Thr Glu Ile Asp Tyr Leu Ile Ser Pro Val Ala 1190 1195 1200

    Asn Glu Lys Gly Ile Phe Tyr Asp Ser Arg Lys Ala Thr Ala Ser 1205 1210 1215

    Leu Pro Ile Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Lys 1220 1225 1230

    Lys Gly Leu Trp Ile Met Glu Gln Ile Asn Lys Thr Asn Ser Glu 1235 1240 1245

    Asp Asp Leu Lys Lys Val Lys Leu Ala Ile Ser Asn Arg Glu Trp 1250 1255 1260

    Leu Gln Tyr Val Gln Gln Val Gln Lys Lys 1265 1270 <210> 1140 <211> 1264 <212> PRT <213> Smithella sp.

    <400> 1140

    Met Gln Thr Leu Phe Glu Asn Phe Thr Asn Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Lys Asp Phe Ile 20 25 30

    Glu Gln Lys Gly Leu Leu Lys Lys Asp Glu Asp Arg Ala Glu Lys Tyr 35 40 45

    Lys Lys Val Lys Asn Ile Ile Asp Glu Tyr His Lys Asp Phe Ile Glu 50 55 60

    Lys Ser Leu Asn Gly Leu Lys Leu Asp Gly Leu Glu Lys Tyr Lys Thr 65 70 75 80

    Leu Tyr Leu Lys Gln Glu Lys Asp Asp Lys Asp Lys Lys Ala Phe Asp 85 90 95

    Lys Glu Lys Glu Asn Leu Arg Lys Gln Ile Ala Asn Ala Phe Arg Asn 100 105 110

    Asn Glu Lys Phe Lys Thr Leu Phe Ala Lys Glu Leu Ile Lys Asn Asp 115 120 125

    Leu Met Ser Phe Ala Cys Glu Glu Asp Lys Lys Asn Val Lys Glu Phe 130 135 140

    Glu Ala Phe Thr Thr Tyr Phe Thr Gly Phe His Gln Asn Arg Ala Asn 145 150 155 160

    Met Tyr Val Ala Asp Glu Lys Arg Thr Ala Ile Ala Ser Arg Leu Ile 165 170 175

    His Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe Glu Lys 180 185 190

    Met Lys Lys Glu Ala Pro Glu Leu Leu Ser Pro Phe Asn Gln Thr Leu 195 200 205

    Lys Asp Met Lys Asp Val Ile Lys Gly Thr Thr Leu Glu Glu Ile Phe 210 215 220

    Ser Leu Asp Tyr Phe Asn Lys Thr Leu Thr Gln Ser Gly Ile Asp Ile 225 230 235 240

    Tyr Asn Ser Val Ile Gly Gly Arg Thr Pro Glu Glu Gly Lys Thr Lys 245 250 255

    Ile Lys Gly Leu Asn Glu Tyr Ile Asn Thr Tyr Phe Thr Gly Phe His 260 265 270

    Gln Asn Arg Ala Asn Met Tyr Val Asp Phe Asn Gln Lys Gln Thr Asp 275 280 285

    Lys Lys Lys Arg Gln Pro Lys Phe Lys Gln Leu Tyr Lys Gln Ile Leu 290 295 300

    Ser Asp Arg Gln Ser Leu Ser Phe Ile Ala Glu Ala Phe Lys Asn Asp 305 310 315 320

    Thr Glu Ile Leu Glu Ala Ile Glu Lys Phe Tyr Val Asn Glu Leu Leu 325 330 335

    His Phe Ser Asn Glu Gly Lys Ser Thr Asn Val Leu Asp Ala Ile Lys 340 345 350

    Asn Ala Val Ser Asn Leu Glu Ser Phe Asn Leu Thr Lys Met Tyr Phe 355 360 365

    Arg Ser Gly Ala Ser Leu Thr Asp Val Ser Arg Lys Val Phe Gly Glu 370 375 380

    Trp Ser Ile Ile Asn Arg Ala Leu Asp Asn Tyr Tyr Ala Thr Thr Tyr 385 390 395 400

    Pro Ile Lys Pro Arg Glu Lys Ser Glu Lys Tyr Glu Glu Arg Lys Glu 405 410 415

    Lys Trp Leu Lys Gln Asp Phe Asn Val Ser Leu Ile Gln Thr Ala Ile 420 425 430

    Asp Glu Tyr Asp Asn Glu Thr Val Lys Gly Lys Asn Ser Gly Lys Val 435 440 445

    Ile Ala Asp Tyr Phe Ala Lys Phe Cys Asp Asp Lys Glu Thr Asp Leu 450 455 460

    Ile Gln Lys Val Asn Glu Gly Tyr Ile Ala Val Lys Asp Leu Leu Asn 465 470 475 480

    Thr Pro Cys Pro Glu Asn Glu Lys Leu Gly Ser Asn Lys Asp Gln Val 485 490 495

    Lys Gln Ile Lys Ala Phe Met Asp Ser Ile Met Asp Ile Met His Phe 500 505 510

    Val Arg Pro Leu Ser Leu Lys Asp Thr Asp Lys Glu Lys Asp Glu Thr 515 520 525

    Phe Tyr Ser Leu Phe Thr Pro Leu Tyr Asp His Leu Thr Gln Thr Ile 530 535 540

    Ala Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro Tyr Ser 545 550 555 560

    Thr Glu Lys Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu Gly Gly 565 570 575

    Trp Asp Leu Asn Lys Glu Thr Asp Asn Thr Ala Ile Ile Leu Arg Lys 580 585 590

    Asp Asn Leu Tyr Tyr Leu Gly Ile Met Asp Lys Arg His Asn Arg Ile

    595

    600

    605

    Phe Arg Asn Val Pro Lys Ala Asp Lys Lys Asp Phe Cys Tyr Glu Lys 610 615 620

    Met Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 625 630 635 640

    Phe Phe Ser Gln Ser Arg Ile Gln Glu Phe Thr Pro Ser Ala Lys Leu 645 650 655

    Leu Glu Asn Tyr Ala Asn Glu Thr His Lys Lys Gly Asp Asn Phe Asn 660 665 670

    Leu Asn His Cys His Lys Leu Ile Asp Phe Phe Lys Asp Ser Ile Asn 675 680 685

    Lys His Glu Asp Trp Lys Asn Phe Asp Phe Arg Phe Ser Ala Thr Ser 690 695 700

    Thr Tyr Ala Asp Leu Ser Gly Phe Tyr His Glu Val Glu His Gln Gly 705 710 715 720

    Tyr Lys Ile Ser Phe Gln Ser Val Ala Asp Ser Phe Ile Asp Asp Leu 725 730 735

    Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 740 745 750

    Ser Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Lys 755 760 765

    Met Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys Leu Asn 770 775 780

    Gly Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala Glu Lys Asn 785 790 795 800

    Thr Thr Ile His Lys Ala Asn Glu Ser Ile Ile Asn Lys Asn Pro Asp 805 810 815

    Asn Pro Lys Ala Thr Ser Thr Phe Asn Tyr Asp Ile Val Lys Asp Lys 820 825 830

    Arg Tyr Thr Ile Asp Lys Phe Gln Phe His Ile Pro Ile Thr Met Asn 835 840 845

    Phe Lys Ala Glu Gly Ile Phe Asn Met Asn Gln Arg Val Asn Gln Phe 850 855 860

    Leu Lys Ala Asn Pro Asp Ile Asn Ile Ile Gly Ile Asp Arg Gly Glu 865 870 875 880

    Arg His Leu Leu Tyr Tyr Ala Leu Ile Asn Gln Lys Gly Lys Ile Leu 885 890 895

    Lys Gln Asp Thr Leu Asn Val Ile Ala Asn Glu Lys Gln Lys Val Asp 900 905 910

    Tyr His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr Ala Arg 915 920 925

    Gln Glu Trp Gly Val Ile Glu Thr Ile Lys Glu Leu Lys Glu Gly Tyr 930 935 940

    Leu Ser Gln Val Ile His Lys Leu Thr Asp Leu Met Ile Glu Asn Asn 945 950 955 960

    Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe Lys Arg Gly Arg 965 970 975

    Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile 980 985 990

    Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Lys Ala Asn Glu Leu 995 1000 1005

    Gly Gly Leu Leu Asn Ala Phe Gln Leu Ala Asn Lys Phe Glu Ser 1010 1015 1020

    Phe Gln Lys Met Gly Lys Gln Asn Gly Phe Ile Phe Tyr Val Pro 1025 1030 1035

    Ala Trp Asn Thr Ser Lys Thr Asp Pro Ala Thr Gly Phe Ile Asp 1040 1045 1050

    Phe Leu Lys Pro Arg Tyr Glu Asn Leu Asn Gln Ala Lys Asp Phe 1055 1060 1065

    Phe Glu Lys Phe Asp Ser Ile Arg Leu Asn Ser Lys Ala Asp Tyr 1070 1075 1080

    Phe Glu Phe Ala Phe Asp Phe Lys Asn Phe Thr Glu Lys Ala Asp 1085 1090 1095

    Gly Gly Arg Thr Lys Trp Thr Val Cys Thr Thr Asn Glu Asp Arg 1100 1105 1110

    Tyr Ala Trp Asn Arg Ala Leu Asn Asn Asn Arg Gly Ser Gln Glu 1115 1120 1125

    Lys Tyr Asp Ile Thr Ala Glu Leu Lys Ser Leu Phe Asp Gly Lys 1130 1135 1140

    Val Asp Tyr Lys Ser Gly Lys Asp Leu Lys Gln Gln Ile Ala Ser 1145 1150 1155

    Gln Glu Ser Ala Asp Phe Phe Lys Ala Leu Met Lys Asn Leu Ser 1160 1165 1170

    Ile Thr Leu Ser Leu Arg His Asn Asn Gly Glu Lys Gly Asp Asn 1175 1180 1185

    Glu Gln Asp Tyr Ile Leu Ser Pro Val Ala Asp Ser Lys Gly Arg 1190 1195 1200

    Phe Phe Asp Ser Arg Lys Ala Asp Asp Asp Met Pro Lys Asn Ala 1205 1210 1215

    Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Trp Cys 1220 1225 1230

    Leu Glu Gln Ile Ser Lys Thr Asp Asp Leu Lys Lys Val Lys Leu 1235 1240 1245

    Ala Ile Ser Asn Lys Glu Trp Leu Glu Phe Val Gln Thr Leu Lys 1250 1255 1260

    Gly <210> 1141 <211> 1250 <212> PRT <213> Smithella sp.

    <400> 1141

    Met Gln Thr Leu Phe Glu Asn Phe Thr Asn Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Lys Asp Phe Ile 20 25 30

    Glu Gln Lys Gly Leu Leu Lys Lys Asp Glu Asp Arg Ala Glu Lys Tyr 35 40 45

    Lys Lys Val Lys Asn Ile Ile Asp Glu Tyr His Lys Asp Phe Ile Glu 50 55 60

    Lys Ser Leu Asn Gly Leu Lys Leu Asp Gly Leu Glu Glu Tyr Lys Thr 65 70 75 80

    Leu Tyr Leu Lys Gln Glu Lys Asp Asp Lys Asp Lys Lys Ala Phe Asp 85 90 95

    Lys Glu Lys Glu Asn Leu Arg Lys Gln Ile Ala Asn Ala Phe Arg Asn 100 105 110

    Asn Glu Lys Phe Lys Thr Leu Phe Ala Lys Glu Leu Ile Lys Asn Asp 115 120 125

    Leu Met Ser Phe Ala Cys Glu Glu Asp Lys Lys Asn Val Lys Glu Phe 130 135 140

    Glu Ala Phe Thr Thr Ala Asp Glu Lys Arg Thr Ala Ile Ala Ser Arg 145 150 155 160

    Leu Ile His Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe 165 170 175

    Glu Lys Met Lys Lys Glu Ala Pro Glu Leu Leu Ser Pro Phe Asn Gln 180 185 190

    Thr Leu Lys Asp Met Lys Asp Val Ile Lys Gly Thr Thr Leu Glu Glu 195 200 205

    Ile Phe Ser Leu Asp Tyr Phe Asn Lys Thr Leu Thr Gln Ser Gly Ile 210 215 220

    Asp Ile Tyr Asn Ser Val Ile Gly Gly Arg Thr Pro Glu Glu Gly Lys 225 230 235 240

    Thr Lys Ile Lys Gly Leu Asn Glu Tyr Ile Asn Thr Tyr Phe Thr Gly 245 250 255

    Phe His Ser Asn Arg Gln Asn Ile Tyr Ser Asp Phe Asn Gln Lys Gln 260 265 270

    Thr Asp Lys Lys Lys Arg Gln Pro Lys Phe Lys Gln Leu Tyr Lys Gln 275 280 285

    Ile Leu Ser Asp Arg Gln Ser Leu Ser Phe Ile Ala Glu Ala Phe Lys 290 295 300

    Asn Asp Thr Glu Ile Leu Glu Ala Ile Glu Lys Phe Tyr Val Asn Glu 305 310 315 320

    Leu Leu His Phe Ser Asn Glu Gly Lys Ser Thr Asn Val Leu Asp Ala 325 330 335

    Ile Lys Asn Ala Val Ser Asn Leu Glu Ser Phe Asn Leu Thr Lys Ile 340 345 350

    Tyr Phe Arg Ser Gly Thr Ser Leu Thr Asp Val Ser Arg Lys Val Phe

    355

    360

    365

    Gly Glu Trp Ser Ile Ile Asn Arg Ala Leu Asp Asn Tyr Tyr Ala Thr 370 375 380

    Thr Tyr Pro Ile Lys Pro Arg Glu Lys Ser Glu Lys Tyr Glu Glu Arg 385 390 395 400

    Lys Glu Lys Trp Leu Lys Gln Asp Phe Asn Val Ser Leu Ile Gln Thr 405 410 415

    Ala Ile Asp Glu Tyr Asp Asn Glu Thr Val Lys Gly Lys Asn Ser Gly 420 425 430

    Lys Val Ile Val Asp Tyr Phe Ala Lys Phe Cys Asp Asp Lys Glu Thr 435 440 445

    Asp Leu Ile Gln Lys Val Asn Glu Gly Tyr Ile Ala Val Lys Asp Leu 450 455 460

    Leu Asn Thr Pro Tyr Pro Glu Asn Glu Lys Leu Gly Ser Asn Lys Asp 465 470 475 480

    Gln Val Lys Gln Ile Lys Ala Phe Met Asp Ser Ile Met Asp Ile Met 485 490 495

    His Phe Val Arg Pro Leu Ser Leu Lys Asp Thr Asp Lys Glu Lys Asp 500 505 510

    Glu Thr Phe Tyr Ser Leu Phe Thr Pro Leu Tyr Asp His Leu Thr Gln 515 520 525

    Thr Ile Ala Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu 545 550 555 560

    Gly Gly Trp Asp Leu Asn Lys Glu Thr Asp Asn Thr Ala Ile Ile Leu 565 570 575

    Arg Lys Glu Asn Leu Tyr Tyr Leu Gly Ile Met Asp Lys Arg His Asn 580 585 590

    Arg Ile Phe Arg Asn Val Pro Lys Ala Asp Lys Lys Asp Ser Cys Tyr 595 600 605

    Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro 610 615 620

    Lys Val Phe Phe Ser Gln Ser Arg Ile Gln Glu Phe Thr Pro Ser Ala 625 630 635 640

    Lys Leu Leu Glu Asn Tyr Glu Asn Glu Thr His Lys Lys Gly Asp Asn 645 650 655

    Phe Asn Leu Asn His Cys His Gln Leu Ile Asp Phe Phe Lys Asp Ser 660 665 670

    Ile Asn Lys His Glu Asp Trp Lys Asn Phe Asp Phe Arg Phe Ser Ala 675 680 685

    Thr Ser Thr Tyr Ala Asp Leu Ser Gly Phe Tyr His Glu Val Glu His 690 695 700

    Gln Gly Tyr Lys Ile Ser Phe Gln Ser Ile Ala Asp Ser Phe Ile Asp 705 710 715 720

    Asp Leu Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 725 730 735

    Asp Phe Ser Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr 740 745 750

    Trp Lys Met Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys 755 760 765

    Leu Asn Gly Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala Glu 770 775 780

    Lys Asn Thr Thr Ile His Lys Ala Asn Glu Ser Ile Ile Asn Lys Asn 785 790 795 800

    Pro Asp Asn Pro Lys Ala Thr Ser Thr Phe Asn Tyr Asp Ile Val Lys 805 810 815

    Asp Lys Arg Tyr Thr Ile Asp Lys Phe Gln Phe His Val Pro Ile Thr 820 825 830

    Met Asn Phe Lys Ala Glu Gly Ile Phe Asn Met Asn Gln Arg Val Asn 835 840 845

    Gln Phe Leu Lys Ala Asn Pro Asp Ile Asn Ile Ile Gly Ile Asp Arg 850 855 860

    Gly Glu Arg His Leu Leu Tyr Tyr Thr Leu Ile Asn Gln Lys Gly Lys 865 870 875 880

    Ile Leu Lys Gln Asp Thr Leu Asn Val Ile Ala Asn Glu Lys Gln Lys 885 890 895

    Val Asp Tyr His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr 900 905 910

    Ala Arg Gln Glu Trp Gly Val Ile Glu Thr Ile Lys Glu Leu Lys Glu 915 920 925

    Gly Tyr Leu Ser Gln Val Ile His Lys Leu Thr Asp Leu Met Ile Glu 930 935 940

    Asn Asn Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe Lys Arg 945 950 955 960

    Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met 965 970 975

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Lys Ala Asn 980 985 990

    Glu Leu Gly Gly Leu Leu Asn Ala Phe Gln Leu Ala Asn Lys Phe Glu 995 1000 1005

    Ser Phe Gln Lys Met Gly Lys Gln Asn Gly Phe Ile Phe Tyr Val 1010 1015 1020

    Pro Ala Trp Asn Thr Ser Lys Thr Asp Pro Ala Thr Gly Phe Ile 1025 1030 1035

    Asp Phe Leu Lys Pro Arg Tyr Glu Asn Leu Lys Gln Ala Lys Asp 1040 1045 1050

    Phe Phe Glu Lys Phe Asp Ser Ile Arg Leu Asn Ser Lys Ala Asp 1055 1060 1065

    Tyr Phe Glu Phe Ala Phe Asp Phe Lys Asn Phe Thr Gly Lys Ala

    1070

    1075

    1080

    Asp Gly Gly Arg Thr Lys Trp Thr Val Cys Thr Thr Asn Glu Asp 1085 1090 1095

    Arg Tyr Ala Trp Asn Arg Ala Leu Asn Asn Asn Arg Gly Ser Gln 1100 1105 1110

    Glu Lys Tyr Asp Ile Thr Ala Glu Leu Lys Ser Leu Phe Asp Gly 1115 1120 1125

    Lys Val Asp Tyr Lys Ser Gly Lys Asp Leu Lys Gln Gln Ile Ala 1130 1135 1140

    Ser Gln Glu Leu Ala Asp Phe Phe Arg Thr Leu Met Lys Tyr Leu 1145 1150 1155

    Ser Val Thr Leu Ser Leu Arg His Asn Asn Gly Glu Lys Gly Glu 1160 1165 1170

    Thr Glu Gln Asp Tyr Ile Leu Ser Pro Val Ala Asp Ser Met Gly 1175 1180 1185

    Lys Phe Phe Asp Ser Arg Lys Ala Gly Asp Asp Met Pro Lys Asn 1190 1195 1200

    Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Trp 1205 1210 1215

    Cys Leu Glu Gln Ile Ser Lys Thr Asp Asp Leu Lys Lys Val Lys 1220 1225 1230

    Leu Ala Ile Ser Asn Lys Glu Trp Leu Glu Phe Met Gln Thr Leu 1235 1240 1245

    Lys Gly 1250 <210> 1142 <211> 1249 <212> PRT <213> Leptospira inadai <400> 1142

    Met Glu Asp Tyr Ser Gly Phe Val Asn Ile Tyr Ser Ile Gln Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu His Ile Glu 20 25 30

    Lys Lys Gly Phe Leu Lys Lys Asp Lys Ile Arg Ala Glu Asp Tyr Lys 35 40 45

    Ala Val Lys Lys Ile Ile Asp Lys Tyr His Arg Ala Tyr Ile Glu Glu 50 55 60

    Val Phe Asp Ser Val Leu His Gln Lys Lys Lys Lys Asp Lys Thr Arg 65 70 75 80

    Phe Ser Thr Gln Phe Ile Lys Glu Ile Lys Glu Phe Ser Glu Leu Tyr 85 90 95

    Tyr Lys Thr Glu Lys Asn Ile Pro Asp Lys Glu Arg Leu Glu Ala Leu 100 105 110

    Ser Glu Lys Leu Arg Lys Met Leu Val Gly Ala Phe Lys Gly Glu Phe 115 120 125

    Ser Glu Glu Val Ala Glu Lys Tyr Lys Asn Leu Phe Ser Lys Glu Leu

    130

    135

    140

    Ile Arg Asn Glu Ile Glu Lys Phe Cys Glu Thr Asp Glu Glu Arg Lys 145 150 155 160

    Gln Val Ser Asn Phe Lys Ser Phe Thr Thr Asp Glu Lys Lys Ser Thr 165 170 175

    Ala Ile Gly Tyr Arg Ile Ile His Gln Asn Leu Pro Lys Phe Leu Asp 180 185 190

    Asn Leu Lys Ile Ile Glu Ser Ile Gln Arg Arg Phe Lys Asp Phe Pro 195 200 205

    Trp Ser Asp Leu Lys Lys Asn Leu Lys Lys Ile Asp Lys Asn Ile Lys 210 215 220

    Leu Thr Glu Tyr Phe Ser Ile Asp Gly Phe Val Asn Val Leu Asn Gln 225 230 235 240

    Lys Gly Ile Asp Ala Tyr Asn Thr Ile Leu Gly Gly Lys Ser Glu Glu 245 250 255

    Ser Gly Glu Lys Ile Gln Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Arg 260 265 270

    Gln Lys Asn Asn Ile Asp Arg Lys Asn Leu Pro Asn Val Lys Ile Leu 275 280 285

    Phe Lys Gln Ile Leu Gly Asp Arg Glu Thr Lys Ser Phe Ile Pro Glu 290 295 300

    Ala Phe Pro Asp Asp Gln Ser Val Leu Asn Ser Ile Thr Glu Phe Ala 305 310 315 320

    Lys Tyr Leu Lys Leu Asp Lys Lys Lys Lys Ser Ile Ile Ala Glu Leu 325 330 335

    Lys Lys Phe Leu Ser Ser Phe Asn Arg Tyr Glu Leu Asp Gly Ile Tyr 340 345 350

    Leu Ala Asn Asp Asn Ser Leu Ala Ser Ile Ser Thr Phe Leu Phe Asp 355 360 365

    Asp Trp Ser Phe Ile Lys Lys Ser Val Ser Phe Lys Tyr Asp Glu Ser 370 375 380

    Val Gly Asp Pro Lys Lys Lys Ile Lys Ser Pro Leu Lys Tyr Glu Lys 385 390 395 400

    Glu Lys Glu Lys Trp Leu Lys Gln Lys Tyr Tyr Thr Ile Ser Phe Leu 405 410 415

    Asn Asp Ala Ile Glu Ser Tyr Ser Lys Ser Gln Asp Glu Lys Arg Val 420 425 430

    Lys Ile Arg Leu Glu Ala Tyr Phe Ala Glu Phe Lys Ser Lys Asp Asp 435 440 445

    Ala Lys Lys Gln Phe Asp Leu Leu Glu Arg Ile Glu Glu Ala Tyr Ala 450 455 460

    Ile Val Glu Pro Leu Leu Gly Ala Glu Tyr Pro Arg Asp Arg Asn Leu 465 470 475 480

    Lys Ala Asp Lys Lys Glu Val Gly Lys Ile Lys Asp Phe Leu Asp Ser 485 490 495

    Ile Lys Ser Leu Gln Phe Phe Leu Lys Pro Leu Leu Ser Ala Glu Ile 500 505 510

    Phe Asp Glu Lys Asp Leu Gly Phe Tyr Asn Gln Leu Glu Gly Tyr Tyr 515 520 525

    Glu Glu Ile Asp Ser Ile Gly His Leu Tyr Asn Lys Val Arg Asn Tyr 530 535 540

    Leu Thr Gly Lys Ile Tyr Ser Lys Glu Lys Phe Lys Leu Asn Phe Glu 545 550 555 560

    Asn Ser Thr Leu Leu Lys Gly Trp Asp Glu Asn Arg Glu Val Ala Asn 565 570 575

    Leu Cys Val Ile Phe Arg Glu Asp Gln Lys Tyr Tyr Leu Gly Val Met 580 585 590

    Asp Lys Glu Asn Asn Thr Ile Leu Ser Asp Ile Pro Lys Val Lys Pro 595 600 605

    Asn Glu Leu Phe Tyr Glu Lys Met Val Tyr Lys Leu Ile Pro Thr Pro 610 615 620

    His Met Gln Leu Pro Arg Ile Ile Phe Ser Ser Asp Asn Leu Ser Ile 625 630 635 640

    Tyr Asn Pro Ser Lys Ser Ile Leu Lys Ile Arg Glu Ala Lys Ser Phe 645 650 655

    Lys Glu Gly Lys Asn Phe Lys Leu Lys Asp Cys His Lys Phe Ile Asp 660 665 670

    Phe Tyr Lys Glu Ser Ile Ser Lys Asn Glu Asp Trp Ser Arg Phe Asp 675 680 685

    Phe Lys Phe Ser Lys Thr Ser Ser Tyr Glu Asn Ile Ser Glu Phe Tyr 690 695 700

    Arg Glu Val Glu Arg Gln Gly Tyr Asn Leu Asp Phe Lys Lys Val Ser 705 710 715 720

    Lys Phe Tyr Ile Asp Ser Leu Val Glu Asp Gly Lys Leu Tyr Leu Phe 725 730 735

    Gln Ile Tyr Asn Lys Asp Phe Ser Ile Phe Ser Lys Gly Lys Pro Asn 740 745 750

    Leu His Thr Ile Tyr Phe Arg Ser Leu Phe Ser Lys Glu Asn Leu Lys 755 760 765

    Asp Val Cys Leu Lys Leu Asn Gly Glu Ala Glu Met Phe Phe Arg Lys 770 775 780

    Lys Ser Ile Asn Tyr Asp Glu Lys Lys Lys Arg Glu Gly His His Pro 785 790 795 800

    Glu Leu Phe Glu Lys Leu Lys Tyr Pro Ile Leu Lys Asp Lys Arg Tyr 805 810 815

    Ser Glu Asp Lys Phe Gln Phe His Leu Pro Ile Ser Leu Asn Phe Lys 820 825 830

    Ser Lys Glu Arg Leu Asn Phe Asn Leu Lys Val Asn Glu Phe Leu Lys 835 840 845

    Arg Asn Lys Asp Ile Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn

    850

    855

    860

    Leu Leu Tyr Leu Val Met Ile Asn Gln Lys Gly Glu Ile Leu Lys Gln 865 870 875 880

    Thr Leu Leu Asp Ser Met Gln Ser Gly Lys Gly Arg Pro Glu Ile Asn 885 890 895

    Tyr Lys Glu Lys Leu Gln Glu Lys Glu Ile Glu Arg Asp Lys Ala Arg 900 905 910

    Lys Ser Trp Gly Thr Val Glu Asn Ile Lys Glu Leu Lys Glu Gly Tyr 915 920 925

    Leu Ser Ile Val Ile His Gln Ile Ser Lys Leu Met Val Glu Asn Asn 930 935 940

    Ala Ile Val Val Leu Glu Asp Leu Asn Ile Gly Phe Lys Arg Gly Arg 945 950 955 960

    Gln Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile 965 970 975

    Asp Lys Leu Asn Phe Leu Val Phe Lys Glu Asn Lys Pro Thr Glu Pro 980 985 990

    Gly Gly Val Leu Lys Ala Tyr Gln Leu Thr Asp Glu Phe Gln Ser Phe 995 1000 1005

    Glu Lys Leu Ser Lys Gln Thr Gly Phe Leu Phe Tyr Val Pro Ser 1010 1015 1020

    Trp Asn Thr Ser Lys Ile Asp Pro Arg Thr Gly Phe Ile Asp Phe 1025 1030 1035

    Leu His Pro Ala Tyr Glu Asn Ile Glu Lys Ala Lys Gln Trp Ile 1040 1045 1050 Asn Lys Phe Asp Ser Ile Arg Phe Asn Ser Lys Met Asp Trp Phe 1055 1060 1065 Glu Phe Thr Ala Asp Thr Arg Lys Phe Ser Glu Asn Leu Met Leu 1070 1075 1080

    Gly Lys Asn Arg Val Trp Val Ile Cys Thr Thr Asn Val Glu Arg 1085 1090 1095

    Tyr Phe Thr Ser Lys Thr Ala Asn Ser Ser Ile Gln Tyr Asn Ser 1100 1105 1110

    Ile Gln Ile Thr Glu Lys Leu Lys Glu Leu Phe Val Asp Ile Pro 1115 1120 1125

    Phe Ser Asn Gly Gln Asp Leu Lys Pro Glu Ile Leu Arg Lys Asn 1130 1135 1140

    Asp Ala Val Phe Phe Lys Ser Leu Leu Phe Tyr Ile Lys Thr Thr 1145 1150 1155

    Leu Ser Leu Arg Gln Asn Asn Gly Lys Lys Gly Glu Glu Glu Lys 1160 1165 1170

    Asp Phe Ile Leu Ser Pro Val Val Asp Ser Lys Gly Arg Phe Phe 1175 1180 1185

    Asn Ser Leu Glu Ala Ser Asp Asp Glu Pro Lys Asp Ala Asp Ala 1190 1195 1200

    Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Met Asn Leu Leu 1205 1210 1215

    Val Leu Asn Glu Thr Lys Glu Glu Asn Leu Ser Arg Pro Lys Trp 1220 1225 1230

    Lys Ile Lys Asn Lys Asp Trp Leu Glu Phe Val Trp Glu Arg Asn 1235 1240 1245

    Arg <210> 1143 <211> 1230 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1143

    Met His Glu Asn Asn Gly Lys Ile Ala Asp Asn Phe Ile Gly Ile Tyr 1 5 10 15

    Pro Val Ser Lys Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr 20 25 30

    Gln Glu Tyr Ile Glu Lys His Gly Ile Leu Asp Glu Asp Leu Lys Arg 35 40 45

    Ala Gly Asp Tyr Lys Ser Val Lys Lys Ile Ile Asp Ala Tyr His Lys 50 55 60

    Tyr Phe Ile Asp Glu Ala Leu Asn Gly Ile Gln Leu Asp Gly Leu Lys 65 70 75 80

    Asn Tyr Tyr Glu Leu Tyr Glu Lys Lys Arg Asp Asn Asn Glu Glu Lys 85 90 95

    Glu Phe Gln Lys Ile Gln Met Ser Leu Arg Lys Gln Ile Val Lys Arg 100 105 110

    Phe Ser Glu His Pro Gln Tyr Lys Tyr Leu Phe Lys Lys Glu Leu Ile 115 120 125

    Lys Asn Val Leu Pro Glu Phe Thr Lys Asp Asn Ala Glu Glu Gln Thr 130 135 140

    Leu Val Lys Ser Phe Gln Glu Phe Thr Thr Tyr Phe Glu Gly Phe His 145 150 155 160

    Gln Asn Arg Lys Asn Met Tyr Ser Asp Glu Glu Lys Ser Thr Ala Ile 165 170 175

    Ala Tyr Arg Val Val His Gln Asn Leu Pro Lys Tyr Ile Asp Asn Met 180 185 190

    Arg Ile Phe Ser Met Ile Leu Asn Thr Asp Ile Arg Ser Asp Leu Thr 195 200 205

    Glu Leu Phe Asn Asn Leu Lys Thr Lys Met Asp Ile Thr Ile Val Glu 210 215 220

    Glu Tyr Phe Ala Ile Asp Gly Phe Asn Lys Val Val Asn Gln Lys Gly 225 230 235 240

    Ile Asp Val Tyr Asn Thr Ile Leu Gly Ala Phe Ser Thr Asp Asp Asn 245 250 255

    Thr Lys Ile Lys Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Asn Gln Lys 260 265 270

    Asn Lys Ala Lys Leu Pro Lys Leu Lys Pro Leu Phe Lys Gln Ile Leu 275 280 285

    Ser Asp Arg Asp Lys Ile Ser Phe Ile Pro Glu Gln Phe Asp Ser Asp 290 295 300

    Thr Glu Val Leu Glu Ala Val Asp Met Phe Tyr Asn Arg Leu Leu Gln 305 310 315 320

    Phe Val Ile Glu Asn Glu Gly Gln Ile Thr Ile Ser Lys Leu Leu Thr 325 330 335

    Asn Phe Ser Ala Tyr Asp Leu Asn Lys Ile Tyr Val Lys Asn Asp Thr 340 345 350

    Thr Ile Ser Ala Ile Ser Asn Asp Leu Phe Asp Asp Trp Ser Tyr Ile 355 360 365

    Ser Lys Ala Val Arg Glu Asn Tyr Asp Ser Glu Asn Val Asp Lys Asn 370 375 380

    Lys Arg Ala Ala Ala Tyr Glu Glu Lys Lys Glu Lys Ala Leu Ser Lys 385 390 395 400

    Ile Lys Met Tyr Ser Ile Glu Glu Leu Asn Phe Phe Val Lys Lys Tyr 405 410 415

    Ser Cys Asn Glu Cys His Ile Glu Gly Tyr Phe Glu Arg Arg Ile Leu 420 425 430

    Glu Ile Leu Asp Lys Met Arg Tyr Ala Tyr Glu Ser Cys Lys Ile Leu 435 440 445

    His Asp Lys Gly Leu Ile Asn Asn Ile Ser Leu Cys Gln Asp Arg Gln 450 455 460

    Ala Ile Ser Glu Leu Lys Asp Phe Leu Asp Ser Ile Lys Glu Val Gln 465 470 475 480

    Trp Leu Leu Lys Pro Leu Met Ile Gly Gln Glu Gln Ala Asp Lys Glu 485 490 495

    Glu Ala Phe Tyr Thr Glu Leu Leu Arg Ile Trp Glu Glu Leu Glu Pro 500 505 510

    Ile Thr Leu Leu Tyr Asn Lys Val Arg Asn Tyr Val Thr Lys Lys Pro 515 520 525

    Tyr Thr Leu Glu Lys Val Lys Leu Asn Phe Tyr Lys Ser Thr Leu Leu 530 535 540

    Asp Gly Trp Asp Lys Asn Lys Glu Lys Asp Asn Leu Gly Ile Ile Leu 545 550 555 560

    Leu Lys Asp Gly Gln Tyr Tyr Leu Gly Ile Met Asn Arg Arg Asn Asn 565 570 575

    Lys Ile Ala Asp Asp Ala Pro Leu Ala Lys Thr Asp Asn Val Tyr Arg 580 585 590

    Lys Met Glu Tyr Lys Leu Leu Thr Lys Val Ser Ala Asn Leu Pro Arg 595 600 605

    Ile Phe Leu Lys Asp Lys Tyr Asn Pro Ser Glu Glu Met Leu Glu Lys

    610

    615

    620

    Tyr Glu Lys Gly Thr His Leu Lys Gly Glu Asn Phe Cys Ile Asp Asp 625 630 635 640

    Cys Arg Glu Leu Ile Asp Phe Phe Lys Lys Gly Ile Lys Gln Tyr Glu 645 650 655

    Asp Trp Gly Gln Phe Asp Phe Lys Phe Ser Asp Thr Glu Ser Tyr Asp 660 665 670

    Asp Ile Ser Ala Phe Tyr Lys Glu Val Glu His Gln Gly Tyr Lys Ile 675 680 685

    Thr Phe Arg Asp Ile Asp Glu Thr Tyr Ile Asp Ser Leu Val Asn Glu 690 695 700

    Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Tyr 705 710 715 720

    Ser Lys Gly Thr Lys Asn Leu His Thr Leu Tyr Trp Glu Met Leu Phe 725 730 735

    Ser Gln Gln Asn Leu Gln Asn Ile Val Tyr Lys Leu Asn Gly Asn Ala 740 745 750

    Glu Ile Phe Tyr Arg Lys Ala Ser Ile Asn Gln Lys Asp Val Val Val 755 760 765

    His Lys Ala Asp Leu Pro Ile Lys Asn Lys Asp Pro Gln Asn Ser Lys 770 775 780

    Lys Glu Ser Met Phe Asp Tyr Asp Ile Ile Lys Asp Lys Arg Phe Thr 785 790 795 800

    Cys Asp Lys Tyr Gln Phe His Val Pro Ile Thr Met Asn Phe Lys Ala 805 810 815

    Leu Gly Glu Asn His Phe Asn Arg Lys Val Asn Arg Leu Ile His Asp 820 825 830

    Ala Glu Asn Met His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu 835 840 845

    Ile Tyr Leu Cys Met Ile Asp Met Lys Gly Asn Ile Val Lys Gln Ile 850 855 860

    Ser Leu Asn Glu Ile Ile Ser Tyr Asp Lys Asn Lys Leu Glu His Lys 865 870 875 880

    Arg Asn Tyr His Gln Leu Leu Lys Thr Arg Glu Asp Glu Asn Lys Ser 885 890 895

    Ala Arg Gln Ser Trp Gln Thr Ile His Thr Ile Lys Glu Leu Lys Glu 900 905 910

    Gly Tyr Leu Ser Gln Val Ile His Val Ile Thr Asp Leu Met Val Glu 915 920 925

    Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly Phe Lys Gln 930 935 940

    Gly Arg Gln Lys Phe Glu Arg Gln Val Tyr Gln Lys Phe Glu Lys Met 945 950 955 960

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Ser Lys Gly Met Asp 965 970 975

    Glu Asp Gly Gly Leu Leu His Ala Tyr Gln Leu Thr Asp Glu Phe Lys 980 985 990

    Ser Phe Lys Gln Leu Gly Lys Gln Ser Gly Phe Leu Tyr Tyr Ile Pro 995 1000 1005

    Ala Trp Asn Thr Ser Lys Leu Asp Pro Thr Thr Gly Phe Val Asn 1010 1015 1020

    Leu Phe Tyr Thr Lys Tyr Glu Ser Val Glu Lys Ser Lys Glu Phe 1025 1030 1035

    Ile Asn Asn Phe Thr Ser Ile Leu Tyr Asn Gln Glu Arg Glu Tyr 1040 1045 1050

    Phe Glu Phe Leu Phe Asp Tyr Ser Ala Phe Thr Ser Lys Ala Glu 1055 1060 1065

    Gly Ser Arg Leu Lys Trp Thr Val Cys Ser Lys Gly Glu Arg Val 1070 1075 1080

    Glu Thr Tyr Arg Asn Pro Lys Lys Asn Asn Glu Trp Asp Thr Gln 1085 1090 1095

    Lys Ile Asp Leu Thr Phe Glu Leu Lys Lys Leu Phe Asn Asp Tyr 1100 1105 1110

    Ser Ile Ser Leu Leu Asp Gly Asp Leu Arg Glu Gln Met Gly Lys 1115 1120 1125

    Ile Asp Lys Ala Asp Phe Tyr Lys Lys Phe Met Lys Leu Phe Ala 1130 1135 1140

    Leu Ile Val Gln Met Arg Asn Ser Asp Glu Arg Glu Asp Lys Leu 1145 1150 1155

    Ile Ser Pro Val Leu Asn Lys Tyr Gly Ala Phe Phe Glu Thr Gly 1160 1165 1170

    Lys Asn Glu Arg Met Pro Leu Asp Ala Asp Ala Asn Gly Ala Tyr 1175 1180 1185

    Asn Ile Ala Arg Lys Gly Leu Trp Ile Ile Glu Lys Ile Lys Asn

    1190 1195 1200 Thr Asp Val Glu Gln Leu Asp Lys Val Lys Leu Thr Ile Ser Asn 1205 1210 1215 Lys Glu Trp Leu Gln Tyr Ala Gln Glu His Ile Leu 1220 1225 1230

    <210> 1144 <211> 1206 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1144

    Met Tyr Tyr Glu Ser Leu Thr Lys Gln Tyr Pro Val Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Ile Pro Ile Gly Lys Thr Leu Asp Asn Ile Arg Gln 20 25 30

    Asn Asn Ile Leu Glu Ser Asp Val Lys Arg Lys Gln Asn Tyr Glu His 35 40 45

    Val Lys Gly Ile Leu Asp Glu Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Cys Thr Leu Pro Ser Leu Lys Ile Ala Ala Glu Ile Tyr 65 70 75 80

    Leu Lys Asn Gln Lys Glu Val Ser Asp Arg Glu Asp Phe Asn Lys Thr 85 90 95

    Gln Asp Leu Leu Arg Lys Glu Val Val Glu Lys Leu Lys Ala His Glu 100 105 110

    Asn Phe Thr Lys Ile Gly Lys Lys Asp Ile Leu Asp Leu Leu Glu Lys 115 120 125

    Leu Pro Ser Ile Ser Glu Asp Asp Tyr Asn Ala Leu Glu Ser Phe Arg 130 135 140

    Asn Phe Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Glu Asn Leu 145 150 155 160

    Tyr Ser Asp Lys Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn 165 170 175

    Glu Asn Phe Pro Lys Phe Leu Asp Asn Val Lys Ser Tyr Arg Phe Val 180 185 190

    Lys Thr Ala Gly Ile Leu Ala Asp Gly Leu Gly Glu Glu Glu Gln Asp 195 200 205

    Ser Leu Phe Ile Val Glu Thr Phe Asn Lys Thr Leu Thr Gln Asp Gly 210 215 220

    Ile Asp Thr Tyr Asn Ser Gln Val Gly Lys Ile Asn Ser Ser Ile Asn 225 230 235 240

    Leu Tyr Asn Gln Lys Asn Gln Lys Ala Asn Gly Phe Arg Lys Ile Pro 245 250 255

    Lys Met Lys Met Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ser 260 265 270

    Phe Ile Asp Glu Phe Gln Ser Asp Glu Val Leu Ile Asp Asn Val Glu 275 280 285

    Ser Tyr Gly Ser Val Leu Ile Glu Ser Leu Lys Ser Ser Lys Val Ser 290 295 300

    Ala Phe Phe Asp Ala Leu Arg Glu Ser Lys Gly Lys Asn Val Tyr Val 305 310 315 320

    Lys Asn Asp Leu Ala Lys Thr Ala Met Ser Asn Ile Val Phe Glu Asn 325 330 335

    Trp Arg Thr Phe Asp Asp Leu Leu Asn Gln Glu Tyr Asp Leu Ala Asn 340 345 350

    Glu Asn Lys Lys Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Glu 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Ser Leu Glu His Leu Cys Asn Leu Ser 370 375 380

    Glu Asp Ser Cys Asn Leu Ile Glu Asn Tyr Ile His Gln Ile Ser Asp 385 390 395 400

    Asp Ile Glu Asn Ile Ile Ile Asn Asn Glu Thr Phe Leu Arg Ile Val

    405

    410

    415

    Ile Asn Glu His Asp Arg Ser Arg Lys Leu Ala Lys Asn Arg Lys Ala 420 425 430

    Val Lys Ala Ile Lys Asp Phe Leu Asp Ser Ile Lys Val Leu Glu Arg 435 440 445

    Glu Leu Lys Leu Ile Asn Ser Ser Gly Gln Glu Leu Glu Lys Asp Leu 450 455 460

    Ile Val Tyr Ser Ala His Glu Glu Leu Leu Val Glu Leu Lys Gln Val 465 470 475 480

    Asp Ser Leu Tyr Asn Met Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe 485 490 495

    Ser Thr Glu Lys Val Lys Leu Asn Phe Asn Arg Ser Thr Leu Leu Asn 500 505 510

    Gly Trp Asp Arg Asn Lys Glu Thr Asp Asn Leu Gly Val Leu Leu Leu 515 520 525

    Lys Asp Gly Lys Tyr Tyr Leu Gly Ile Met Asn Thr Ser Ala Asn Lys 530 535 540

    Ala Phe Val Asn Pro Pro Val Ala Lys Thr Glu Lys Val Phe Lys Lys 545 550 555 560

    Val Asp Tyr Lys Leu Leu Pro Val Pro Asn Gln Met Leu Pro Lys Val 565 570 575

    Phe Phe Ala Lys Ser Asn Ile Asp Phe Tyr Asn Pro Ser Ser Glu Ile 580 585 590

    Tyr Ser Asn Tyr Lys Lys Gly Thr His Lys Lys Gly Asn Met Phe Ser 595 600 605

    Leu Glu Asp Cys His Asn Leu Ile Asp Phe Phe Lys Glu Ser Ile Ser 610 615 620

    Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser Asp Thr Ala 625 630 635 640

    Ser Tyr Asn Asp Ile Ser Glu Phe Tyr Arg Glu Val Glu Lys Gln Gly 645 650 655

    Tyr Lys Leu Thr Tyr Thr Asp Ile Asp Glu Thr Tyr Ile Asn Asp Leu 660 665 670

    Ile Glu Arg Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 675 680 685

    Ser Met Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met 690 695 700

    Met Leu Phe Asp Gln Arg Asn Ile Asp Asp Val Val Tyr Lys Leu Asn 705 710 715 720

    Gly Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ser Glu Asp Glu 725 730 735

    Leu Ile Ile His Lys Ala Gly Glu Glu Ile Lys Asn Lys Asn Pro Asn 740 745 750

    Arg Ala Arg Thr Lys Glu Thr Ser Thr Phe Ser Tyr Asp Ile Val Lys 755 760 765

    Asp Lys Arg Tyr Ser Lys Asp Lys Phe Thr Leu His Ile Pro Ile Thr 770 775 780

    Met Asn Phe Gly Val Asp Glu Val Lys Arg Phe Asn Asp Ala Val Asn 785 790 795 800

    Ser Ala Ile Arg Ile Asp Glu Asn Val Asn Val Ile Gly Ile Asp Arg 805 810 815

    Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asp Ser Lys Gly Asn 820 825 830

    Ile Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Lys Glu Tyr Asp 835 840 845

    Ile Glu Thr Asp Tyr His Ala Leu Leu Asp Glu Arg Glu Gly Gly Arg 850 855 860

    Asp Lys Ala Arg Lys Asp Trp Asn Thr Val Glu Asn Ile Arg Asp Leu 865 870 875 880

    Lys Ala Gly Tyr Leu Ser Gln Val Val Asn Val Val Ala Lys Leu Val 885 890 895

    Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe 900 905 910

    Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 915 920 925

    Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg 930 935 940

    Glu Gln Thr Ser Pro Lys Glu Leu Gly Gly Ala Leu Asn Ala Leu Gln 945 950 955 960

    Leu Thr Ser Lys Phe Lys Ser Phe Lys Glu Leu Gly Lys Gln Ser Gly 965 970 975

    Val Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr 980 985 990

    Thr Gly Phe Ala Asn Leu Phe Tyr Met Lys Cys Glu Asn Val Glu Lys 995 1000 1005

    Ser Lys Arg Phe Phe Asp Gly Phe Asp Phe Ile Arg Phe Asn Ala 1010 1015 1020

    Leu Glu Asn Val Phe Glu Phe Gly Phe Asp Tyr Arg Ser Phe Thr 1025 1030 1035

    Gln Arg Ala Cys Gly Ile Asn Ser Lys Trp Thr Val Cys Thr Asn 1040 1045 1050

    Gly Glu Arg Ile Ile Lys Tyr Arg Asn Pro Asp Lys Asn Asn Met 1055 1060 1065

    Phe Asp Glu Lys Val Val Val Val Thr Asp Glu Met Lys Asn Leu 1070 1075 1080

    Phe Glu Gln Tyr Lys Ile Pro Tyr Glu Asp Gly Arg Asn Val Lys 1085 1090 1095

    Asp Met Ile Ile Ser Asn Glu Glu Ala Glu Phe Tyr Arg Arg Leu 1100 1105 1110

    Tyr Arg Leu Leu Gln Gln Thr Leu Gln Met Arg Asn Ser Thr Ser

    1115

    1120

    1125

    Asp Gly Thr Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Lys Arg 1130 1135 1140

    Glu Ala Tyr Phe Asn Ser Glu Leu Ser Asp Gly Ser Val Pro Lys 1145 1150 1155

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1160 1165 1170

    Trp Val Leu Glu Gln Ile Arg Gln Lys Ser Glu Gly Glu Lys Ile 1175 1180 1185

    Asn Leu Ala Met Thr Asn Ala Glu Trp Leu Glu Tyr Ala Gln Thr 1190 1195 1200

    His Leu Leu 1205 <210> 1145 <211> 1206 <212> PRT <213> Butyrivibrio sp.

    <400> 1145

    Met Tyr Tyr Gln Asn Leu Thr Lys Lys Tyr Pro Val Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Ile Pro Ile Gly Lys Thr Leu Glu Asn Ile Arg Lys 20 25 30

    Asn Asn Ile Leu Glu Ser Asp Val Lys Arg Lys Gln Asp Tyr Glu His 35 40 45

    Val Lys Gly Ile Met Asp Glu Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Tyr Met Leu Pro Ser Leu Asn Gln Ala Ala Glu Ile Tyr 65 70 75 80

    Leu Lys Lys His Val Asp Val Glu Asp Arg Glu Glu Phe Lys Lys Thr 85 90 95

    Gln Asp Leu Leu Arg Arg Glu Val Thr Gly Arg Leu Lys Glu His Glu 100 105 110

    Asn Tyr Thr Lys Ile Gly Lys Lys Asp Ile Leu Asp Leu Leu Glu Lys 115 120 125

    Leu Pro Ser Ile Ser Glu Glu Asp Tyr Asn Ala Leu Glu Ser Phe Arg 130 135 140

    Asn Phe Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Glu Asn Leu 145 150 155 160

    Tyr Ser Asp Glu Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn 165 170 175

    Glu Asn Leu Pro Lys Phe Leu Asp Asn Ile Lys Ser Tyr Ala Phe Val 180 185 190

    Lys Ala Ala Gly Val Leu Ala Asp Cys Ile Glu Glu Glu Glu Gln Asp 195 200 205

    Ala Leu Phe Met Val Glu Thr Phe Asn Met Thr Leu Thr Gln Glu Gly 210 215 220

    Ile Asp Met Tyr Asn Tyr Gln Ile Gly Lys Val Asn Ser Ala Ile Asn

    225

    230

    235

    240

    Leu Tyr Asn Gln Lys Asn His Lys Val Glu Glu Phe Lys Lys Ile Pro 245 250 255

    Lys Met Lys Val Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Val 260 265 270

    Phe Ile Gly Glu Phe Lys Asp Asp Glu Thr Leu Leu Ser Ser Ile Gly 275 280 285

    Ala Tyr Gly Asn Val Leu Met Thr Tyr Leu Lys Ser Glu Lys Ile Asn 290 295 300

    Ile Phe Phe Asp Ala Leu Arg Glu Ser Glu Gly Lys Asn Val Tyr Val 305 310 315 320

    Lys Asn Asp Leu Ser Lys Thr Thr Met Ser Asn Ile Val Phe Gly Ser 325 330 335

    Trp Ser Ala Phe Asp Glu Leu Leu Asn Gln Glu Tyr Asp Leu Ala Asn 340 345 350

    Glu Asn Lys Lys Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Glu 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Thr Leu Glu Gln Met Ser Asn Leu Ser 370 375 380

    Lys Glu Asp Ile Ser Pro Ile Glu Asn Tyr Ile Glu Arg Ile Ser Glu 385 390 395 400

    Asp Ile Glu Lys Ile Cys Ile Tyr Asn Gly Glu Phe Glu Lys Ile Val 405 410 415

    Val Asn Glu His Asp Ser Ser Arg Lys Leu Ser Lys Asn Ile Lys Ala 420 425 430

    Val Lys Val Ile Lys Asp Tyr Leu Asp Ser Ile Lys Glu Leu Glu His 435 440 445

    Asp Ile Lys Leu Ile Asn Gly Ser Gly Gln Glu Leu Glu Lys Asn Leu 450 455 460

    Val Val Tyr Val Gly Gln Glu Glu Ala Leu Glu Gln Leu Arg Pro Val 465 470 475 480

    Asp Ser Leu Tyr Asn Leu Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe 485 490 495

    Ser Thr Glu Lys Val Lys Leu Asn Phe Asn Lys Ser Thr Leu Leu Asn 500 505 510

    Gly Trp Asp Lys Asn Lys Glu Thr Asp Asn Leu Gly Ile Leu Phe Phe 515 520 525

    Lys Asp Gly Lys Tyr Tyr Leu Gly Ile Met Asn Thr Thr Ala Asn Lys 530 535 540

    Ala Phe Val Asn Pro Pro Ala Ala Lys Thr Glu Asn Val Phe Lys Lys 545 550 555 560

    Val Asp Tyr Lys Leu Leu Pro Gly Ser Asn Lys Met Leu Pro Lys Val 565 570 575

    Phe Phe Ala Lys Ser Asn Ile Gly Tyr Tyr Asn Pro Ser Thr Glu Leu 580 585 590

    Tyr Ser Asn Tyr Lys Lys Gly Thr His Lys Lys Gly Pro Ser Phe Ser 595 600 605

    Ile Asp Asp Cys His Asn Leu Ile Asp Phe Phe Lys Glu Ser Ile Lys 610 615 620

    Lys His Glu Asp Trp Ser Lys Phe Gly Phe Glu Phe Ser Asp Thr Ala 625 630 635 640

    Asp Tyr Arg Asp Ile Ser Glu Phe Tyr Arg Glu Val Glu Lys Gln Gly 645 650 655

    Tyr Lys Leu Thr Phe Thr Asp Ile Asp Glu Ser Tyr Ile Asn Asp Leu 660 665 670

    Ile Glu Lys Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 675 680 685

    Ser Glu Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met 690 695 700

    Met Leu Phe Asp Gln Arg Asn Leu Asp Asn Val Val Tyr Lys Leu Asn 705 710 715 720

    Gly Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ala Glu Asn Glu 725 730 735

    Leu Val Ile His Lys Ala Gly Glu Gly Ile Lys Asn Lys Asn Pro Asn 740 745 750

    Arg Ala Lys Val Lys Glu Thr Ser Thr Phe Ser Tyr Asp Ile Val Lys 755 760 765

    Asp Lys Arg Tyr Ser Lys Tyr Lys Phe Thr Leu His Ile Pro Ile Thr 770 775 780

    Met Asn Phe Gly Val Asp Glu Val Arg Arg Phe Asn Asp Val Ile Asn 785 790 795 800

    Asn Ala Leu Arg Thr Asp Asp Asn Val Asn Val Ile Gly Ile Asp Arg 805 810 815

    Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asn Ser Glu Gly Lys 820 825 830

    Ile Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Lys Glu Tyr Asp 835 840 845

    Ile Glu Thr Asn Tyr His Ala Leu Leu Asp Glu Arg Glu Asp Asp Arg 850 855 860

    Asn Lys Ala Arg Lys Asp Trp Asn Thr Ile Glu Asn Ile Lys Glu Leu 865 870 875 880

    Lys Thr Gly Tyr Leu Ser Gln Val Val Asn Val Val Ala Lys Leu Val 885 890 895

    Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe 900 905 910

    Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 915 920 925

    Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg 930 935 940

    Glu Gln Val Ser Pro Glu Lys Met Gly Gly Ala Leu Asn Ala Leu Gln

    945

    950

    955

    960

    Leu Thr Ser Lys Phe Lys Ser Phe Ala Glu Leu Gly Lys Gln Ser Gly 965 970 975

    Ile Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr 980 985 990

    Thr Gly Phe Val Asn Leu Phe Tyr Ile Lys Tyr Glu Asn Ile Glu Lys 995 1000 1005

    Ala Lys Gln Phe Phe Asp Gly Phe Asp Phe Ile Arg Phe Asn Lys 1010 1015 1020

    Lys Asp Asp Met Phe Glu Phe Ser Phe Asp Tyr Lys Ser Phe Thr 1025 1030 1035

    Gln Lys Ala Cys Gly Ile Arg Ser Lys Trp Ile Val Tyr Thr Asn 1040 1045 1050

    Gly Glu Arg Ile Ile Lys Tyr Pro Asn Pro Glu Lys Asn Asn Leu 1055 1060 1065

    Phe Asp Glu Lys Val Ile Asn Val Thr Asp Glu Ile Lys Gly Leu 1070 1075 1080

    Phe Lys Gln Tyr Arg Ile Pro Tyr Glu Asn Gly Glu Asp Ile Lys 1085 1090 1095

    Glu Ile Ile Ile Ser Lys Ala Glu Ala Asp Phe Tyr Lys Arg Leu 1100 1105 1110

    Phe Arg Leu Leu His Gln Thr Leu Gln Met Arg Asn Ser Thr Ser 1115 1120 1125

    Asp Gly Thr Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Asp Arg 1130 1135 1140

    Gly Glu Phe Phe Cys Ser Glu Phe Ser Glu Gly Thr Met Pro Lys 1145 1150 1155

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1160 1165 1170

    Trp Val Leu Glu Gln Ile Arg Gln Lys Asp Glu Gly Glu Lys Val 1175 1180 1185

    Asn Leu Ser Met Thr Asn Ala Glu Trp Leu Lys Tyr Ala Gln Leu 1190 1195 1200

    His Leu Leu 1205 <210> 1146 <211> 1205 <212> PRT <213> Oribacterium sp.

    <400> 1146

    Met Tyr Tyr Asp Gly Leu Thr Lys Gln Tyr Ala Leu Ser Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Val Pro Ile Gly Lys Thr Leu Asp Asn Ile Lys Lys 20 25 30

    Asn Arg Ile Leu Glu Ala Asp Ile Lys Arg Lys Ser Asp Tyr Glu His 35 40 45

    Val Lys Lys Leu Met Asp Met Tyr His Lys Lys Ile Ile Asn Glu Ala

    Leu Asp Asn Phe Lys Leu Ser Val Leu Glu Asp Ala Ala Asp Ile Tyr 65 70 75 80

    Phe Asn Lys Gln Asn Asp Glu Arg Asp Ile Asp Ala Phe Leu Lys Ile 85 90 95

    Gln Asp Lys Leu Arg Lys Glu Ile Val Glu Gln Leu Lys Gly His Thr 100 105 110

    Asp Tyr Ser Lys Val Gly Asn Lys Asp Phe Leu Gly Leu Leu Lys Ala 115 120 125

    Ala Ser Thr Glu Glu Asp Arg Ile Leu Ile Glu Ser Phe Asp Asn Phe 130 135 140

    Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Ser Asn Leu Tyr Ser 145 150 155 160

    Ala Glu Asp Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn Glu Asn 165 170 175

    Leu Pro Lys Phe Phe Asp Asn Ile Lys Ala Tyr Arg Thr Val Arg Asn 180 185 190

    Ala Gly Val Ile Ser Gly Asp Met Ser Ile Val Glu Gln Asp Glu Leu 195 200 205

    Phe Glu Val Asp Thr Phe Asn His Thr Leu Thr Gln Tyr Gly Ile Asp 210 215 220

    Thr Tyr Asn His Met Ile Gly Gln Leu Asn Ser Ala Ile Asn Leu Tyr 225 230 235 240

    Asn Gln Lys Met His Gly Ala Gly Ser Phe Lys Lys Leu Pro Lys Met 245 250 255

    Lys Glu Leu Tyr Lys Gln Leu Leu Thr Glu Arg Glu Glu Glu Phe Ile 260 265 270

    Glu Glu Tyr Thr Asp Asp Glu Val Leu Ile Thr Ser Val His Asn Tyr 275 280 285

    Val Ser Tyr Leu Ile Asp Tyr Leu Asn Ser Asp Lys Val Glu Ser Phe 290 295 300

    Phe Asp Thr Leu Arg Lys Ser Asp Gly Lys Glu Val Phe Ile Lys Asn 305 310 315 320

    Asp Val Ser Lys Thr Thr Met Ser Asn Ile Leu Phe Asp Asn Trp Ser 325 330 335

    Thr Ile Asp Asp Leu Ile Asn His Glu Tyr Asp Ser Ala Pro Glu Asn 340 345 350

    Val Lys Lys Thr Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Asp 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Ser Leu Ser Lys Ile Ala Ala Leu Cys 370 375 380

    Arg Asp Thr Thr Ile Leu Glu Lys Tyr Ile Arg Arg Leu Val Asp Asp 385 390 395 400

    Ile Glu Lys Ile Tyr Thr Ser Asn Asn Val Phe Ser Asp Ile Val Leu 405 410 415

    Ser Lys His Asp Arg Ser Lys Lys Leu Ser Lys Asn Thr Asn Ala Val 420 425 430

    Gln Ala Ile Lys Asn Met Leu Asp Ser Ile Lys Asp Phe Glu His Asp 435 440 445

    Val Met Leu Ile Asn Gly Ser Gly Gln Glu Ile Lys Lys Asn Leu Asn 450 455 460

    Val Tyr Ser Glu Gln Glu Ala Leu Ala Gly Ile Leu Arg Gln Val Asp 465 470 475 480

    His Ile Tyr Asn Leu Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe Ser 485 490 495

    Thr Glu Lys Ile Lys Leu Asn Phe Asn Arg Pro Thr Phe Leu Asp Gly 500 505 510

    Trp Asp Lys Asn Lys Glu Glu Ala Asn Leu Gly Ile Leu Leu Ile Lys 515 520 525

    Asp Asn Arg Tyr Tyr Leu Gly Ile Met Asn Thr Ser Ser Asn Lys Ala 530 535 540

    Phe Val Asn Pro Pro Lys Ala Ile Ser Asn Asp Ile Tyr Lys Lys Val 545 550 555 560

    Asp Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met Leu Pro Lys Val Phe 565 570 575

    Phe Ala Thr Lys Asn Ile Ala Tyr Tyr Ala Pro Ser Glu Glu Leu Leu 580 585 590

    Ser Lys Tyr Arg Lys Gly Thr His Lys Lys Gly Asp Ser Phe Ser Ile 595 600 605

    Asp Asp Cys Arg Asn Leu Ile Asp Phe Phe Lys Ser Ser Ile Asn Lys 610 615 620

    Asn Thr Asp Trp Ser Thr Phe Gly Phe Asn Phe Ser Asp Thr Asn Ser 625 630 635 640

    Tyr Asn Asp Ile Ser Asp Phe Tyr Arg Glu Val Glu Lys Gln Gly Tyr 645 650 655

    Lys Leu Ser Phe Thr Asp Ile Asp Ala Cys Tyr Ile Lys Asp Leu Val 660 665 670

    Asp Asn Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 675 680 685

    Pro Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Lys Met 690 695 700

    Leu Phe Asp Gln Arg Asn Leu Asp Asn Val Val Tyr Lys Leu Asn Gly 705 710 715 720

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Glu Ser Asp Glu Gln 725 730 735

    Ile Ile His Lys Ser Gly Gln Asn Ile Lys Asn Lys Asn Gln Lys Arg 740 745 750

    Ser Asn Cys Lys Lys Thr Ser Thr Phe Asp Tyr Asp Ile Val Lys Asp 755 760 765

    Arg Arg Tyr Cys Lys Asp Lys Phe Met Leu His Leu Pro Ile Thr Val

    770

    775

    780

    Asn Phe Gly Thr Asn Glu Ser Gly Lys Phe Asn Glu Leu Val Asn Asn 785 790 795 800

    Ala Ile Arg Ala Asp Lys Asp Val Asn Val Ile Gly Ile Asp Arg Gly 805 810 815

    Glu Arg Asn Leu Leu Tyr Val Val Val Val Asp Pro Cys Gly Lys Ile 820 825 830

    Ile Glu Gln Ile Ser Leu Asn Thr Ile Val Asp Lys Glu Tyr Asp Ile 835 840 845

    Glu Thr Asp Tyr His Gln Leu Leu Asp Glu Lys Glu Gly Ser Arg Asp 850 855 860

    Lys Ala Arg Lys Asp Trp Asn Thr Ile Glu Asn Ile Lys Glu Leu Lys 865 870 875 880

    Glu Gly Tyr Leu Ser Gln Val Val Asn Ile Ile Ala Lys Leu Val Leu 885 890 895

    Lys Tyr Asp Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe Lys 900 905 910

    Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys 915 920 925

    Met Leu Ile Asp Lys Met Asn Tyr Leu Val Leu Asp Lys Ser Arg Lys 930 935 940

    Gln Glu Ser Pro Gln Lys Pro Gly Gly Ala Leu Asn Ala Leu Gln Leu 945 950 955 960

    Thr Ser Ala Phe Lys Ser Phe Lys Glu Leu Gly Lys Gln Thr Gly Ile 965 970 975

    Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr Thr 980 985 990

    Gly Phe Ala Asn Leu Phe Tyr Ile Lys Tyr Glu Ser Val Asp Lys Ala 995 1000 1005

    Arg Asp Phe Phe Ser Lys Phe Asp Phe Ile Arg Tyr Asn Gln Met 1010 1015 1020

    Asp Asn Tyr Phe Glu Phe Gly Phe Asp Tyr Lys Ser Phe Thr Glu 1025 1030 1035

    Arg Ala Ser Gly Cys Lys Ser Lys Trp Ile Ala Cys Thr Asn Gly 1040 1045 1050

    Glu Arg Ile Val Lys Tyr Arg Asn Ser Asp Lys Asn Asn Ser Phe 1055 1060 1065

    Asp Asp Lys Thr Val Ile Leu Thr Asp Glu Tyr Arg Ser Leu Phe 1070 1075 1080

    Asp Lys Tyr Leu Gln Asn Tyr Ile Asp Glu Asp Asp Leu Lys Asp 1085 1090 1095

    Gln Ile Leu Gln Ile Asp Ser Ala Asp Phe Tyr Lys Asn Leu Ile 1100 1105 1110

    Lys Leu Phe Gln Leu Thr Leu Gln Met Arg Asn Ser Ser Ser Asp 1115 1120 1125

    Gly Lys Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Tyr Arg Glu 1130 1135 1140

    Glu Phe Phe Cys Ser Glu Phe Ser Asp Asp Thr Phe Pro Arg Asp 1145 1150 1155

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp 1160 1165 1170

    Val Ile Lys Gln Ile Arg Glu Thr Lys Ser Gly Thr Lys Ile Asn 1175 1180 1185

    Leu Ala Met Ser Asn Ser Glu Trp Leu Glu Tyr Ala Gln Cys Asn 1190 1195 1200

    Leu Leu 1205 <210> 1147 <211> 1205 <212> PRT <213> Pseudobutyrivibrio ruminis <400> 1147

    Met Tyr Tyr Gln Asn Leu Thr Lys Met Tyr Pro Ile Ser Lys Thr Leu 1 5 10 15

    Arg Asn Glu Leu Ile Pro Val Gly Lys Thr Leu Glu Asn Ile Arg Lys 20 25 30

    Asn Gly Ile Leu Glu Ala Asp Ile Gln Arg Lys Ala Asp Tyr Glu His 35 40 45

    Val Lys Lys Leu Met Asp Asn Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Gln Gly Val His Leu Ser Asp Leu Ser Asp Ala Tyr Asp Leu Tyr 65 70 75 80

    Phe Asn Leu Ser Lys Glu Lys Asn Ser Val Asp Ala Phe Ser Lys Cys 85 90 95

    Gln Asp Lys Leu Arg Lys Glu Ile Val Ser Leu Leu Lys Asn His Glu 100 105 110

    Asn Phe Pro Lys Ile Gly Asn Lys Glu Ile Ile Lys Leu Leu Gln Ser 115 120 125

    Leu Tyr Asp Asn Asp Thr Asp Tyr Lys Ala Leu Asp Ser Phe Ser Asn 130 135 140

    Phe Tyr Thr Tyr Phe Ser Ser Tyr Asn Glu Val Arg Lys Asn Leu Tyr 145 150 155 160

    Ser Asp Glu Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn Glu 165 170 175

    Asn Leu Pro Lys Phe Leu Asp Asn Ile Lys Ala Tyr Ala Ile Ala Lys 180 185 190

    Lys Ala Gly Val Arg Ala Glu Gly Leu Ser Glu Glu Asp Gln Asp Cys 195 200 205

    Leu Phe Ile Ile Glu Thr Phe Glu Arg Thr Leu Thr Gln Asp Gly Ile 210 215 220

    Asp Asn Tyr Asn Ala Ala Ile Gly Lys Leu Asn Thr Ala Ile Asn Leu 225 230 235 240

    Phe Asn Gln Gln Asn Lys Lys Gln Glu Gly Phe Arg Lys Val Pro Gln 245 250 255

    Met Lys Cys Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ala Phe 260 265 270

    Ile Asp Glu Phe Ser Asp Asp Glu Asp Leu Ile Thr Asn Ile Glu Ser 275 280 285

    Phe Ala Glu Asn Met Asn Val Phe Leu Asn Ser Glu Ile Ile Thr Asp 290 295 300

    Phe Lys Ile Ala Leu Val Glu Ser Asp Gly Ser Leu Val Tyr Ile Lys 305 310 315 320

    Asn Asp Val Ser Lys Thr Ser Phe Ser Asn Ile Val Phe Gly Ser Trp 325 330 335

    Asn Ala Ile Asp Glu Lys Leu Ser Asp Glu Tyr Asp Leu Ala Asn Ser 340 345 350

    Lys Lys Lys Lys Asp Glu Lys Tyr Tyr Glu Lys Arg Gln Lys Glu Leu 355 360 365

    Lys Lys Asn Lys Ser Tyr Asp Leu Glu Thr Ile Ile Gly Leu Phe Asp 370 375 380

    Asp Asn Ser Asp Val Ile Gly Lys Tyr Ile Glu Lys Leu Glu Ser Asp 385 390 395 400

    Ile Thr Ala Ile Ala Glu Ala Lys Asn Asp Phe Asp Glu Ile Val Leu 405 410 415

    Arg Lys His Asp Lys Asn Lys Ser Leu Arg Lys Asn Thr Asn Ala Val 420 425 430

    Glu Ala Ile Lys Ser Tyr Leu Asp Thr Val Lys Asp Phe Glu Arg Asp 435 440 445

    Ile Lys Leu Ile Asn Gly Ser Gly Gln Glu Val Glu Lys Asn Leu Val 450 455 460

    Val Tyr Ala Glu Gln Glu Asn Ile Leu Ala Glu Ile Lys Asn Val Asp 465 470 475 480

    Ser Leu Tyr Asn Met Ser Arg Asn Tyr Leu Thr Gln Lys Pro Phe Ser 485 490 495

    Thr Glu Lys Phe Lys Leu Asn Phe Asn Arg Ala Thr Leu Leu Asn Gly 500 505 510

    Trp Asp Lys Asn Lys Glu Thr Asp Asn Leu Gly Ile Leu Phe Glu Lys 515 520 525

    Asp Gly Met Tyr Tyr Leu Gly Ile Met Asn Thr Lys Ala Asn Lys Ile 530 535 540

    Phe Val Asn Ile Pro Lys Ala Thr Ser Asn Asp Val Tyr His Lys Val 545 550 555 560

    Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met Leu Pro Lys Val Phe 565 570 575

    Phe Ala Gln Ser Asn Leu Asp Tyr Tyr Lys Pro Ser Glu Glu Leu Leu 580 585 590

    Ala Lys Tyr Lys Ala Gly Thr His Lys Lys Gly Asp Asn Phe Ser Leu

    595

    600

    605

    Glu Asp Cys His Ala Leu Ile Asp Phe Phe Lys Ala Ser Ile Glu Lys 610 615 620

    His Pro Asp Trp Ser Ser Phe Gly Phe Glu Phe Ser Glu Thr Cys Thr 625 630 635 640

    Tyr Glu Asp Leu Ser Gly Phe Tyr Arg Glu Val Glu Lys Gln Gly Tyr 645 650 655

    Lys Ile Thr Tyr Thr Asp Val Asp Ala Asp Tyr Ile Thr Ser Leu Val 660 665 670

    Glu Arg Asp Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 675 680 685

    Pro Tyr Ser Lys Gly Asn Leu Asn Leu His Thr Ile Tyr Leu Gln Met 690 695 700

    Leu Phe Asp Gln Arg Asn Leu Asn Asn Val Val Tyr Lys Leu Asn Gly 705 710 715 720

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Asn Asp Glu Glu Val 725 730 735

    Ile Ile His Lys Ala Gly Glu Glu Ile Lys Asn Lys Asn Ser Lys Arg 740 745 750

    Ala Val Asp Lys Pro Thr Ser Lys Phe Gly Tyr Asp Ile Ile Lys Asp 755 760 765

    Arg Arg Tyr Ser Lys Asp Lys Phe Met Leu His Ile Pro Val Thr Met 770 775 780

    Asn Phe Gly Val Asp Glu Thr Arg Arg Phe Asn Asp Val Val Asn Asp 785 790 795 800

    Ala Leu Arg Asn Asp Glu Lys Val Arg Val Ile Gly Ile Asp Arg Gly 805 810 815

    Glu Arg Asn Leu Leu Tyr Val Val Val Val Asp Thr Asp Gly Thr Ile 820 825 830

    Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Asn Glu Tyr Ser Ile 835 840 845

    Glu Thr Asp Tyr His Lys Leu Leu Asp Glu Lys Glu Gly Asp Arg Asp 850 855 860

    Arg Ala Arg Lys Asn Trp Thr Thr Ile Glu Asn Ile Lys Glu Leu Lys 865 870 875 880

    Glu Gly Tyr Leu Ser Gln Val Val Asn Val Ile Ala Lys Leu Val Leu 885 890 895

    Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe Lys 900 905 910

    Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys 915 920 925

    Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg Lys 930 935 940

    Gln Asp Lys Pro Glu Glu Phe Gly Gly Ala Leu Asn Ala Leu Gln Leu 945 950 955 960

    Thr Ser Lys Phe Thr Ser Phe Lys Asp Met Gly Lys Gln Thr Gly Ile 965 970 975

    Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr Thr 980 985 990

    Gly Phe Ala Asn Leu Phe Tyr Val Lys Tyr Glu Asn Val Glu Lys Ala 995 1000 1005

    Lys Glu Phe Phe Ser Arg Phe Asp Ser Ile Ser Tyr Asn Asn Glu 1010 1015 1020

    Ser Gly Tyr Phe Glu Phe Ala Phe Asp Tyr Lys Lys Phe Thr Asp 1025 1030 1035

    Arg Ala Cys Gly Ala Arg Ser Gln Trp Thr Val Cys Thr Tyr Gly 1040 1045 1050

    Glu Arg Ile Ile Lys Phe Arg Asn Thr Glu Lys Asn Asn Ser Phe 1055 1060 1065

    Asp Asp Lys Thr Ile Val Leu Ser Glu Glu Phe Lys Glu Leu Phe 1070 1075 1080

    Ser Ile Tyr Gly Ile Ser Tyr Glu Asp Gly Ala Glu Leu Lys Asn 1085 1090 1095

    Lys Ile Met Ser Val Asp Glu Ala Asp Phe Phe Arg Ser Leu Thr 1100 1105 1110

    Arg Leu Phe Gln Gln Thr Met Gln Met Arg Asn Ser Ser Asn Asp 1115 1120 1125

    Val Thr Arg Asp Tyr Ile Ile Ser Pro Ile Met Asn Asp Arg Gly 1130 1135 1140

    Glu Phe Phe Asn Ser Glu Ala Cys Asp Ala Ser Lys Pro Lys Asp 1145 1150 1155

    Ala Asp Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Leu Trp 1160 1165 1170

    Val Leu Glu Gln Ile Arg Asn Thr Pro Ser Gly Asp Lys Leu Asn 1175 1180 1185

    Leu Ala Met Ser Asn Ala Glu Trp Leu Glu Tyr Ala Gln Arg Asn 1190 1195 1200

    Gln Ile 1205 <210> 1148 <211> 1231 <212> PRT <213> Butyrivibrio fibrisolvens <400> 1148

    Met Tyr Tyr Glu Ser Leu Thr Lys Leu Tyr Pro Ile Lys Lys Thr Ile 1 5 10 15

    Arg Asn Glu Leu Val Pro Ile Gly Lys Thr Leu Glu Asn Ile Lys Lys 20 25 30

    Asn Asn Ile Leu Glu Ala Asp Glu Asp Arg Lys Ile Ala Tyr Ile Arg 35 40 45

    Val Lys Ala Ile Met Asp Asp Tyr His Lys Arg Leu Ile Asn Glu Ala 50 55 60

    Leu Ser Gly Phe Ala Leu Ile Asp Leu Asp Lys Ala Ala Asn Leu Tyr 65 70 75 80

    Leu Ser Arg Ser Lys Ser Ala Asp Asp Ile Glu Ser Phe Ser Arg Phe 85 90 95

    Gln Asp Lys Leu Arg Lys Ala Ile Ala Lys Arg Leu Arg Glu His Glu 100 105 110

    Asn Phe Gly Lys Ile Gly Asn Lys Asp Ile Ile Pro Leu Leu Gln Lys 115 120 125

    Leu Ser Glu Asn Glu Asp Asp Tyr Asn Ala Leu Glu Ser Phe Lys Asn 130 135 140

    Phe Tyr Thr Tyr Phe Glu Ser Tyr Asn Asp Val Arg Leu Asn Leu Tyr 145 150 155 160

    Ser Asp Lys Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn Glu 165 170 175

    Asn Leu Pro Arg Phe Leu Asp Asn Ile Arg Ala Tyr Asp Ala Val Gln 180 185 190

    Lys Ala Gly Ile Thr Ser Glu Glu Leu Ser Ser Glu Ala Gln Asp Gly 195 200 205

    Leu Phe Leu Val Asn Thr Phe Asn Asn Val Leu Ile Gln Asp Gly Ile 210 215 220

    Asn Thr Tyr Asn Glu Asp Ile Gly Lys Leu Asn Val Ala Ile Asn Leu 225 230 235 240

    Tyr Asn Gln Lys Asn Ala Ser Val Gln Gly Phe Arg Lys Val Pro Lys 245 250 255

    Met Lys Val Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ser Phe 260 265 270

    Ile Asp Glu Phe Glu Ser Asp Thr Glu Leu Leu Asp Ser Leu Glu Ser 275 280 285

    His Tyr Ala Asn Leu Ala Lys Tyr Phe Gly Ser Asn Lys Val Gln Leu 290 295 300

    Leu Phe Thr Ala Leu Arg Glu Ser Lys Gly Val Asn Val Tyr Val Lys 305 310 315 320

    Asn Asp Ile Ala Lys Thr Ser Phe Ser Asn Val Val Phe Gly Ser Trp 325 330 335

    Ser Arg Ile Asp Glu Leu Ile Asn Gly Glu Tyr Asp Asp Asn Asn Asn 340 345 350

    Arg Lys Lys Asp Glu Lys Tyr Tyr Asp Lys Arg Gln Lys Glu Leu Lys 355 360 365

    Lys Asn Lys Ser Tyr Thr Ile Glu Lys Ile Ile Thr Leu Ser Thr Glu 370 375 380

    Asp Val Asp Val Ile Gly Lys Tyr Ile Glu Lys Leu Glu Ser Asp Ile 385 390 395 400

    Asp Asp Ile Arg Phe Lys Gly Lys Asn Phe Tyr Glu Ala Val Leu Cys 405 410 415

    Gly His Asp Arg Ser Lys Lys Leu Ser Lys Asn Lys Gly Ala Val Glu

    420

    425

    430

    Ala Ile Lys Gly Tyr Leu Asp Ser Val Lys Asp Phe Glu Arg Asp Leu 435 440 445

    Lys Leu Ile Asn Gly Ser Gly Gln Glu Leu Glu Lys Asn Leu Val Val 450 455 460

    Tyr Gly Glu Gln Glu Ala Val Leu Ser Glu Leu Ser Gly Ile Asp Ser 465 470 475 480

    Leu Tyr Asn Met Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe Ser Thr 485 490 495

    Glu Lys Ile Lys Leu Asn Phe Asn Lys Pro Thr Phe Leu Asp Gly Trp 500 505 510

    Asp Tyr Gly Asn Glu Glu Ala Tyr Leu Gly Phe Phe Met Ile Lys Glu 515 520 525

    Gly Asn Tyr Phe Leu Ala Val Met Asp Ala Asn Trp Asn Lys Glu Phe 530 535 540

    Arg Asn Ile Pro Ser Val Asp Lys Ser Asp Cys Tyr Lys Lys Val Ile 545 550 555 560

    Tyr Lys Gln Ile Ser Ser Pro Glu Lys Ser Ile Gln Asn Leu Met Val 565 570 575

    Ile Asp Gly Lys Thr Val Lys Lys Asn Gly Arg Lys Glu Lys Glu Gly 580 585 590

    Ile His Ser Gly Glu Asn Leu Ile Leu Glu Glu Leu Lys Asn Thr Tyr 595 600 605

    Leu Pro Lys Lys Ile Asn Asp Ile Arg Lys Arg Arg Ser Tyr Leu Asn 610 615 620

    Gly Asp Thr Phe Ser Lys Lys Asp Leu Thr Glu Phe Ile Gly Tyr Tyr 625 630 635 640

    Lys Gln Arg Val Ile Glu Tyr Tyr Asn Gly Tyr Ser Phe Tyr Phe Lys 645 650 655

    Ser Asp Asp Asp Tyr Ala Ser Phe Lys Glu Phe Gln Glu Asp Val Gly 660 665 670

    Arg Gln Ala Tyr Gln Ile Ser Tyr Val Asp Val Pro Val Ser Phe Val 675 680 685

    Asp Asp Leu Ile Asn Ser Gly Lys Leu Tyr Leu Phe Arg Val Tyr Asn 690 695 700

    Lys Asp Phe Ser Glu Tyr Ser Lys Gly Arg Leu Asn Leu His Thr Leu 705 710 715 720

    Tyr Phe Lys Met Leu Phe Asp Glu Arg Asn Leu Lys Asn Val Val Tyr 725 730 735

    Lys Leu Asn Gly Gln Ala Glu Val Phe Tyr Arg Pro Ser Ser Ile Lys 740 745 750

    Lys Glu Glu Leu Ile Val His Arg Ala Gly Glu Glu Ile Lys Asn Lys 755 760 765

    Asn Pro Lys Arg Ala Ala Gln Lys Pro Thr Arg Arg Leu Asp Tyr Asp 770 775 780

    Ile Val Lys Asp Arg Arg Tyr Ser Gln Asp Lys Phe Met Leu His Thr 785 790 795 800

    Ser Ile Ile Met Asn Phe Gly Ala Glu Glu Asn Val Ser Phe Asn Asp 805 810 815

    Ile Val Asn Gly Val Leu Arg Asn Glu Asp Lys Val Asn Val Ile Gly 820 825 830

    Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asp Pro 835 840 845

    Glu Gly Lys Ile Leu Glu Gln Arg Ser Leu Asn Cys Ile Thr Asp Ser 850 855 860

    Asn Leu Asp Ile Glu Thr Asp Tyr His Arg Leu Leu Asp Glu Lys Glu 865 870 875 880

    Ser Asp Arg Lys Ile Ala Arg Arg Asp Trp Thr Thr Ile Glu Asn Ile 885 890 895

    Lys Glu Leu Lys Ala Gly Tyr Leu Ser Gln Val Val His Ile Val Ala 900 905 910

    Glu Leu Val Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn 915 920 925

    Phe Gly Phe Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln 930 935 940

    Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Met Asp 945 950 955 960

    Lys Ser Arg Glu Gln Leu Ser Pro Glu Lys Ile Ser Gly Ala Leu Asn 965 970 975

    Ala Leu Gln Leu Thr Pro Asp Phe Lys Ser Phe Lys Val Leu Gly Lys 980 985 990

    Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile 995 1000 1005

    Asp Pro Met Thr Gly Phe Ala Asn Leu Phe Tyr Val Lys Tyr Glu 1010 1015 1020

    Asn Val Asp Lys Ala Lys Glu Phe Phe Ser Lys Phe Asp Ser Ile 1025 1030 1035

    Lys Tyr Asn Lys Asp Gly Lys Asn Trp Asn Thr Lys Gly Tyr Phe 1040 1045 1050

    Glu Phe Ala Phe Asp Tyr Lys Lys Phe Thr Asp Arg Ala Tyr Gly 1055 1060 1065

    Arg Val Ser Glu Trp Thr Val Cys Thr Val Gly Glu Arg Ile Ile 1070 1075 1080

    Lys Phe Lys Asn Lys Glu Lys Asn Asn Ser Tyr Asp Asp Lys Val 1085 1090 1095

    Ile Asp Leu Thr Asn Ser Leu Lys Glu Leu Phe Asp Ser Tyr Lys 1100 1105 1110

    Val Thr Tyr Glu Ser Glu Val Asp Leu Lys Asp Ala Ile Leu Ala 1115 1120 1125

    Ile Asp Asp Pro Ala Phe Tyr Arg Asp Leu Thr Arg Arg Leu Gln

    1130

    1135

    1140

    Gln Thr Leu Gln Met Arg Asn Ser Ser Cys Asp Gly Ser Arg Asp 1145 1150 1155

    Tyr Ile Ile Ser Pro Val Lys Asn Ser Lys Gly Glu Phe Phe Cys 1160 1165 1170

    Ser Asp Asn Asn Asp Asp Thr Thr Pro Asn Asp Ala Asp Ala Asn 1175 1180 1185

    Gly Ala Phe Asn Ile Ala Arg Lys Gly Leu Trp Val Leu Asn Glu 1190 1195 1200

    Ile Arg Asn Ser Glu Glu Gly Ser Lys Ile Asn Leu Ala Met Ser 1205 1210 1215

    Asn Ala Gln Trp Leu Glu Tyr Ala Gln Asp Asn Thr Ile 1220 1225 1230 <210> 1149 <211> 1206 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1149

    Met Glu Asn Tyr Tyr Asp Ser Leu Thr Arg Gln Tyr Pro Val Thr Lys 1 5 10 15

    Thr Ile Arg Gln Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile 20 25 30

    Lys Asn Ala Glu Ile Ile Glu Ala Asp Lys Gln Lys Lys Glu Ala Tyr 35 40 45

    Val Lys Val Lys Glu Leu Met Asp Glu Phe His Lys Ser Ile Ile Glu 50 55 60

    Lys Ser Leu Val Gly Ile Lys Leu Asp Gly Leu Ser Glu Phe Glu Lys 65 70 75 80

    Leu Tyr Lys Ile Lys Thr Lys Thr Asp Glu Asp Lys Asn Arg Ile Ser 85 90 95

    Glu Leu Phe Tyr Tyr Met Arg Lys Gln Ile Ala Asp Ala Leu Lys Asn 100 105 110

    Ser Arg Asp Tyr Gly Tyr Val Asp Asn Lys Asp Leu Ile Glu Lys Ile 115 120 125

    Leu Pro Glu Arg Val Lys Asp Glu Asn Ser Leu Asn Ala Leu Ser Cys 130 135 140

    Phe Lys Gly Phe Thr Thr Tyr Phe Thr Asp Tyr Tyr Lys Asn Arg Lys 145 150 155 160

    Asn Ile Tyr Ser Asp Glu Glu Lys His Ser Thr Val Gly Tyr Arg Cys 165 170 175

    Ile Asn Glu Asn Leu Leu Ile Phe Met Ser Asn Ile Glu Val Tyr Gln 180 185 190

    Ile Tyr Lys Lys Ala Asn Ile Lys Asn Asp Asn Tyr Asp Glu Glu Thr 195 200 205

    Leu Asp Lys Thr Phe Met Ile Glu Ser Phe Asn Glu Cys Leu Thr Gln

    210

    215

    220

    Ser Gly Val Glu Ala Tyr Asn Ser Val Val Ala Ser Ile Lys Thr Ala 225 230 235 240

    Thr Asn Leu Tyr Ile Gln Lys Asn Asn Lys Glu Glu Asn Phe Val Arg 245 250 255

    Val Pro Lys Met Lys Val Leu Phe Lys Gln Ile Leu Ser Asp Arg Thr 260 265 270

    Ser Leu Phe Asp Gly Leu Ile Ile Glu Ser Asp Asp Glu Leu Leu Asp 275 280 285

    Lys Leu Cys Ser Phe Ser Ala Glu Val Asp Lys Phe Leu Pro Ile Asn 290 295 300

    Ile Asp Arg Tyr Ile Lys Thr Leu Met Asp Ser Asn Asn Gly Thr Gly 305 310 315 320

    Ile Tyr Val Lys Asn Asp Ser Ser Leu Thr Thr Leu Ser Asn Tyr Leu 325 330 335

    Thr Asp Ser Trp Ser Ser Ile Arg Asn Ala Phe Asn Glu Asn Tyr Asp 340 345 350

    Ala Lys Tyr Thr Gly Lys Val Asn Asp Lys Tyr Glu Glu Lys Arg Glu 355 360 365

    Lys Ala Tyr Lys Ser Asn Asp Ser Phe Glu Leu Asn Tyr Ile Gln Asn 370 375 380

    Leu Leu Gly Ile Asn Val Ile Asp Lys Tyr Ile Glu Arg Ile Asn Phe 385 390 395 400

    Asp Ile Lys Glu Ile Cys Glu Ala Tyr Lys Glu Met Thr Lys Asn Cys 405 410 415

    Phe Glu Asp His Asp Lys Thr Lys Lys Leu Gln Lys Asn Ile Lys Ala 420 425 430

    Val Ala Ser Ile Lys Ser Tyr Leu Asp Ser Leu Lys Asn Ile Glu Arg 435 440 445

    Asp Ile Lys Leu Leu Asn Gly Thr Gly Leu Glu Ser Arg Asn Glu Phe 450 455 460

    Phe Tyr Gly Glu Gln Ser Thr Val Leu Glu Glu Ile Thr Lys Val Asp 465 470 475 480

    Glu Leu Tyr Asn Ile Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe Ser 485 490 495

    Thr Glu Lys Met Lys Leu Asn Phe Asn Asn Pro Gln Leu Leu Gly Gly 500 505 510

    Trp Asp Val Asn Lys Glu Arg Asp Cys Tyr Gly Val Ile Leu Ile Lys 515 520 525

    Asp Asn Asn Tyr Tyr Leu Gly Ile Met Asp Lys Ser Ala Asn Lys Ser 530 535 540

    Phe Leu Asn Ile Lys Glu Ser Lys Asn Glu Asn Ala Tyr Lys Lys Val 545 550 555 560

    Asn Cys Lys Leu Leu Pro Gly Pro Asn Lys Met Phe Pro Lys Val Phe 565 570 575

    Phe Ala Lys Ser Asn Ile Asp Tyr Tyr Asp Pro Thr His Glu Ile Lys 580 585 590

    Lys Leu Tyr Asp Lys Gly Thr Phe Lys Lys Gly Asn Ser Phe Asn Leu 595 600 605

    Glu Asp Cys His Lys Leu Ile Asp Phe Tyr Lys Glu Ser Ile Lys Lys 610 615 620

    Asn Asp Asp Trp Lys Asn Phe Asn Phe Asn Phe Ser Asp Thr Lys Asp 625 630 635 640

    Tyr Glu Asp Ile Ser Gly Phe Phe Arg Glu Val Glu Ala Gln Asn Tyr 645 650 655

    Lys Ile Thr Tyr Thr Asn Val Ser Cys Asp Phe Ile Glu Ser Leu Val 660 665 670

    Asp Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 675 680 685

    Glu Tyr Ala Thr Gly Asn Leu Asn Leu His Thr Leu Tyr Leu Lys Met 690 695 700

    Leu Phe Asp Glu Arg Asn Leu Lys Asp Leu Cys Ile Lys Met Asn Gly 705 710 715 720

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Leu Asp Glu Asp Lys 725 730 735

    Val Val His Lys Ala Asn Gln Lys Ile Thr Asn Lys Asn Thr Asn Ser 740 745 750

    Lys Lys Lys Glu Ser Ile Phe Ser Tyr Asp Ile Val Lys Asp Lys Arg 755 760 765

    Tyr Thr Val Asp Lys Phe Phe Ile His Leu Pro Ile Thr Leu Asn Tyr 770 775 780

    Lys Glu Gln Asn Val Ser Arg Phe Asn Asp Tyr Ile Arg Glu Ile Leu 785 790 795 800

    Lys Lys Ser Lys Asn Ile Arg Val Ile Gly Ile Asp Arg Gly Glu Arg 805 810 815

    Asn Leu Leu Tyr Val Val Val Cys Asp Ser Asp Gly Ser Ile Leu Tyr 820 825 830

    Gln Arg Ser Ile Asn Glu Ile Val Ser Gly Ser His Lys Thr Asp Tyr 835 840 845

    His Lys Leu Leu Asp Asn Lys Glu Lys Glu Arg Leu Ser Ser Arg Arg 850 855 860

    Asp Trp Lys Thr Ile Glu Asn Ile Lys Asp Leu Lys Ala Gly Tyr Met 865 870 875 880

    Ser Gln Val Val Asn Glu Ile Tyr Asn Leu Ile Leu Lys Tyr Asn Ala 885 890 895

    Ile Val Val Leu Glu Asp Leu Asn Ile Gly Phe Lys Asn Gly Arg Lys 900 905 910

    Lys Val Glu Lys Gln Val Tyr Gln Asn Phe Glu Lys Ala Leu Ile Asp 915 920 925

    Lys Leu Asn Tyr Leu Cys Ile Asp Lys Thr Arg Glu Gln Leu Ser Pro

    930

    935

    940

    Ser Ser Pro Gly Gly Val Leu Asn Ala Tyr Gln Leu Thr Ala Lys Phe 945 950 955 960

    Glu Ser Phe Glu Lys Ile Gly Lys Gln Thr Gly Cys Ile Phe Tyr Val 965 970 975

    Pro Ala Tyr Leu Thr Ser Gln Ile Asp Pro Thr Thr Gly Phe Val Asn 980 985 990

    Leu Phe Tyr Gln Lys Asp Thr Ser Lys Gln Gly Leu Gln Leu Phe Phe 995 1000 1005

    Arg Lys Phe Lys Lys Ile Asn Phe Asp Lys Val Ala Ser Asn Phe 1010 1015 1020

    Glu Phe Val Phe Asp Tyr Asn Asp Phe Thr Asn Lys Ala Glu Gly 1025 1030 1035

    Thr Lys Thr Asn Trp Thr Ile Ser Thr Gln Gly Thr Arg Ile Ala 1040 1045 1050

    Lys Tyr Arg Ser Asp Asp Ala Asn Gly Lys Trp Ile Ser Arg Thr 1055 1060 1065

    Val His Pro Thr Asp Ile Ile Lys Glu Ala Leu Asn Arg Glu Lys 1070 1075 1080

    Ile Asn Tyr Asn Asp Gly His Asp Leu Ile Asp Glu Ile Val Ser 1085 1090 1095

    Ile Glu Lys Ser Ala Val Leu Lys Glu Ile Tyr Tyr Gly Phe Lys 1100 1105 1110

    Leu Thr Leu Gln Leu Arg Asn Ser Thr Leu Ala Asn Glu Glu Glu 1115 1120 1125

    Gln Glu Asp Tyr Ile Ile Ser Pro Val Lys Asn Ser Ser Gly Asn 1130 1135 1140

    Tyr Phe Asp Ser Arg Ile Thr Ser Lys Glu Leu Pro Cys Asp Ala 1145 1150 1155

    Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Ala 1160 1165 1170

    Leu Glu Gln Ile Arg Asn Ser Glu Asn Val Ser Lys Val Lys Leu 1175 1180 1185

    Ala Ile Ser Asn Lys Glu Trp Phe Glu Tyr Thr Gln Asn Asn Ile 1190 1195 1200

    Pro Ser Leu 1205 <210> 1150 <211> 1228 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1150

    Met Ser Lys Leu Glu Lys Phe Thr Asn Cys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Lys Ala Ile Pro Val Gly Lys Thr Gln Glu Asn Ile Asp

    Asn Lys Arg Leu Leu Val Glu Asp Glu Lys Arg Ala Glu Asp Tyr Lys 35 40 45

    Gly Val Lys Lys Leu Leu Asp Arg Tyr Tyr Leu Ser Phe Ile Asn Asp 50 55 60

    Val Leu His Ser Ile Lys Leu Lys Asn Leu Asn Asn Tyr Ile Ser Leu 65 70 75 80

    Phe Arg Lys Lys Thr Arg Thr Glu Lys Glu Asn Lys Glu Leu Glu Asn 85 90 95

    Leu Glu Ile Asn Leu Arg Lys Glu Ile Ala Lys Ala Phe Lys Gly Asn 100 105 110

    Glu Gly Tyr Lys Ser Leu Phe Lys Lys Asp Ile Ile Glu Thr Ile Leu 115 120 125

    Pro Glu Phe Leu Asp Asp Lys Asp Glu Ile Ala Leu Val Asn Ser Phe 130 135 140

    Asn Gly Phe Thr Thr Ala Phe Thr Gly Phe Phe Asp Asn Arg Glu Asn 145 150 155 160

    Met Phe Ser Glu Glu Ala Lys Ser Thr Ser Ile Ala Phe Arg Cys Ile 165 170 175

    Asn Glu Asn Leu Thr Arg Tyr Ile Ser Asn Met Asp Ile Phe Glu Lys 180 185 190

    Val Asp Ala Ile Phe Asp Lys His Glu Val Gln Glu Ile Lys Glu Lys 195 200 205

    Ile Leu Asn Ser Asp Tyr Asp Val Glu Asp Phe Phe Glu Gly Glu Phe 210 215 220

    Phe Asn Phe Val Leu Thr Gln Glu Gly Ile Asp Val Tyr Asn Ala Ile 225 230 235 240

    Ile Gly Gly Phe Val Thr Glu Ser Gly Glu Lys Ile Lys Gly Leu Asn 245 250 255

    Glu Tyr Ile Asn Leu Tyr Asn Gln Lys Thr Lys Gln Lys Leu Pro Lys 260 265 270

    Phe Lys Pro Leu Tyr Lys Gln Val Leu Ser Asp Arg Glu Ser Leu Ser 275 280 285

    Phe Tyr Gly Glu Gly Tyr Thr Ser Asp Glu Glu Val Leu Glu Val Phe 290 295 300

    Arg Asn Thr Leu Asn Lys Asn Ser Glu Ile Phe Ser Ser Ile Lys Lys 305 310 315 320

    Leu Glu Lys Leu Phe Lys Asn Phe Asp Glu Tyr Ser Ser Ala Gly Ile 325 330 335

    Phe Val Lys Asn Gly Pro Ala Ile Ser Thr Ile Ser Lys Asp Ile Phe 340 345 350

    Gly Glu Trp Asn Val Ile Arg Asp Lys Trp Asn Ala Glu Tyr Asp Asp 355 360 365

    Ile His Leu Lys Lys Lys Ala Val Val Thr Glu Lys Tyr Glu Asp Asp 370 375 380

    Arg Arg Lys Ser Phe Lys Lys Ile Gly Ser Phe Ser Leu Glu Gln Leu 385 390 395 400

    Gln Glu Tyr Ala Asp Ala Asp Leu Ser Val Val Glu Lys Leu Lys Glu 405 410 415

    Ile Ile Ile Gln Lys Val Asp Glu Ile Tyr Lys Val Tyr Gly Ser Ser 420 425 430

    Glu Lys Leu Phe Asp Ala Asp Phe Val Leu Glu Lys Ser Leu Lys Lys 435 440 445

    Asn Asp Ala Val Val Ala Ile Met Lys Asp Leu Leu Asp Ser Val Lys 450 455 460

    Ser Phe Glu Asn Tyr Ile Lys Ala Phe Phe Gly Glu Gly Lys Glu Thr 465 470 475 480

    Asn Arg Asp Glu Ser Phe Tyr Gly Asp Phe Val Leu Ala Tyr Asp Ile 485 490 495

    Leu Leu Lys Val Asp His Ile Tyr Asp Ala Ile Arg Asn Tyr Val Thr 500 505 510

    Gln Lys Pro Tyr Ser Lys Asp Lys Phe Lys Leu Tyr Phe Gln Asn Pro 515 520 525

    Gln Phe Met Gly Gly Trp Asp Lys Asp Lys Glu Thr Asp Tyr Arg Ala 530 535 540

    Thr Ile Leu Arg Tyr Gly Ser Lys Tyr Tyr Leu Ala Ile Met Asp Lys 545 550 555 560

    Lys Tyr Ala Lys Cys Leu Gln Lys Ile Asp Lys Asp Asp Val Asn Gly 565 570 575

    Asn Tyr Glu Lys Ile Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met 580 585 590

    Leu Pro Lys Val Phe Phe Ser Lys Lys Trp Met Ala Tyr Tyr Asn Pro 595 600 605

    Ser Glu Asp Ile Gln Lys Ile Tyr Lys Asn Gly Thr Phe Lys Lys Gly 610 615 620

    Asp Met Phe Asn Leu Asn Asp Cys His Lys Leu Ile Asp Phe Phe Lys 625 630 635 640

    Asp Ser Ile Ser Arg Tyr Pro Lys Trp Ser Asn Ala Tyr Asp Phe Asn 645 650 655

    Phe Ser Glu Thr Glu Lys Tyr Lys Asp Ile Ala Gly Phe Tyr Arg Glu 660 665 670

    Val Glu Glu Gln Gly Tyr Lys Val Ser Phe Glu Ser Ala Ser Lys Lys 675 680 685

    Glu Val Asp Lys Leu Val Glu Glu Gly Lys Leu Tyr Met Phe Gln Ile 690 695 700

    Tyr Asn Lys Asp Phe Ser Asp Lys Ser His Gly Thr Pro Asn Leu His 705 710 715 720

    Thr Met Tyr Phe Lys Leu Leu Phe Asp Glu Asn Asn His Gly Gln Ile 725 730 735

    Arg Leu Ser Gly Gly Ala Glu Leu Phe Met Arg Arg Ala Ser Leu Lys

    740

    745

    750

    Lys Glu Glu Leu Val Val His Pro Ala Asn Ser Pro Ile Ala Asn Lys 755 760 765

    Asn Pro Asp Asn Pro Lys Lys Thr Thr Thr Leu Ser Tyr Asp Val Tyr 770 775 780

    Lys Asp Lys Arg Phe Ser Glu Asp Gln Tyr Glu Leu His Ile Pro Ile 785 790 795 800

    Ala Ile Asn Lys Cys Pro Lys Asn Ile Phe Lys Ile Asn Thr Glu Val 805 810 815

    Arg Val Leu Leu Lys His Asp Asp Asn Pro Tyr Val Ile Gly Ile Asp 820 825 830

    Arg Gly Glu Arg Asn Leu Leu Tyr Ile Val Val Val Asp Gly Lys Gly 835 840 845

    Asn Ile Val Glu Gln Tyr Ser Leu Asn Glu Ile Ile Asn Asn Phe Asn 850 855 860

    Gly Ile Arg Ile Lys Thr Asp Tyr His Ser Leu Leu Asp Lys Lys Glu 865 870 875 880

    Lys Glu Arg Phe Glu Ala Arg Gln Asn Trp Thr Ser Ile Glu Asn Ile 885 890 895

    Lys Glu Leu Lys Ala Gly Tyr Ile Ser Gln Val Val His Lys Ile Cys 900 905 910

    Glu Leu Val Glu Lys Tyr Asp Ala Val Ile Ala Leu Glu Asp Leu Asn 915 920 925

    Ser Gly Phe Lys Asn Ser Arg Val Lys Val Glu Lys Gln Val Tyr Gln 930 935 940

    Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Met Val Asp Lys 945 950 955 960

    Lys Ser Asn Pro Cys Ala Thr Gly Gly Ala Leu Lys Gly Tyr Gln Ile 965 970 975

    Thr Asn Lys Phe Glu Ser Phe Lys Ser Met Ser Thr Gln Asn Gly Phe 980 985 990

    Ile Phe Tyr Ile Pro Ala Trp Leu Thr Ser Lys Ile Asp Pro Ser Thr 995 1000 1005

    Gly Phe Val Asn Leu Leu Lys Thr Lys Tyr Thr Ser Ile Ala Asp 1010 1015 1020

    Ser Lys Lys Phe Ile Ser Ser Phe Asp Arg Ile Met Tyr Val Pro 1025 1030 1035

    Glu Glu Asp Leu Phe Glu Phe Ala Leu Asp Tyr Lys Asn Phe Ser 1040 1045 1050

    Arg Thr Asp Ala Asp Tyr Ile Lys Lys Trp Lys Leu Tyr Ser Tyr 1055 1060 1065

    Gly Asn Arg Ile Arg Ile Phe Arg Asn Pro Lys Lys Asn Asn Val 1070 1075 1080

    Phe Asp Trp Glu Glu Val Cys Leu Thr Ser Ala Tyr Lys Glu Leu 1085 1090 1095

    Phe Asn Lys Tyr Gly Ile Asn Tyr Gln Gln Gly Asp Ile Arg Ala 1100 1105 1110

    Leu Leu Cys Glu Gln Ser Asp Lys Ala Phe Tyr Ser Ser Phe Met 1115 1120 1125

    Ala Leu Met Ser Leu Met Leu Gln Met Arg Asn Ser Ile Thr Gly 1130 1135 1140

    Arg Thr Asp Val Asp Phe Leu Ile Ser Pro Val Lys Asn Ser Asp 1145 1150 1155

    Gly Ile Phe Tyr Asp Ser Arg Asn Tyr Glu Ala Gln Glu Asn Ala 1160 1165 1170

    Ile Leu Pro Lys Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala 1175 1180 1185

    Arg Lys Val Leu Trp Ala Ile Gly Gln Phe Lys Lys Ala Glu Asp 1190 1195 1200

    Glu Lys Leu Asp Lys Val Lys Ile Ala Ile Ser Asn Lys Glu Trp 1205 1210 1215

    Leu Glu Tyr Ala Gln Thr Ser Val Lys His 1220 1225 <210> 1151 <211> 1373 <212> PRT <213> Moraxella bovoculi <400> 1151

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Val

    1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Asp Arg Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met His Gln Lys 35 40 45

    Val Lys Val Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Glu Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly 100 105 110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Ala Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Thr Thr 195 200 205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Pro Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met 290 295 300

    Ser Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys 325 330 335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Val Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe

    545

    550

    555

    560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn 565 570 575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Val Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Ser Ile Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Tyr Leu Glu Val Arg Lys Gln Phe Pro Lys Val Phe Phe 625 630 635 640

    Ser Lys Glu Ala Ile Ala Ile Asn Tyr His Pro Ser Lys Glu Leu Val 645 650 655

    Glu Ile Lys Asp Lys Gly Arg Gln Arg Ser Asp Asp Glu Arg Leu Lys 660 665 670

    Leu Tyr Arg Phe Ile Leu Glu Cys Leu Lys Ile His Pro Lys Tyr Asp 675 680 685

    Lys Lys Phe Glu Gly Ala Ile Gly Asp Ile Gln Leu Phe Lys Lys Asp 690 695 700

    Lys Lys Gly Arg Glu Val Pro Ile Ser Glu Lys Asp Leu Phe Asp Lys 705 710 715 720

    Ile Asn Gly Ile Phe Ser Ser Lys Pro Lys Leu Glu Met Glu Asp Phe 725 730 735

    Phe Ile Gly Glu Phe Lys Arg Tyr Asn Pro Ser Gln Asp Leu Val Asp 740 745 750

    Gln Tyr Asn Ile Tyr Lys Lys Ile Asp Ser Asn Asp Asn Arg Lys Lys 755 760 765

    Glu Asn Phe Tyr Asn Asn His Pro Lys Phe Lys Lys Asp Leu Val Arg 770 775 780

    Tyr Tyr Tyr Glu Ser Met Cys Lys His Glu Glu Trp Glu Glu Ser Phe 785 790 795 800

    Glu Phe Ser Lys Lys Leu Gln Asp Ile Gly Cys Tyr Val Asp Val Asn 805 810 815

    Glu Leu Phe Thr Glu Ile Glu Thr Arg Arg Leu Asn Tyr Lys Ile Ser 820 825 830

    Phe Cys Asn Ile Asn Ala Asp Tyr Ile Asp Glu Leu Val Glu Gln Gly 835 840 845

    Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Lys Ala 850 855 860

    His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala Leu Phe Ser 865 870 875 880

    Glu Asp Asn Leu Ala Asp Pro Ile Tyr Lys Leu Asn Gly Glu Ala Gln 885 890 895

    Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr Thr Ile His 900 905 910

    Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn Pro Lys Lys 915 920 925

    Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr Thr Gln Asp 930 935 940

    Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly Val Gln Gly 945 950 955 960

    Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser Ile Gln Gln 965 970 975

    Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu Arg His Leu 980 985 990

    Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu Glu Gln Cys 995 1000 1005

    Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr Gln Met 1010 1015 1020

    Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu Arg 1025 1030 1035

    Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu 1040 1045 1050

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln 1055 1060 1065

    Leu Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 1070 1075 1080

    Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 1085 1090 1095

    Gln Asn Phe Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val 1100 1105 1110

    Leu Lys Asp Lys Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala 1115 1120 1125

    Leu Gln Leu Thr Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys 1130 1135 1140

    Gln Thr Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys 1145 1150 1155

    Ile Asp Pro Glu Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr 1160 1165 1170

    Glu Asn Ile Ala Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys 1175 1180 1185

    Ile Cys Tyr Asn Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp 1190 1195 1200

    Tyr Ala Lys Phe Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp 1205 1210 1215

    Thr Ile Cys Ser His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr 1220 1225 1230

    Ala Asn Gln Asn Lys Gly Ala Ala Lys Gly Ile Asn Val Asn Asp 1235 1240 1245

    Glu Leu Lys Ser Leu Phe Ala Arg His His Ile Asn Glu Lys Gln

    1250

    1255

    1260

    Pro Asn Leu Val Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe 1265 1270 1275

    His Lys Ser Leu Met Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg 1280 1285 1290

    Tyr Ser Asn Ala Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val 1295 1300 1305

    Ala Asn Asp Glu Gly Val Phe Phe Asn Ser Ala Leu Ala Asp Asp 1310 1315 1320

    Thr Gln Pro Gln Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala 1325 1330 1335

    Leu Lys Gly Leu Trp Leu Leu Asn Glu Leu Lys Asn Ser Asp Asp 1340 1345 1350

    Leu Asn Lys Val Lys Leu Ala Ile Asp Asn Gln Thr Trp Leu Asn 1355 1360 1365

    Phe Ala Gln Asn Arg 1370 <210> 1152 <211> 1373 <212> PRT <213> Moraxella bovoculi <400> 1152

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Val

    1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Asp Arg Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met His Gln Lys 35 40 45

    Val Lys Val Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Glu Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly 100 105 110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Ala Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Thr Thr

    195

    200

    205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Pro Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met 290 295 300

    Ser Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys 325 330 335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Val Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe 545 550 555 560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn 565 570 575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Val Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Ser Ile Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Tyr Leu Glu Val Arg Lys Gln Phe Pro Lys Val Phe Phe 625 630 635 640

    Ser Lys Glu Ala Ile Ala Ile Asn Tyr His Pro Ser Lys Glu Leu Val 645 650 655

    Glu Ile Lys Asp Lys Gly Arg Gln Arg Ser Asp Asp Glu Arg Leu Lys 660 665 670

    Leu Tyr Arg Phe Ile Leu Glu Cys Leu Lys Ile His Pro Lys Tyr Asp 675 680 685

    Lys Lys Phe Glu Gly Ala Ile Gly Asp Ile Gln Leu Phe Lys Lys Asp 690 695 700

    Lys Lys Gly Arg Glu Val Pro Ile Ser Glu Lys Asp Leu Phe Asp Lys 705 710 715 720

    Ile Asn Gly Ile Phe Ser Ser Lys Pro Lys Leu Glu Met Glu Asp Phe 725 730 735

    Phe Ile Gly Glu Phe Lys Arg Tyr Asn Pro Ser Gln Asp Leu Val Asp 740 745 750

    Gln Tyr Asn Ile Tyr Lys Lys Ile Asp Ser Asn Asp Asn Arg Lys Lys 755 760 765

    Glu Asn Phe Tyr Asn Asn His Pro Lys Phe Lys Lys Asp Leu Val Arg 770 775 780

    Tyr Tyr Tyr Glu Ser Met Cys Lys His Glu Glu Trp Glu Glu Ser Phe 785 790 795 800

    Glu Phe Ser Lys Lys Leu Gln Asp Ile Gly Cys Tyr Val Asp Val Asn 805 810 815

    Glu Leu Phe Thr Glu Ile Glu Thr Arg Arg Leu Asn Tyr Lys Ile Ser 820 825 830

    Phe Cys Asn Ile Asn Ala Asp Tyr Ile Asp Glu Leu Val Glu Gln Gly 835 840 845

    Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Lys Ala 850 855 860

    His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala Leu Phe Ser 865 870 875 880

    Glu Asp Asn Leu Ala Asp Pro Ile Tyr Lys Leu Asn Gly Glu Ala Gln 885 890 895

    Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr Thr Ile His 900 905 910

    Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn Pro Lys Lys

    915

    920

    925

    Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr Thr Gln Asp 930 935 940

    Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly Val Gln Gly 945 950 955 960

    Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser Ile Gln Gln 965 970 975

    Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu Arg His Leu 980 985 990

    Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu Glu Gln Cys 995 1000 1005

    Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr Gln Met 1010 1015 1020

    Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu Arg 1025 1030 1035

    Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu 1040 1045 1050

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln 1055 1060 1065

    Leu Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 1070 1075 1080

    Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 1085 1090 1095

    Gln Asn Phe Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val 1100 1105 1110

    Leu Lys Asp Lys Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala 1115 1120 1125

    Leu Gln Leu Thr Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys 1130 1135 1140

    Gln Thr Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys 1145 1150 1155

    Ile Asp Pro Glu Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr 1160 1165 1170

    Glu Asn Ile Ala Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys 1175 1180 1185

    Ile Cys Tyr Asn Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp 1190 1195 1200

    Tyr Ala Lys Phe Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp 1205 1210 1215

    Thr Ile Cys Ser His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr 1220 1225 1230

    Ala Asn Gln Asn Lys Gly Ala Ala Lys Gly Ile Asn Val Asn Asp 1235 1240 1245

    Glu Leu Lys Ser Leu Phe Ala Arg His His Ile Asn Glu Lys Gln 1250 1255 1260

    Pro Asn Leu Val Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe 1265 1270 1275

    His Lys Ser Leu Met Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg 1280 1285 1290

    Tyr Ser Asn Ala Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val 1295 1300 1305

    Ala Asn Asp Glu Gly Val Phe Phe Asn Ser Ala Leu Ala Asp Asp 1310 1315 1320

    Thr Gln Pro Gln Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala 1325 1330 1335

    Leu Lys Gly Leu Trp Leu Leu Asn Glu Leu Lys Asn Ser Asp Asp 1340 1345 1350

    Leu Asn Lys Val Lys Leu Ala Ile Asp Asn Gln Thr Trp Leu Asn 1355 1360 1365

    Phe Ala Gln Asn Arg 1370 <210> 1153 <211> 1264 <212> PRT <213> Moraxella caprae <400> 1153

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Met 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met Tyr Gln Lys 35 40 45

    Val Lys Ala Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Gly Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly 100 105 110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Thr Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Ala Thr 195 200 205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Arg Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met 290 295 300

    Gly Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys 325 330 335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Ala Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe 545 550 555 560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn

    565

    570

    575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Ile Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Asn Val Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met Leu Pro Lys Val Phe 625 630 635 640

    Phe Ala Lys Ser Asn Leu Asp Tyr Tyr Asn Pro Ser Ala Glu Leu Leu 645 650 655

    Asp Lys Tyr Ala Gln Gly Thr His Lys Lys Gly Asn Asn Phe Asn Leu 660 665 670

    Lys Asp Cys His Ala Leu Ile Asp Phe Phe Lys Ala Gly Ile Asn Lys 675 680 685

    His Pro Glu Trp Gln His Phe Gly Phe Lys Phe Ser Pro Thr Ser Ser 690 695 700

    Tyr Gln Asp Leu Ser Asp Phe Tyr Arg Glu Val Glu Pro Gln Gly Tyr 705 710 715 720

    Gln Val Lys Phe Val Asp Ile Asn Ala Asp Tyr Ile Asn Glu Leu Val 725 730 735

    Glu Gln Gly Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser 740 745 750

    Pro Lys Ala His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala 755 760 765

    Leu Phe Ser Lys Asp Asn Leu Ala Asn Pro Ile Tyr Lys Leu Asn Gly 770 775 780

    Glu Ala Gln Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr 785 790 795 800

    Thr Ile His Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn 805 810 815

    Pro Lys Lys Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr 820 825 830

    Thr Gln Asp Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly 835 840 845

    Val Gln Gly Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser 850 855 860

    Ile Gln Gln Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu 865 870 875 880

    Arg His Leu Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu 885 890 895

    Glu Gln Arg Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr 900 905 910

    Gln Met Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu 915 920 925

    Arg Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu 930 935 940

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln Leu 945 950 955 960

    Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn Phe Gly 965 970 975

    Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr Gln Asn Phe 980 985 990

    Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val Leu Lys Asp Glu 995 1000 1005

    Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala Leu Gln Leu Thr 1010 1015 1020

    Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys Gln Thr Gly Phe 1025 1030 1035

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Glu 1040 1045 1050

    Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr Glu Asn Ile Ala 1055 1060 1065

    Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys Ile Cys Tyr Asn 1070 1075 1080

    Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp Tyr Ala Lys Phe 1085 1090 1095

    Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp Lys Ile Cys Ser 1100 1105 1110

    His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr Ala Asn Gln Asn 1115 1120 1125

    Lys Gly Ala Thr Lys Gly Ile Asn Val Asn Asp Glu Leu Lys Ser 1130 1135 1140

    Leu Phe Ala Arg His His Ile Asn Asp Lys Gln Pro Asn Leu Val 1145 1150 1155

    Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe His Lys Ser Leu 1160 1165 1170

    Ile Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg Tyr Ser Asn Ala 1175 1180 1185

    Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val Ala Asn Asp Glu 1190 1195 1200

    Gly Met Phe Phe Asn Ser Ala Leu Ala Asp Asp Thr Gln Pro Gln 1205 1210 1215

    Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu 1220 1225 1230

    Trp Val Leu Glu Gln Ile Lys Asn Ser Asp Asp Leu Asn Lys Val 1235 1240 1245

    Lys Leu Ala Ile Asp Asn Gln Thr Trp Leu Asn Phe Ala Gln Asn 1250 1255 1260

    Arg <210> 1154 <211> 1235 <212> PRT <213> Anaerovibrio sp.

    <400> 1154

    Met Val Ala Phe Ile Asp Glu Phe Val Gly Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Ala Arg Pro Val Pro Glu Thr Lys Lys Trp Leu 20 25 30

    Glu Ser Asp Gln Cys Ser Val Leu Phe Asn Asp Gln Lys Arg Asn Glu 35 40 45

    Tyr Tyr Gly Val Leu Lys Glu Leu Leu Asp Asp Tyr Tyr Arg Ala Tyr 50 55 60

    Ile Glu Asp Ala Leu Thr Ser Phe Thr Leu Asp Lys Ala Leu Leu Glu 65 70 75 80

    Asn Ala Tyr Asp Leu Tyr Cys Asn Arg Asp Thr Asn Ala Phe Ser Ser 85 90 95

    Cys Cys Glu Lys Leu Arg Lys Asp Leu Val Lys Ala Phe Gly Asn Leu 100 105 110

    Lys Asp Tyr Leu Leu Gly Ser Asp Gln Leu Lys Asp Leu Val Lys Leu 115 120 125

    Lys Ala Lys Val Asp Ala Pro Ala Gly Lys Gly Lys Lys Lys Ile Glu 130 135 140

    Val Asp Ser Arg Leu Ile Asn Trp Leu Asn Asn Asn Ala Lys Tyr Ser 145 150 155 160

    Ala Glu Asp Arg Glu Lys Tyr Ile Lys Ala Ile Glu Ser Phe Glu Gly 165 170 175

    Phe Val Thr Tyr Leu Thr Asn Tyr Lys Gln Ala Arg Glu Asn Met Phe 180 185 190

    Ser Ser Glu Asp Lys Ser Thr Ala Ile Ala Phe Arg Val Ile Asp Gln 195 200 205

    Asn Met Val Thr Tyr Phe Gly Asn Ile Arg Ile Tyr Glu Lys Ile Lys 210 215 220

    Ala Lys Tyr Pro Glu Leu Tyr Ser Ala Leu Lys Gly Phe Glu Lys Phe 225 230 235 240

    Phe Ser Pro Thr Ala Tyr Ser Glu Ile Leu Ser Gln Ser Lys Ile Asp 245 250 255

    Glu Tyr Asn Tyr Gln Cys Ile Gly Arg Pro Ile Asp Asp Ala Asp Phe 260 265 270

    Lys Gly Val Asn Ser Leu Ile Asn Glu Tyr Arg Gln Lys Asn Gly Ile 275 280 285

    Lys Ala Arg Glu Leu Pro Val Met Ser Met Leu Tyr Lys Gln Ile Leu 290 295 300

    Ser Asp Arg Asp Asn Ser Phe Met Ser Glu Val Ile Asn Arg Asn Glu 305 310 315 320

    Glu Ala Ile Glu Cys Ala Lys Asn Gly Tyr Lys Val Ser Tyr Ala Leu

    325

    330

    335

    Phe Asn Glu Leu Leu Gln Leu Tyr Lys Lys Ile Phe Thr Glu Asp Asn 340 345 350

    Tyr Gly Asn Ile Tyr Val Lys Thr Gln Pro Leu Thr Glu Leu Ser Gln 355 360 365

    Ala Leu Phe Gly Asp Trp Ser Ile Leu Arg Asn Ala Leu Asp Asn Gly 370 375 380

    Lys Tyr Asp Lys Asp Ile Ile Asn Leu Ala Glu Leu Glu Lys Tyr Phe 385 390 395 400

    Ser Glu Tyr Cys Lys Val Leu Asp Ala Asp Asp Ala Ala Lys Ile Gln 405 410 415

    Asp Lys Phe Asn Leu Lys Asp Tyr Phe Ile Gln Lys Asn Ala Leu Asp 420 425 430

    Ala Thr Leu Pro Asp Leu Asp Lys Ile Thr Gln Tyr Lys Pro His Leu 435 440 445

    Asp Ala Met Leu Gln Ala Ile Arg Lys Tyr Lys Leu Phe Ser Met Tyr 450 455 460

    Asn Gly Arg Lys Lys Met Asp Val Pro Glu Asn Gly Ile Asp Phe Ser 465 470 475 480

    Asn Glu Phe Asn Ala Ile Tyr Asp Lys Leu Ser Glu Phe Ser Ile Leu 485 490 495

    Tyr Asp Arg Ile Arg Asn Phe Ala Thr Lys Lys Pro Tyr Ser Asp Glu 500 505 510

    Lys Met Lys Leu Ser Phe Asn Met Pro Thr Met Leu Ala Gly Trp Asp 515 520 525

    Tyr Asn Asn Glu Thr Ala Asn Gly Cys Phe Leu Phe Ile Lys Asp Gly 530 535 540

    Lys Tyr Phe Leu Gly Val Ala Asp Ser Lys Ser Lys Asn Ile Phe Asp 545 550 555 560

    Phe Lys Lys Asn Pro His Leu Leu Asp Lys Tyr Ser Ser Lys Asp Ile 565 570 575

    Tyr Tyr Lys Val Lys Tyr Lys Gln Val Ser Gly Ser Ala Lys Met Leu 580 585 590

    Pro Lys Val Val Phe Ala Gly Ser Asn Glu Lys Ile Phe Gly His Leu 595 600 605

    Ile Ser Lys Arg Ile Leu Glu Ile Arg Glu Lys Lys Leu Tyr Thr Ala 610 615 620

    Ala Ala Gly Asp Arg Lys Ala Val Ala Glu Trp Ile Asp Phe Met Lys 625 630 635 640

    Ser Ala Ile Ala Ile His Pro Glu Trp Asn Glu Tyr Phe Lys Phe Lys 645 650 655

    Phe Lys Asn Thr Ala Glu Tyr Asp Asn Ala Asn Lys Phe Tyr Glu Asp 660 665 670

    Ile Asp Lys Gln Thr Tyr Ser Leu Glu Lys Val Glu Ile Pro Thr Glu 675 680 685

    Tyr Ile Asp Glu Met Val Ser Gln His Lys Leu Tyr Leu Phe Gln Leu 690 695 700

    Tyr Thr Lys Asp Phe Ser Asp Lys Lys Lys Lys Lys Gly Thr Asp Asn 705 710 715 720

    Leu His Thr Met Tyr Trp His Gly Val Phe Ser Asp Glu Asn Leu Lys 725 730 735

    Ala Val Thr Glu Gly Thr Gln Pro Ile Ile Lys Leu Asn Gly Glu Ala 740 745 750

    Glu Met Phe Met Arg Asn Pro Ser Ile Glu Phe Gln Val Thr His Glu 755 760 765

    His Asn Lys Pro Ile Ala Asn Lys Asn Pro Leu Asn Thr Lys Lys Glu 770 775 780

    Ser Val Phe Asn Tyr Asp Leu Ile Lys Asp Lys Arg Tyr Thr Glu Arg 785 790 795 800

    Lys Phe Tyr Phe His Cys Pro Ile Thr Leu Asn Phe Arg Ala Asp Lys 805 810 815

    Pro Ile Lys Tyr Asn Glu Lys Ile Asn Arg Phe Val Glu Asn Asn Pro 820 825 830

    Asp Val Cys Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr 835 840 845

    Tyr Thr Val Ile Asn Gln Thr Gly Asp Ile Leu Glu Gln Gly Ser Leu 850 855 860

    Asn Lys Ile Ser Gly Ser Tyr Thr Asn Asp Lys Gly Glu Lys Val Asn 865 870 875 880

    Lys Glu Thr Asp Tyr His Asp Leu Leu Asp Arg Lys Glu Lys Gly Lys 885 890 895

    His Val Ala Gln Gln Ala Trp Glu Thr Ile Glu Asn Ile Lys Glu Leu 900 905 910

    Lys Ala Gly Tyr Leu Ser Gln Val Val Tyr Lys Leu Thr Gln Leu Met 915 920 925

    Leu Gln Tyr Asn Ala Val Ile Val Leu Glu Asn Leu Asn Val Gly Phe 930 935 940

    Lys Arg Gly Arg Thr Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 945 950 955 960

    Lys Ala Met Ile Asp Lys Leu Asn Tyr Leu Val Phe Lys Asp Arg Gly 965 970 975

    Tyr Glu Met Asn Gly Ser Tyr Ala Lys Gly Leu Gln Leu Thr Asp Lys 980 985 990

    Phe Glu Ser Phe Asp Lys Ile Gly Lys Gln Thr Gly Cys Ile Tyr Tyr 995 1000 1005

    Val Ile Pro Ser Tyr Thr Ser His Ile Asp Pro Lys Thr Gly Phe 1010 1015 1020

    Val Asn Leu Leu Asn Ala Lys Leu Arg Tyr Glu Asn Ile Thr Lys 1025 1030 1035

    Ala Gln Asp Thr Ile Arg Lys Phe Asp Ser Ile Ser Tyr Asn Ala

    1040

    1045

    1050

    Lys Ala Asp Tyr Phe Glu Phe Ala Phe Asp Tyr Arg Ser Phe Gly 1055 1060 1065

    Val Asp Met Ala Arg Asn Glu Trp Val Val Cys Thr Cys Gly Asp 1070 1075 1080

    Leu Arg Trp Glu Tyr Ser Ala Lys Thr Arg Glu Thr Lys Ala Tyr 1085 1090 1095

    Ser Val Thr Asp Arg Leu Lys Glu Leu Phe Lys Ala His Gly Ile 1100 1105 1110

    Asp Tyr Val Gly Gly Glu Asn Leu Val Ser His Ile Thr Glu Val 1115 1120 1125

    Ala Asp Lys His Phe Leu Ser Thr Leu Leu Phe Tyr Leu Arg Leu 1130 1135 1140

    Val Leu Lys Met Arg Tyr Thr Val Ser Gly Thr Glu Asn Glu Asn 1145 1150 1155

    Asp Phe Ile Leu Ser Pro Val Glu Tyr Ala Pro Gly Lys Phe Phe 1160 1165 1170

    Asp Ser Arg Glu Ala Thr Ser Thr Glu Pro Met Asn Ala Asp Ala 1175 1180 1185

    Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Met Thr Ile Arg 1190 1195 1200

    Gly Ile Glu Asp Gly Lys Leu His Asn Tyr Gly Lys Gly Gly Glu 1205 1210 1215

    Asn Ala Ala Trp Phe Lys Phe Met Gln Asn Gln Glu Tyr Lys Asn 1220 1225 1230

    Asn Gly 1235 <210> 1155 <211> 1154 <212> PRT <213> Proteocatella sphenisci <400> 1155

    Met Glu Asn Phe Lys Asn Leu Tyr Pro Ile Asn Lys Thr Leu Arg Phe 1 5 10 15

    Glu Leu Arg Pro Tyr Gly Lys Thr Leu Glu Asn Phe Lys Lys Ser Gly 20 25 30

    Leu Leu Glu Lys Asp Ala Phe Lys Ala Asn Ser Arg Arg Ser Met Gln 35 40 45

    Ala Ile Ile Asp Glu Lys Phe Lys Glu Thr Ile Glu Glu Arg Leu Lys 50 55 60

    Tyr Thr Glu Phe Ser Glu Cys Asp Leu Gly Asn Met Thr Ser Lys Asp 65 70 75 80

    Lys Lys Ile Thr Asp Lys Ala Ala Thr Asn Leu Lys Lys Gln Val Ile 85 90 95

    Leu Ser Phe Asp Asp Glu Ile Phe Asn Asn Tyr Leu Lys Pro Asp Lys 100 105 110

    Asn Ile Asp Ala Leu Phe Lys Asn Asp Pro Ser Asn Pro Val Ile Ser

    115

    120

    125

    Thr Phe Lys Gly Phe Thr Thr Tyr Phe Val Asn Phe Phe Glu Ile Arg 130 135 140

    Lys His Ile Phe Lys Gly Glu Ser Ser Gly Ser Met Ala Tyr Arg Ile 145 150 155 160

    Ile Asp Glu Asn Leu Thr Thr Tyr Leu Asn Asn Ile Glu Lys Ile Lys 165 170 175

    Lys Leu Pro Glu Glu Leu Lys Ser Gln Leu Glu Gly Ile Asp Gln Ile 180 185 190

    Asp Lys Leu Asn Asn Tyr Asn Glu Phe Ile Thr Gln Ser Gly Ile Thr 195 200 205

    His Tyr Asn Glu Ile Ile Gly Gly Ile Ser Lys Ser Glu Asn Val Lys 210 215 220

    Ile Gln Gly Ile Asn Glu Gly Ile Asn Leu Tyr Cys Gln Lys Asn Lys 225 230 235 240

    Val Lys Leu Pro Arg Leu Thr Pro Leu Tyr Lys Met Ile Leu Ser Asp 245 250 255

    Arg Val Ser Asn Ser Phe Val Leu Asp Thr Ile Glu Asn Asp Thr Glu 260 265 270

    Leu Ile Glu Met Ile Ser Asp Leu Ile Asn Lys Thr Glu Ile Ser Gln 275 280 285

    Asp Val Ile Met Ser Asp Ile Gln Asn Ile Phe Ile Lys Tyr Lys Gln 290 295 300

    Leu Gly Asn Leu Pro Gly Ile Ser Tyr Ser Ser Ile Val Asn Ala Ile 305 310 315 320

    Cys Ser Asp Tyr Asp Asn Asn Phe Gly Asp Gly Lys Arg Lys Lys Ser 325 330 335

    Tyr Glu Asn Asp Arg Lys Lys His Leu Glu Thr Asn Val Tyr Ser Ile 340 345 350

    Asn Tyr Ile Ser Glu Leu Leu Thr Asp Thr Asp Val Ser Ser Asn Ile 355 360 365

    Lys Met Arg Tyr Lys Glu Leu Glu Gln Asn Tyr Gln Val Cys Lys Glu 370 375 380

    Asn Phe Asn Ala Thr Asn Trp Met Asn Ile Lys Asn Ile Lys Gln Ser 385 390 395 400

    Glu Lys Thr Asn Leu Ile Lys Asp Leu Leu Asp Ile Leu Lys Ser Ile 405 410 415

    Gln Arg Phe Tyr Asp Leu Phe Asp Ile Val Asp Glu Asp Lys Asn Pro 420 425 430

    Ser Ala Glu Phe Tyr Thr Trp Leu Ser Lys Asn Ala Glu Lys Leu Asp 435 440 445

    Phe Glu Phe Asn Ser Val Tyr Asn Lys Ser Arg Asn Tyr Leu Thr Arg 450 455 460

    Lys Gln Tyr Ser Asp Lys Lys Ile Lys Leu Asn Phe Asp Ser Pro Thr 465 470 475 480

    Leu Ala Lys Gly Trp Asp Ala Asn Lys Glu Ile Asp Asn Ser Thr Ile 485 490 495

    Ile Met Arg Lys Phe Asn Asn Asp Arg Gly Asp Tyr Asp Tyr Phe Leu 500 505 510

    Gly Ile Trp Asn Lys Ser Thr Pro Ala Asn Glu Lys Ile Ile Pro Leu 515 520 525

    Glu Asp Asn Gly Leu Phe Glu Lys Met Gln Tyr Lys Leu Tyr Pro Asp 530 535 540

    Pro Ser Lys Met Leu Pro Lys Gln Phe Leu Ser Lys Ile Trp Lys Ala 545 550 555 560

    Lys His Pro Thr Thr Pro Glu Phe Asp Lys Lys Tyr Lys Glu Gly Arg 565 570 575

    His Lys Lys Gly Pro Asp Phe Glu Lys Glu Phe Leu His Glu Leu Ile 580 585 590

    Asp Cys Phe Lys His Gly Leu Val Asn His Asp Glu Lys Tyr Gln Asp 595 600 605

    Val Phe Gly Phe Asn Leu Arg Asn Thr Glu Asp Tyr Asn Ser Tyr Thr 610 615 620

    Glu Phe Leu Glu Asp Val Glu Arg Cys Asn Tyr Asn Leu Ser Phe Asn 625 630 635 640

    Lys Ile Ala Asp Thr Ser Asn Leu Ile Asn Asp Gly Lys Leu Tyr Val 645 650 655

    Phe Gln Ile Trp Ser Lys Asp Phe Ser Ile Asp Ser Lys Gly Thr Lys 660 665 670

    Asn Leu Asn Thr Ile Tyr Phe Glu Ser Leu Phe Ser Glu Glu Asn Met 675 680 685

    Ile Glu Lys Met Phe Lys Leu Ser Gly Glu Ala Glu Ile Phe Tyr Arg 690 695 700

    Pro Ala Ser Leu Asn Tyr Cys Glu Asp Ile Ile Lys Lys Gly His His 705 710 715 720

    His Ala Glu Leu Lys Asp Lys Phe Asp Tyr Pro Ile Ile Lys Asp Lys 725 730 735

    Arg Tyr Ser Gln Asp Lys Phe Phe Phe His Val Pro Met Val Ile Asn 740 745 750

    Tyr Lys Ser Glu Lys Leu Asn Ser Lys Ser Leu Asn Asn Arg Thr Asn 755 760 765

    Glu Asn Leu Gly Gln Phe Thr His Ile Ile Gly Ile Asp Arg Gly Glu 770 775 780

    Arg His Leu Ile Tyr Leu Thr Val Val Asp Val Ser Thr Gly Glu Ile 785 790 795 800

    Val Glu Gln Lys His Leu Asp Glu Ile Ile Asn Thr Asp Thr Lys Gly 805 810 815

    Val Glu His Lys Thr His Tyr Leu Asn Lys Leu Glu Glu Lys Ser Lys 820 825 830

    Thr Arg Asp Asn Glu Arg Lys Ser Trp Glu Ala Ile Glu Thr Ile Lys

    835

    840

    845

    Glu Leu Lys Glu Gly Tyr Ile Ser His Val Ile Asn Glu Ile Gln Lys 850 855 860

    Leu Gln Glu Lys Tyr Asn Ala Leu Ile Val Met Glu Asn Leu Asn Tyr 865 870 875 880

    Gly Phe Lys Asn Ser Arg Ile Lys Val Glu Lys Gln Val Tyr Gln Lys 885 890 895

    Phe Glu Thr Ala Leu Ile Lys Lys Phe Asn Tyr Ile Ile Asp Lys Lys 900 905 910

    Asp Pro Glu Thr Tyr Ile His Gly Tyr Gln Leu Thr Asn Pro Ile Thr 915 920 925

    Thr Leu Asp Lys Ile Gly Asn Gln Ser Gly Ile Val Leu Tyr Ile Pro 930 935 940

    Ala Trp Asn Thr Ser Lys Ile Asp Pro Val Thr Gly Phe Val Asn Leu 945 950 955 960

    Leu Tyr Ala Asp Asp Leu Lys Tyr Lys Asn Gln Glu Gln Ala Lys Ser 965 970 975

    Phe Ile Gln Lys Ile Asp Asn Ile Tyr Phe Glu Asn Gly Glu Phe Lys 980 985 990

    Phe Asp Ile Asp Phe Ser Lys Trp Asn Asn Arg Tyr Ser Ile Ser Lys 995 1000 1005

    Thr Lys Trp Thr Leu Thr Ser Tyr Gly Thr Arg Ile Gln Thr Phe 1010 1015 1020

    Arg Asn Pro Gln Lys Asn Asn Lys Trp Asp Ser Ala Glu Tyr Asp 1025 1030 1035

    Leu Thr Glu Glu Phe Lys Leu Ile Leu Asn Ile Asp Gly Thr Leu 1040 1045 1050

    Lys Ser Gln Asp Val Glu Thr Tyr Lys Lys Phe Met Ser Leu Phe 1055 1060 1065

    Lys Leu Met Leu Gln Leu Arg Asn Ser Val Thr Gly Thr Asp Ile 1070 1075 1080

    Asp Tyr Met Ile Ser Pro Val Thr Asp Lys Thr Gly Thr His Phe 1085 1090 1095

    Asp Ser Arg Glu Asn Ile Lys Asn Leu Pro Ala Asp Ala Asp Ala 1100 1105 1110

    Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Ile Met Ala Ile Glu 1115 1120 1125

    Asn Ile Met Asn Gly Ile Ser Asp Pro Leu Lys Ile Ser Asn Glu 1130 1135 1140

    Asp Tyr Leu Lys Tyr Ile Gln Asn Gln Gln Glu 1145 1150 <210> 1156 <211> 1282 <212> PRT <213> Eubacterium eligens <400> 1156

    Met Asn Gly Asn Arg Ser Ile Val Tyr Arg Glu Phe Val Gly Val Thr

    Pro Val Ala Lys Thr Leu Arg Asn Glu Leu Arg Pro Val Gly His Thr 20 25 30

    Gln Glu His Ile Ile Gln Asn Gly Leu Ile Gln Glu Asp Glu Leu Arg 35 40 45

    Gln Glu Lys Ser Thr Glu Leu Lys Asn Ile Met Asp Asp Tyr Tyr Arg 50 55 60

    Glu Tyr Ile Asp Lys Ser Leu Ser Gly Leu Thr Asp Leu Asp Phe Thr 65 70 75 80

    Leu Leu Phe Glu Leu Met Asn Ser Val Gln Ser Ser Leu Ser Lys Asp 85 90 95

    Asn Lys Lys Ala Leu Glu Lys Glu His Asn Lys Met Arg Glu Gln Ile 100 105 110

    Cys Thr His Leu Gln Ser Asp Ser Asp Tyr Lys Asn Met Phe Asn Ala 115 120 125

    Lys Leu Phe Lys Glu Ile Leu Pro Asp Phe Ile Lys Asn Tyr Asn Gln 130 135 140

    Tyr Asp Val Lys Asp Lys Ala Gly Lys Leu Glu Thr Leu Ala Leu Phe 145 150 155 160

    Asn Gly Phe Ser Thr Tyr Phe Thr Asp Phe Phe Glu Lys Arg Lys Asn 165 170 175

    Val Phe Thr Lys Glu Ala Val Ser Thr Ser Ile Ala Tyr Arg Ile Val 180 185 190

    His Glu Asn Ser Leu Ile Phe Leu Ala Asn Met Thr Ser Tyr Lys Lys 195 200 205

    Ile Ser Glu Lys Ala Leu Asp Glu Ile Glu Val Ile Glu Lys Asn Asn 210 215 220

    Gln Asp Lys Met Gly Asp Trp Glu Leu Asn Gln Ile Phe Asn Pro Asp 225 230 235 240

    Phe Tyr Asn Met Val Leu Ile Gln Ser Gly Ile Asp Phe Tyr Asn Glu 245 250 255

    Ile Cys Gly Val Val Asn Ala His Met Asn Leu Tyr Cys Gln Gln Thr 260 265 270

    Lys Asn Asn Tyr Asn Leu Phe Lys Met Arg Lys Leu His Lys Gln Ile 275 280 285

    Leu Ala Tyr Thr Ser Thr Ser Phe Glu Val Pro Lys Met Phe Glu Asp 290 295 300

    Asp Met Ser Val Tyr Asn Ala Val Asn Ala Phe Ile Asp Glu Thr Glu 305 310 315 320

    Lys Gly Asn Ile Ile Gly Lys Leu Lys Asp Ile Val Asn Lys Tyr Asp 325 330 335

    Glu Leu Asp Glu Lys Arg Ile Tyr Ile Ser Lys Asp Phe Tyr Glu Thr 340 345 350

    Leu Ser Cys Phe Met Ser Gly Asn Trp Asn Leu Ile Thr Gly Cys Val 355 360 365

    Glu Asn Phe Tyr Asp Glu Asn Ile His Ala Lys Gly Lys Ser Lys Glu 370 375 380

    Glu Lys Val Lys Lys Ala Val Lys Glu Asp Lys Tyr Lys Ser Ile Asn 385 390 395 400

    Asp Val Asn Asp Leu Val Glu Lys Tyr Ile Asp Glu Lys Glu Arg Asn 405 410 415

    Glu Phe Lys Asn Ser Asn Ala Lys Gln Tyr Ile Arg Glu Ile Ser Asn 420 425 430

    Ile Ile Thr Asp Thr Glu Thr Ala His Leu Glu Tyr Asp Glu His Ile 435 440 445

    Ser Leu Ile Glu Ser Glu Glu Lys Ala Asp Glu Ile Lys Lys Arg Leu 450 455 460

    Asp Met Tyr Met Asn Met Tyr His Trp Val Lys Ala Phe Ile Val Asp 465 470 475 480

    Glu Val Leu Asp Arg Asp Glu Met Phe Tyr Ser Asp Ile Asp Asp Ile 485 490 495

    Tyr Asn Ile Leu Glu Asn Ile Val Pro Leu Tyr Asn Arg Val Arg Asn 500 505 510

    Tyr Val Thr Gln Lys Pro Tyr Thr Ser Lys Lys Ile Lys Leu Asn Phe 515 520 525

    Gln Ser Pro Thr Leu Ala Asn Gly Trp Ser Gln Ser Lys Glu Phe Asp 530 535 540

    Asn Asn Ala Ile Ile Leu Ile Arg Asp Asn Lys Tyr Tyr Leu Ala Ile 545 550 555 560

    Phe Asn Ala Lys Asn Lys Pro Asp Lys Lys Ile Ile Gln Gly Asn Ser 565 570 575

    Asp Lys Lys Asn Asp Asn Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu 580 585 590

    Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Leu Ser Lys Lys Gly 595 600 605

    Ile Glu Thr Phe Lys Pro Ser Asp Tyr Ile Ile Ser Gly Tyr Asn Ala 610 615 620

    His Lys His Ile Lys Thr Ser Glu Asn Phe Asp Ile Ser Phe Cys Arg 625 630 635 640

    Asp Leu Ile Asp Tyr Phe Lys Asn Ser Ile Glu Lys His Ala Glu Trp 645 650 655

    Arg Lys Tyr Glu Phe Lys Phe Ser Ala Thr Asp Ser Tyr Asn Asp Ile 660 665 670

    Ser Glu Phe Tyr Arg Glu Val Glu Met Gln Gly Tyr Arg Ile Asp Trp 675 680 685

    Thr Tyr Ile Ser Glu Ala Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys 690 695 700

    Ile Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Glu Asn Ser Thr 705 710 715 720

    Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn Ile Phe Ser Glu

    725

    730

    735

    Glu Asn Leu Lys Asn Ile Val Ile Lys Leu Asn Gly Gln Ala Glu Leu 740 745 750

    Phe Tyr Arg Lys Ala Ser Val Lys Asn Pro Val Lys His Lys Lys Asp 755 760 765

    Ser Val Leu Val Asn Lys Thr Tyr Lys Asn Gln Leu Asp Asn Gly Asp 770 775 780

    Val Val Arg Ile Pro Ile Pro Asp Asp Ile Tyr Asn Glu Ile Tyr Lys 785 790 795 800

    Met Tyr Asn Gly Tyr Ile Lys Glu Ser Asp Leu Ser Glu Ala Ala Lys 805 810 815

    Glu Tyr Leu Asp Lys Val Glu Val Arg Thr Ala Gln Lys Asp Ile Val 820 825 830

    Lys Asp Tyr Arg Tyr Thr Val Asp Lys Tyr Phe Ile His Thr Pro Ile 835 840 845

    Thr Ile Asn Tyr Lys Val Thr Ala Arg Asn Asn Val Asn Asp Met Ala 850 855 860

    Val Lys Tyr Ile Ala Gln Asn Asp Asp Ile His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Ile Tyr Ile Ser Val Ile Asp Ser His Gly 885 890 895

    Asn Ile Val Lys Gln Lys Ser Tyr Asn Ile Leu Asn Asn Tyr Asp Tyr 900 905 910

    Lys Lys Lys Leu Val Glu Lys Glu Lys Thr Arg Glu Tyr Ala Arg Lys 915 920 925

    Asn Trp Lys Ser Ile Gly Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 930 935 940

    Ser Gly Val Val His Glu Ile Ala Met Leu Met Val Glu Tyr Asn Ala 945 950 955 960

    Ile Ile Ala Met Glu Asp Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe 965 970 975

    Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 980 985 990

    Lys Leu Asn Tyr Phe Ala Ser Lys Gly Lys Ser Val Asp Glu Pro Gly 995 1000 1005

    Gly Leu Leu Lys Gly Tyr Gln Leu Thr Tyr Val Pro Asp Asn Ile 1010 1015 1020

    Lys Asn Leu Gly Lys Gln Cys Gly Val Ile Phe Tyr Val Pro Ala 1025 1030 1035

    Ala Phe Thr Ser Lys Ile Asp Pro Ser Thr Gly Phe Ile Ser Ala 1040 1045 1050

    Phe Asn Phe Lys Ser Ile Ser Thr Asn Ala Ser Arg Lys Gln Phe 1055 1060 1065

    Phe Met Gln Phe Asp Glu Ile Arg Tyr Cys Ala Glu Lys Asp Met 1070 1075 1080

    Phe Ser Phe Gly Phe Asp Tyr Asn Asn Phe Asp Thr Tyr Asn Ile 1085 1090 1095

    Thr Met Gly Lys Thr Gln Trp Thr Val Tyr Thr Asn Gly Glu Arg 1100 1105 1110

    Leu Gln Ser Glu Phe Asn Asn Ala Arg Arg Thr Gly Lys Thr Lys 1115 1120 1125

    Ser Ile Asn Leu Thr Glu Thr Ile Lys Leu Leu Leu Glu Asp Asn 1130 1135 1140

    Glu Ile Asn Tyr Ala Asp Gly His Asp Val Arg Ile Asp Met Glu 1145 1150 1155

    Lys Met Tyr Glu Asp Lys Asn Ser Glu Phe Phe Ala Gln Leu Leu 1160 1165 1170

    Ser Leu Tyr Lys Leu Thr Val Gln Met Arg Asn Ser Tyr Thr Glu 1175 1180 1185

    Ala Glu Glu Gln Glu Lys Gly Ile Ser Tyr Asp Lys Ile Ile Ser 1190 1195 1200

    Pro Val Ile Asn Asp Glu Gly Glu Phe Phe Asp Ser Asp Asn Tyr 1205 1210 1215

    Lys Glu Ser Asp Asp Lys Glu Cys Lys Met Pro Lys Asp Ala Asp 1220 1225 1230

    Ala Asn Gly Ala Tyr Cys Ile Ala Leu Lys Gly Leu Tyr Glu Val 1235 1240 1245

    Leu Lys Ile Lys Ser Glu Trp Thr Glu Asp Gly Phe Asp Arg Asn 1250 1255 1260

    Cys Leu Lys Leu Pro His Ala Glu Trp Leu Asp Phe Ile Gln Asn 1265 1270 1275

    Lys Arg Tyr Glu 1280 <210> 1157 <211> 1282 <212> PRT <213> Eubacterium eligens <400> 1157

    Met Asn Gly Asn Arg Ser Ile Val Tyr Arg Glu Phe Val Gly Val Ile 1 5 10 15

    Pro Val Ala Lys Thr Leu Arg Asn Glu Leu Arg Pro Val Gly His Thr 20 25 30

    Gln Glu His Ile Ile Gln Asn Gly Leu Ile Gln Glu Asp Glu Leu Arg 35 40 45

    Gln Glu Lys Ser Thr Glu Leu Lys Asn Ile Met Asp Asp Tyr Tyr Arg 50 55 60

    Glu Tyr Ile Asp Lys Ser Leu Ser Gly Val Thr Asp Leu Asp Phe Thr 65 70 75 80

    Leu Leu Phe Glu Leu Met Asn Leu Val Gln Ser Ser Pro Ser Lys Asp 85 90 95

    Asn Lys Lys Ala Leu Glu Lys Glu Gln Ser Lys Met Arg Glu Gln Ile 100 105 110

    Cys Thr His Leu Gln Ser Asp Ser Asn Tyr Lys Asn Ile Phe Asn Ala 115 120 125

    Lys Leu Leu Lys Glu Ile Leu Pro Asp Phe Ile Lys Asn Tyr Asn Gln 130 135 140

    Tyr Asp Val Lys Asp Lys Ala Gly Lys Leu Glu Thr Leu Ala Leu Phe 145 150 155 160

    Asn Gly Phe Ser Thr Tyr Phe Thr Asp Phe Phe Glu Lys Arg Lys Asn 165 170 175

    Val Phe Thr Lys Glu Ala Val Ser Thr Ser Ile Ala Tyr Arg Ile Val 180 185 190

    His Glu Asn Ser Leu Ile Phe Leu Ala Asn Met Thr Ser Tyr Lys Lys 195 200 205

    Ile Ser Glu Lys Ala Leu Asp Glu Ile Glu Val Ile Glu Lys Asn Asn 210 215 220

    Gln Asp Lys Met Gly Asp Trp Glu Leu Asn Gln Ile Phe Asn Pro Asp 225 230 235 240

    Phe Tyr Asn Met Val Leu Ile Gln Ser Gly Ile Asp Phe Tyr Asn Glu 245 250 255

    Ile Cys Gly Val Val Asn Ala His Met Asn Leu Tyr Cys Gln Gln Thr 260 265 270

    Lys Asn Asn Tyr Asn Leu Phe Lys Met Arg Lys Leu His Lys Gln Ile 275 280 285

    Leu Ala Tyr Thr Ser Thr Ser Phe Glu Val Pro Lys Met Phe Glu Asp 290 295 300

    Asp Met Ser Val Tyr Asn Ala Val Asn Ala Phe Ile Asp Glu Thr Glu 305 310 315 320

    Lys Gly Asn Ile Ile Gly Lys Leu Lys Asp Ile Val Asn Lys Tyr Asp 325 330 335

    Glu Leu Asp Glu Lys Arg Ile Tyr Ile Ser Lys Asp Phe Tyr Glu Thr 340 345 350

    Leu Ser Cys Phe Met Ser Gly Asn Trp Asn Leu Ile Thr Gly Cys Val 355 360 365

    Glu Asn Phe Tyr Asp Glu Asn Ile His Ala Lys Gly Lys Ser Lys Glu 370 375 380

    Glu Lys Val Lys Lys Ala Val Lys Glu Asp Lys Tyr Lys Ser Ile Asn 385 390 395 400

    Asp Val Asn Asp Leu Val Glu Lys Tyr Ile Asp Glu Lys Glu Arg Asn 405 410 415

    Glu Phe Lys Asn Ser Asn Ala Lys Gln Tyr Ile Arg Glu Ile Ser Asn 420 425 430

    Ile Ile Thr Asp Thr Glu Thr Ala His Leu Glu Tyr Asp Asp His Ile 435 440 445

    Ser Leu Ile Glu Ser Glu Glu Lys Ala Asp Glu Met Lys Lys Arg Leu 450 455 460

    Asp Met Tyr Met Asn Met Tyr His Trp Ala Lys Ala Phe Ile Val Asp

    465

    470

    475

    480

    Glu Val Leu Asp Arg Asp Glu Met Phe Tyr Ser Asp Ile Asp Asp Ile 485 490 495

    Tyr Asn Ile Leu Glu Asn Ile Val Pro Leu Tyr Asn Arg Val Arg Asn 500 505 510

    Tyr Val Thr Gln Lys Pro Tyr Asn Ser Lys Lys Ile Lys Leu Asn Phe 515 520 525

    Gln Ser Pro Thr Leu Ala Asn Gly Trp Ser Gln Ser Lys Glu Phe Asp 530 535 540

    Asn Asn Ala Ile Ile Leu Ile Arg Asp Asn Lys Tyr Tyr Leu Ala Ile 545 550 555 560

    Phe Asn Ala Lys Asn Lys Pro Asp Lys Lys Ile Ile Gln Gly Asn Ser 565 570 575

    Asp Lys Lys Asn Asp Asn Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu 580 585 590

    Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Leu Ser Lys Lys Gly 595 600 605

    Ile Glu Thr Phe Lys Pro Ser Asp Tyr Ile Ile Ser Gly Tyr Asn Ala 610 615 620

    His Lys His Ile Lys Thr Ser Glu Asn Phe Asp Ile Ser Phe Cys Arg 625 630 635 640

    Asp Leu Ile Asp Tyr Phe Lys Asn Ser Ile Glu Lys His Ala Glu Trp 645 650 655

    Arg Lys Tyr Glu Phe Lys Phe Ser Ala Thr Asp Ser Tyr Ser Asp Ile 660 665 670

    Ser Glu Phe Tyr Arg Glu Val Glu Met Gln Gly Tyr Arg Ile Asp Trp 675 680 685

    Thr Tyr Ile Ser Glu Ala Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys 690 695 700

    Ile Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Glu Asn Ser Thr 705 710 715 720

    Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asp Ile Ile Ile Lys Leu Asn Gly Gln Ala Glu Leu 740 745 750

    Phe Tyr Arg Arg Ala Ser Val Lys Asn Pro Val Lys His Lys Lys Asp 755 760 765

    Ser Val Leu Val Asn Lys Thr Tyr Lys Asn Gln Leu Asp Asn Gly Asp 770 775 780

    Val Val Arg Ile Pro Ile Pro Asp Asp Ile Tyr Asn Glu Ile Tyr Lys 785 790 795 800

    Met Tyr Asn Gly Tyr Ile Lys Glu Ser Asp Leu Ser Glu Ala Ala Lys 805 810 815

    Glu Tyr Leu Asp Lys Val Glu Val Arg Thr Ala Gln Lys Asp Ile Val 820 825 830

    Lys Asp Tyr Arg Tyr Thr Val Asp Lys Tyr Phe Ile His Thr Pro Ile 835 840 845

    Thr Ile Asn Tyr Lys Val Thr Ala Arg Asn Asn Val Asn Asp Met Val 850 855 860

    Val Lys Tyr Ile Ala Gln Asn Asp Asp Ile His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Ile Tyr Ile Ser Val Ile Asp Ser His Gly 885 890 895

    Asn Ile Val Lys Gln Lys Ser Tyr Asn Ile Leu Asn Asn Tyr Asp Tyr 900 905 910

    Lys Lys Lys Leu Val Glu Lys Glu Lys Thr Arg Glu Tyr Ala Arg Lys 915 920 925

    Asn Trp Lys Ser Ile Gly Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 930 935 940

    Ser Gly Val Val His Glu Ile Ala Met Leu Ile Val Glu Tyr Asn Ala 945 950 955 960

    Ile Ile Ala Met Glu Asp Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe 965 970 975

    Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 980 985 990

    Lys Leu Asn Tyr Phe Ala Ser Lys Glu Lys Ser Val Asp Glu Pro Gly 995 1000 1005

    Gly Leu Leu Lys Gly Tyr Gln Leu Thr Tyr Val Pro Asp Asn Ile 1010 1015 1020

    Lys Asn Leu Gly Lys Gln Cys Gly Val Ile Phe Tyr Val Pro Ala 1025 1030 1035

    Ala Phe Thr Ser Lys Ile Asp Pro Ser Thr Gly Phe Ile Ser Ala 1040 1045 1050

    Phe Asn Phe Lys Ser Ile Ser Thr Asn Ala Ser Arg Lys Gln Phe 1055 1060 1065

    Phe Met Gln Phe Asp Glu Ile Arg Tyr Cys Ala Glu Lys Asp Met 1070 1075 1080

    Phe Ser Phe Gly Phe Asp Tyr Asn Asn Phe Asp Thr Tyr Asn Ile 1085 1090 1095

    Thr Met Gly Lys Thr Gln Trp Thr Val Tyr Thr Asn Gly Glu Arg 1100 1105 1110

    Leu Gln Ser Glu Phe Asn Asn Ala Arg Arg Thr Gly Lys Thr Lys 1115 1120 1125

    Ser Ile Asn Leu Thr Glu Thr Ile Lys Leu Leu Leu Glu Asp Asn 1130 1135 1140

    Glu Ile Asn Tyr Ala Asp Gly His Asp Ile Arg Ile Asp Met Glu 1145 1150 1155

    Lys Met Asp Glu Asp Lys Lys Ser Glu Phe Phe Ala Gln Leu Leu 1160 1165 1170

    Ser Leu Tyr Lys Leu Thr Val Gln Met Arg Asn Ser Tyr Thr Glu

    1175 1180 1185

    Ala Glu Glu Gln Glu Asn Gly Ile Ser Tyr Asp Lys Ile Ile Ser 1190 1195 1200

    Pro Val Ile Asn Asp Glu Gly Glu Phe Phe Asp Ser Asp Asn Tyr 1205 1210 1215

    Lys Glu Ser Asp Asp Lys Glu Cys Lys Met Pro Lys Asp Ala Asp 1220 1225 1230

    Ala Asn Gly Ala Tyr Cys Ile Ala Leu Lys Gly Leu Tyr Glu Val 1235 1240 1245

    Leu Lys Ile Lys Ser Glu Trp Thr Glu Asp Gly Phe Asp Arg Asn 1250 1255 1260

    Cys Leu Lys Leu Pro His Ala Glu Trp Leu Asp Phe Ile Gln Asn 1265 1270 1275

    Lys Arg Tyr Glu 1280 <210> 1158 <211> 1305 <212> PRT <213> Eubacterium sp.

    <400> 1158

    Met Asn Lys Ala Ala Asp Asn Tyr Thr Gly Gly Asn Tyr Asp Glu Phe 1 5 10 15

    Ile Ala Leu Ser Lys Val Gln Lys Thr Leu Arg Asn Glu Leu Lys Pro 20 25 30

    Thr Pro Phe Thr Ala Glu His Ile Lys Gln Arg Gly Ile Ile Ser Glu 35 40 45

    Asp Glu Tyr Arg Ala Gln Gln Ser Leu Glu Leu Lys Lys Ile Ala Asp 50 55 60

    Glu Tyr Tyr Arg Asn Tyr Ile Thr His Lys Leu Asn Asp Ile Asn Asn 65 70 75 80

    Leu Asp Phe Tyr Asn Leu Phe Asp Ala Ile Glu Glu Lys Tyr Lys Lys 85 90 95

    Asn Asp Lys Asp Asn Arg Asp Lys Leu Asp Leu Val Glu Lys Ser Lys 100 105 110

    Arg Gly Glu Ile Ala Lys Met Leu Ser Ala Asp Asp Asn Phe Lys Ser 115 120 125

    Met Phe Glu Ala Lys Leu Ile Thr Lys Leu Leu Pro Asp Tyr Val Glu 130 135 140

    Arg Asn Tyr Thr Gly Glu Asp Lys Glu Lys Ala Leu Glu Thr Leu Ala 145 150 155 160

    Leu Phe Lys Gly Phe Thr Thr Tyr Phe Lys Gly Tyr Phe Lys Thr Arg 165 170 175

    Lys Asn Met Phe Ser Gly Glu Gly Gly Ala Ser Ser Ile Cys His Arg 180 185 190

    Ile Val Asn Val Asn Ala Ser Ile Phe Tyr Asp Asn Leu Lys Thr Phe 195 200 205

    Met Arg Ile Gln Glu Lys Ala Gly Asp Glu Ile Ala Leu Ile Glu Glu

    210

    215

    220

    Glu Leu Thr Glu Lys Leu Asp Gly Trp Arg Leu Glu His Ile Phe Ser 225 230 235 240

    Arg Asp Tyr Tyr Asn Glu Val Leu Ala Gln Lys Gly Ile Asp Tyr Tyr 245 250 255

    Asn Gln Ile Cys Gly Asp Ile Asn Lys His Met Asn Leu Tyr Cys Gln 260 265 270

    Gln Asn Lys Phe Lys Ala Asn Ile Phe Lys Met Met Lys Ile Gln Lys 275 280 285

    Gln Ile Met Gly Ile Ser Glu Lys Ala Phe Glu Ile Pro Pro Met Tyr 290 295 300

    Gln Asn Asp Glu Glu Val Tyr Ala Ser Phe Asn Glu Phe Ile Ser Arg 305 310 315 320

    Leu Glu Glu Val Lys Leu Thr Asp Arg Leu Ile Asn Ile Leu Gln Asn 325 330 335

    Ile Asn Ile Tyr Asn Thr Ala Lys Ile Tyr Ile Asn Ala Arg Tyr Tyr 340 345 350

    Thr Asn Val Ser Ser Tyr Val Tyr Gly Gly Trp Gly Val Ile Asp Ser 355 360 365

    Ala Ile Glu Arg Tyr Leu Tyr Asn Thr Ile Ala Gly Lys Gly Gln Ser 370 375 380

    Lys Val Lys Lys Ile Glu Asn Ala Lys Lys Asp Asn Lys Phe Met Ser 385 390 395 400

    Val Lys Glu Leu Asp Ser Ile Val Ala Glu Tyr Glu Pro Asp Tyr Phe 405 410 415

    Asn Ala Pro Tyr Ile Asp Asp Asp Asp Asn Ala Val Lys Ala Phe Gly 420 425 430

    Gly Gln Gly Val Leu Gly Tyr Phe Asn Lys Met Ser Glu Leu Leu Ala 435 440 445

    Asp Val Ser Leu Tyr Thr Ile Asp Tyr Asn Ser Asp Asp Ser Leu Ile 450 455 460

    Glu Asn Lys Glu Ser Ala Leu Arg Ile Lys Lys Gln Leu Asp Asp Ile 465 470 475 480

    Met Ser Leu Tyr His Trp Leu Gln Thr Phe Ile Ile Asp Glu Val Val 485 490 495

    Glu Lys Asp Asn Ala Phe Tyr Ala Glu Leu Glu Asp Ile Cys Cys Glu 500 505 510

    Leu Glu Asn Val Val Thr Leu Tyr Asp Arg Ile Arg Asn Tyr Val Thr 515 520 525

    Lys Lys Pro Tyr Ser Thr Gln Lys Phe Lys Leu Asn Phe Ala Ser Pro 530 535 540

    Thr Leu Ala Ala Gly Trp Ser Arg Ser Lys Glu Phe Asp Asn Asn Ala 545 550 555 560

    Ile Ile Leu Leu Arg Asn Asn Lys Tyr Tyr Ile Ala Ile Phe Asn Val 565 570 575

    Asn Asn Lys Pro Asp Lys Gln Ile Ile Lys Gly Ser Glu Glu Gln Arg 580 585 590

    Leu Ser Thr Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu Pro Gly Pro 595 600 605

    Asn Lys Met Leu Pro Lys Val Phe Ile Lys Ser Asp Thr Gly Lys Arg 610 615 620

    Asp Tyr Asn Pro Ser Ser Tyr Ile Leu Glu Gly Tyr Glu Lys Asn Arg 625 630 635 640

    His Ile Lys Ser Ser Gly Asn Phe Asp Ile Asn Tyr Cys His Asp Leu 645 650 655

    Ile Asp Tyr Tyr Lys Ala Cys Ile Asn Lys His Pro Glu Trp Lys Asn 660 665 670

    Tyr Gly Phe Lys Phe Lys Glu Thr Asn Gln Tyr Asn Asp Ile Gly Gln 675 680 685

    Phe Tyr Lys Asp Val Glu Lys Gln Gly Tyr Ser Ile Ser Trp Ala Tyr 690 695 700

    Ile Ser Glu Glu Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys Ile Tyr 705 710 715 720

    Leu Phe Glu Ile Tyr Asn Lys Asp Leu Ser Ala His Ser Thr Gly Arg 725 730 735

    Asp Asn Leu His Thr Met Tyr Leu Lys Asn Ile Phe Ser Glu Asp Asn 740 745 750

    Leu Lys Asn Ile Cys Ile Glu Leu Asn Gly Glu Ala Glu Leu Phe Tyr 755 760 765

    Arg Lys Ser Ser Met Lys Ser Asn Ile Thr His Lys Lys Asp Thr Ile 770 775 780

    Leu Val Asn Lys Thr Tyr Ile Asn Glu Thr Gly Val Arg Val Ser Leu 785 790 795 800

    Ser Asp Glu Asp Tyr Met Lys Val Tyr Asn Tyr Tyr Asn Asn Asn Tyr 805 810 815

    Val Ile Asp Thr Glu Asn Asp Lys Asn Leu Ile Asp Ile Ile Glu Lys 820 825 830

    Ile Gly His Arg Lys Ser Lys Ile Asp Ile Val Lys Asp Lys Arg Tyr 835 840 845

    Thr Glu Asp Lys Tyr Phe Leu Tyr Leu Pro Ile Thr Ile Asn Tyr Gly 850 855 860

    Ile Glu Asp Glu Asn Val Asn Ser Lys Ile Ile Glu Tyr Ile Ala Lys 865 870 875 880

    Gln Asp Asn Met Asn Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu 885 890 895

    Ile Tyr Ile Ser Val Ile Asp Asn Lys Gly Asn Ile Ile Glu Gln Lys 900 905 910

    Ser Phe Asn Leu Val Asn Asn Tyr Asp Tyr Lys Asn Lys Leu Lys Asn 915 920 925

    Met Glu Lys Thr Arg Asp Asn Ala Arg Lys Asn Trp Gln Glu Ile Gly

    930

    935

    940

    Lys Ile Lys Asp Val Lys Ser Gly Tyr Leu Ser Gly Val Ile Ser Lys 945 950 955 960

    Ile Ala Arg Met Val Ile Asp Tyr Asn Ala Ile Ile Val Met Glu Asp 965 970 975

    Leu Asn Lys Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Arg Gln Val 980 985 990

    Tyr Gln Lys Phe Glu Asn Met Leu Ile Ser Lys Leu Asn Tyr Leu Val 995 1000 1005

    Phe Lys Glu Arg Lys Ala Asp Glu Asn Gly Gly Ile Leu Arg Gly 1010 1015 1020

    Tyr Gln Leu Thr Tyr Ile Pro Lys Ser Ile Lys Asn Val Gly Lys 1025 1030 1035

    Gln Cys Gly Cys Ile Phe Tyr Val Pro Ala Ala Tyr Thr Ser Lys 1040 1045 1050

    Ile Asp Pro Ala Thr Gly Phe Ile Asn Ile Phe Asp Phe Lys Lys 1055 1060 1065

    Tyr Ser Gly Ser Gly Ile Asn Ala Lys Val Lys Asp Lys Lys Glu 1070 1075 1080

    Phe Leu Met Ser Met Asn Ser Ile Arg Tyr Ile Asn Glu Cys Ser 1085 1090 1095

    Glu Glu Tyr Glu Lys Ile Gly His Arg Glu Leu Phe Ala Phe Ser 1100 1105 1110

    Phe Asp Tyr Asn Asn Phe Lys Thr Tyr Asn Val Ser Ser Pro Val 1115 1120 1125

    Asn Glu Trp Thr Ala Tyr Thr Tyr Gly Glu Arg Ile Lys Lys Leu 1130 1135 1140

    Tyr Lys Asp Gly Arg Trp Leu Arg Ser Glu Val Leu Asn Leu Thr 1145 1150 1155

    Glu Asn Leu Ile Lys Leu Met Glu Gln Tyr Asn Ile Glu Tyr Lys 1160 1165 1170

    Asp Gly His Asp Ile Arg Glu Asp Ile Ser His Met Asp Glu Thr 1175 1180 1185

    Arg Asn Ala Asp Phe Ile Cys Ser Leu Phe Glu Glu Leu Lys Tyr 1190 1195 1200

    Thr Val Gln Leu Arg Asn Ser Lys Ser Glu Ala Glu Asp Glu Asn 1205 1210 1215

    Tyr Asp Arg Leu Val Ser Pro Ile Leu Asn Ser Ser Asn Gly Phe 1220 1225 1230

    Tyr Asp Ser Ser Asp Tyr Met Glu Asn Glu Asn Asn Thr Thr His 1235 1240 1245

    Thr Met Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Cys Ile Ala 1250 1255 1260

    Leu Lys Gly Leu Tyr Glu Ile Asn Lys Ile Lys Gln Asn Trp Ser 1265 1270 1275

    Asp Asp Lys Lys Phe Lys Glu Asn Glu Leu Tyr Ile Asn Val Thr 1280 1285 1290

    Glu Trp Leu Asp Tyr Ile Gln Asn Arg Arg Phe Glu 1295 1300 1305 <210> 1159 <211> 1259 <212> PRT <213> Synergistes jonesii <400> 1159

    Met Ala Asn Ser Leu Lys Asp Phe Thr Asn Ile Tyr Gln Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Glu Glu His Ile 20 25 30

    Asn Arg Lys Leu Ile Ile Met His Asp Glu Lys Arg Gly Glu Asp Tyr 35 40 45

    Lys Ser Val Thr Lys Leu Ile Asp Asp Tyr His Arg Lys Phe Ile His 50 55 60

    Glu Thr Leu Asp Pro Ala His Phe Asp Trp Asn Pro Leu Ala Glu Ala 65 70 75 80

    Leu Ile Gln Ser Gly Ser Lys Asn Asn Lys Ala Leu Pro Ala Glu Gln 85 90 95

    Lys Glu Met Arg Glu Lys Ile Ile Ser Met Phe Thr Ser Gln Ala Val 100 105 110

    Tyr Lys Lys Leu Phe Lys Lys Glu Leu Phe Ser Glu Leu Leu Pro Glu 115 120 125

    Met Ile Lys Ser Glu Leu Val Ser Asp Leu Glu Lys Gln Ala Gln Leu 130 135 140

    Asp Ala Val Lys Ser Phe Asp Lys Phe Ser Thr Tyr Phe Thr Gly Phe 145 150 155 160

    His Glu Asn Arg Lys Asn Ile Tyr Ser Lys Lys Asp Thr Ser Thr Ser 165 170 175

    Ile Ala Phe Arg Ile Val His Gln Asn Phe Pro Lys Phe Leu Ala Asn 180 185 190

    Val Arg Ala Tyr Thr Leu Ile Lys Glu Arg Ala Pro Glu Val Ile Asp 195 200 205

    Lys Ala Gln Lys Glu Leu Ser Gly Ile Leu Gly Gly Lys Thr Leu Asp 210 215 220

    Asp Ile Phe Ser Ile Glu Ser Phe Asn Asn Val Leu Thr Gln Asp Lys 225 230 235 240

    Ile Asp Tyr Tyr Asn Gln Ile Ile Gly Gly Val Ser Gly Lys Ala Gly 245 250 255

    Asp Lys Lys Leu Arg Gly Val Asn Glu Phe Ser Asn Leu Tyr Arg Gln 260 265 270

    Gln His Pro Glu Val Ala Ser Leu Arg Ile Lys Met Val Pro Leu Tyr 275 280 285

    Lys Gln Ile Leu Ser Asp Arg Thr Thr Leu Ser Phe Val Pro Glu Ala 290 295 300

    Leu Lys Asp Asp Glu Gln Ala Ile Asn Ala Val Asp Gly Leu Arg Ser 305 310 315 320

    Glu Leu Glu Arg Asn Asp Ile Phe Asn Arg Ile Lys Arg Leu Phe Gly 325 330 335

    Lys Asn Asn Leu Tyr Ser Leu Asp Lys Ile Trp Ile Lys Asn Ser Ser 340 345 350

    Ile Ser Ala Phe Ser Asn Glu Leu Phe Lys Asn Trp Ser Phe Ile Glu 355 360 365

    Asp Ala Leu Lys Glu Phe Lys Glu Asn Glu Phe Asn Gly Ala Arg Ser 370 375 380

    Ala Gly Lys Lys Ala Glu Lys Trp Leu Lys Ser Lys Tyr Phe Ser Phe 385 390 395 400

    Ala Asp Ile Asp Ala Ala Val Lys Ser Tyr Ser Glu Gln Val Ser Ala 405 410 415

    Asp Ile Ser Ser Ala Pro Ser Ala Ser Tyr Phe Ala Lys Phe Thr Asn 420 425 430

    Leu Ile Glu Thr Ala Ala Glu Asn Gly Arg Lys Phe Ser Tyr Phe Ala 435 440 445

    Ala Glu Ser Lys Ala Phe Arg Gly Asp Asp Gly Lys Thr Glu Ile Ile 450 455 460

    Lys Ala Tyr Leu Asp Ser Leu Asn Asp Ile Leu His Cys Leu Lys Pro 465 470 475 480

    Phe Glu Thr Glu Asp Ile Ser Asp Ile Asp Thr Glu Phe Tyr Ser Ala 485 490 495

    Phe Ala Glu Ile Tyr Asp Ser Val Lys Asp Val Ile Pro Val Tyr Asn 500 505 510

    Ala Val Arg Asn Tyr Thr Thr Gln Lys Pro Phe Ser Thr Glu Lys Phe 515 520 525

    Lys Leu Asn Phe Glu Asn Pro Ala Leu Ala Lys Gly Trp Asp Lys Asn 530 535 540

    Lys Glu Gln Asn Asn Thr Ala Ile Ile Leu Met Lys Asp Gly Lys Tyr 545 550 555 560

    Tyr Leu Gly Val Ile Asp Lys Asn Asn Lys Leu Arg Ala Asp Asp Leu 565 570 575

    Ala Asp Asp Gly Ser Ala Tyr Gly Tyr Met Lys Met Asn Tyr Lys Phe 580 585 590

    Ile Pro Thr Pro His Met Glu Leu Pro Lys Val Phe Leu Pro Lys Arg 595 600 605

    Ala Pro Lys Arg Tyr Asn Pro Ser Arg Glu Ile Leu Leu Ile Lys Glu 610 615 620

    Asn Lys Thr Phe Ile Lys Asp Lys Asn Phe Asn Arg Thr Asp Cys His 625 630 635 640

    Lys Leu Ile Asp Phe Phe Lys Asp Ser Ile Asn Lys His Lys Asp Trp 645 650 655

    Arg Thr Phe Gly Phe Asp Phe Ser Asp Thr Asp Ser Tyr Glu Asp Ile

    660

    665

    670

    Ser Asp Phe Tyr Met Glu Val Gln Asp Gln Gly Tyr Lys Leu Thr Phe 675 680 685

    Thr Arg Leu Ser Ala Glu Lys Ile Asp Lys Trp Val Glu Glu Gly Arg 690 695 700

    Leu Phe Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Asp Gly Ala Gln 705 710 715 720

    Gly Ser Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asp Val Val Leu Lys Leu Asn Gly Glu Ala Glu Leu 740 745 750

    Phe Phe Arg Arg Lys Ser Ile Asp Lys Pro Ala Val His Ala Lys Gly 755 760 765

    Ser Met Lys Val Asn Arg Arg Asp Ile Asp Gly Asn Pro Ile Asp Glu 770 775 780

    Gly Thr Tyr Val Glu Ile Cys Gly Tyr Ala Asn Gly Lys Arg Asp Met 785 790 795 800

    Ala Ser Leu Asn Ala Gly Ala Arg Gly Leu Ile Glu Ser Gly Leu Val 805 810 815

    Arg Ile Thr Glu Val Lys His Glu Leu Val Lys Asp Lys Arg Tyr Thr 820 825 830

    Ile Asp Lys Tyr Phe Phe His Val Pro Phe Thr Ile Asn Phe Lys Ala 835 840 845

    Gln Gly Gln Gly Asn Ile Asn Ser Asp Val Asn Leu Phe Leu Arg Asn 850 855 860

    Asn Lys Asp Val Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu 865 870 875 880

    Val Tyr Val Ser Leu Ile Asp Arg Asp Gly His Ile Lys Leu Gln Lys 885 890 895

    Asp Phe Asn Ile Ile Gly Gly Met Asp Tyr His Ala Lys Leu Asn Gln 900 905 910

    Lys Glu Lys Glu Arg Asp Thr Ala Arg Lys Ser Trp Lys Thr Ile Gly 915 920 925

    Thr Ile Lys Glu Leu Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu 930 935 940

    Ile Val Arg Leu Ala Val Asp Asn Asn Ala Val Ile Val Met Glu Asp 945 950 955 960

    Leu Asn Ile Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 965 970 975

    Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val 980 985 990

    Phe Lys Asp Ala Gly Tyr Asp Ala Pro Cys Gly Ile Leu Lys Gly Leu 995 1000 1005

    Gln Leu Thr Glu Lys Phe Glu Ser Phe Thr Lys Leu Gly Lys Gln 1010 1015 1020

    Cys Gly Ile Ile Phe Tyr Ile Pro Ala Gly Tyr Thr Ser Lys Ile 1025 1030 1035

    Asp Pro Thr Thr Gly Phe Val Asn Leu Phe Asn Ile Asn Asp Val 1040 1045 1050

    Ser Ser Lys Glu Lys Gln Lys Asp Phe Ile Gly Lys Leu Asp Ser 1055 1060 1065

    Ile Arg Phe Asp Ala Lys Arg Asp Met Phe Thr Phe Glu Phe Asp 1070 1075 1080

    Tyr Asp Lys Phe Arg Thr Tyr Gln Thr Ser Tyr Arg Lys Lys Trp 1085 1090 1095

    Ala Val Trp Thr Asn Gly Lys Arg Ile Val Arg Glu Lys Asp Lys 1100 1105 1110

    Asp Gly Lys Phe Arg Met Asn Asp Arg Leu Leu Thr Glu Asp Met 1115 1120 1125

    Lys Asn Ile Leu Asn Lys Tyr Ala Leu Ala Tyr Lys Ala Gly Glu 1130 1135 1140

    Asp Ile Leu Pro Asp Val Ile Ser Arg Asp Lys Ser Leu Ala Ser 1145 1150 1155

    Glu Ile Phe Tyr Val Phe Lys Asn Thr Leu Gln Met Arg Asn Ser 1160 1165 1170

    Lys Arg Asp Thr Gly Glu Asp Phe Ile Ile Ser Pro Val Leu Asn 1175 1180 1185

    Ala Lys Gly Arg Phe Phe Asp Ser Arg Lys Thr Asp Ala Ala Leu 1190 1195 1200

    Pro Ile Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys 1205 1210 1215 Gly Ser Leu Val Leu Asp Ala Ile Asp Glu Lys Leu Lys Glu Asp 1220 1225 1230 Gly Arg Ile Asp Tyr Lys Asp Met Ala Val Ser Asn Pro Lys Trp 1235 1240 1245

    Phe Glu Phe Met Gln Thr Arg Lys Phe Asp Phe 1250 1255 <210> 1160 <211> 1238 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanoplasma termitum sequence <400> 1160

    Met Asn Asn Tyr Asp Glu Phe Thr Lys Leu Tyr Pro Ile Gln Lys Thr 1 5 10 15

    Ile Arg Phe Glu Leu Lys Pro Gln Gly Arg Thr Met Glu His Leu Glu 20 25 30

    Thr Phe Asn Phe Phe Glu Glu Asp Arg Asp Arg Ala Glu Lys Tyr Lys 35 40 45

    Ile Leu Lys Glu Ala Ile Asp Glu Tyr His Lys Lys Phe Ile Asp Glu 50 55 60

    His Leu Thr Asn Met Ser Leu Asp Trp Asn Ser Leu Lys Gln Ile Ser 65 70 75 80

    Glu Lys Tyr Tyr Lys Ser Arg Glu Glu Lys Asp Lys Lys Val Phe Leu 85 90 95

    Ser Glu Gln Lys Arg Met Arg Gln Glu Ile Val Ser Glu Phe Lys Lys 100 105 110

    Asp Asp Arg Phe Lys Asp Leu Phe Ser Lys Lys Leu Phe Ser Glu Leu 115 120 125

    Leu Lys Glu Glu Ile Tyr Lys Lys Gly Asn His Gln Glu Ile Asp Ala 130 135 140

    Leu Lys Ser Phe Asp Lys Phe Ser Gly Tyr Phe Ile Gly Leu His Glu 145 150 155 160

    Asn Arg Lys Asn Met Tyr Ser Asp Gly Asp Glu Ile Thr Ala Ile Ser 165 170 175

    Asn Arg Ile Val Asn Glu Asn Phe Pro Lys Phe Leu Asp Asn Leu Gln 180 185 190

    Lys Tyr Gln Glu Ala Arg Lys Lys Tyr Pro Glu Trp Ile Ile Lys Ala 195 200 205

    Glu Ser Ala Leu Val Ala His Asn Ile Lys Met Asp Glu Val Phe Ser 210 215 220

    Leu Glu Tyr Phe Asn Lys Val Leu Asn Gln Glu Gly Ile Gln Arg Tyr 225 230 235 240

    Asn Leu Ala Leu Gly Gly Tyr Val Thr Lys Ser Gly Glu Lys Met Met 245 250 255

    Gly Leu Asn Asp Ala Leu Asn Leu Ala His Gln Ser Glu Lys Ser Ser 260 265 270

    Lys Gly Arg Ile His Met Thr Pro Leu Phe Lys Gln Ile Leu Ser Glu 275 280 285

    Lys Glu Ser Phe Ser Tyr Ile Pro Asp Val Phe Thr Glu Asp Ser Gln 290 295 300

    Leu Leu Pro Ser Ile Gly Gly Phe Phe Ala Gln Ile Glu Asn Asp Lys 305 310 315 320

    Asp Gly Asn Ile Phe Asp Arg Ala Leu Glu Leu Ile Ser Ser Tyr Ala 325 330 335

    Glu Tyr Asp Thr Glu Arg Ile Tyr Ile Arg Gln Ala Asp Ile Asn Arg 340 345 350

    Val Ser Asn Val Ile Phe Gly Glu Trp Gly Thr Leu Gly Gly Leu Met 355 360 365

    Arg Glu Tyr Lys Ala Asp Ser Ile Asn Asp Ile Asn Leu Glu Arg Thr 370 375 380

    Cys Lys Lys Val Asp Lys Trp Leu Asp Ser Lys Glu Phe Ala Leu Ser 385 390 395 400

    Asp Val Leu Glu Ala Ile Lys Arg Thr Gly Asn Asn Asp Ala Phe Asn 405 410 415

    Glu Tyr Ile Ser Lys Met Arg Thr Ala Arg Glu Lys Ile Asp Ala Ala

    420

    425

    430

    Arg Lys Glu Met Lys Phe Ile Ser Glu Lys Ile Ser Gly Asp Glu Glu 435 440 445

    Ser Ile His Ile Ile Lys Thr Leu Leu Asp Ser Val Gln Gln Phe Leu 450 455 460

    His Phe Phe Asn Leu Phe Lys Ala Arg Gln Asp Ile Pro Leu Asp Gly 465 470 475 480

    Ala Phe Tyr Ala Glu Phe Asp Glu Val His Ser Lys Leu Phe Ala Ile 485 490 495

    Val Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Lys Asn Asn Leu 500 505 510

    Asn Thr Lys Lys Ile Lys Leu Asn Phe Lys Asn Pro Thr Leu Ala Asn 515 520 525

    Gly Trp Asp Gln Asn Lys Val Tyr Asp Tyr Ala Ser Leu Ile Phe Leu 530 535 540

    Arg Asp Gly Asn Tyr Tyr Leu Gly Ile Ile Asn Pro Lys Arg Lys Lys 545 550 555 560

    Asn Ile Lys Phe Glu Gln Gly Ser Gly Asn Gly Pro Phe Tyr Arg Lys 565 570 575

    Met Val Tyr Lys Gln Ile Pro Gly Pro Asn Lys Asn Leu Pro Arg Val 580 585 590

    Phe Leu Thr Ser Thr Lys Gly Lys Lys Glu Tyr Lys Pro Ser Lys Glu 595 600 605

    Ile Ile Glu Gly Tyr Glu Ala Asp Lys His Ile Arg Gly Asp Lys Phe 610 615 620

    Asp Leu Asp Phe Cys His Lys Leu Ile Asp Phe Phe Lys Glu Ser Ile 625 630 635 640

    Glu Lys His Lys Asp Trp Ser Lys Phe Asn Phe Tyr Phe Ser Pro Thr 645 650 655

    Glu Ser Tyr Gly Asp Ile Ser Glu Phe Tyr Leu Asp Val Glu Lys Gln 660 665 670

    Gly Tyr Arg Met His Phe Glu Asn Ile Ser Ala Glu Thr Ile Asp Glu 675 680 685

    Tyr Val Glu Lys Gly Asp Leu Phe Leu Phe Gln Ile Tyr Asn Lys Asp 690 695 700

    Phe Val Lys Ala Ala Thr Gly Lys Lys Asp Met His Thr Ile Tyr Trp 705 710 715 720

    Asn Ala Ala Phe Ser Pro Glu Asn Leu Gln Asp Val Val Val Lys Leu 725 730 735

    Asn Gly Glu Ala Glu Leu Phe Tyr Arg Asp Lys Ser Asp Ile Lys Glu 740 745 750

    Ile Val His Arg Glu Gly Glu Ile Leu Val Asn Arg Thr Tyr Asn Gly 755 760 765

    Arg Thr Pro Val Pro Asp Lys Ile His Lys Lys Leu Thr Asp Tyr His 770 775 780

    Asn Gly Arg Thr Lys Asp Leu Gly Glu Ala Lys Glu Tyr Leu Asp Lys 785 790 795 800

    Val Arg Tyr Phe Lys Ala His Tyr Asp Ile Thr Lys Asp Arg Arg Tyr 805 810 815

    Leu Asn Asp Lys Ile Tyr Phe His Val Pro Leu Thr Leu Asn Phe Lys 820 825 830

    Ala Asn Gly Lys Lys Asn Leu Asn Lys Met Val Ile Glu Lys Phe Leu 835 840 845

    Ser Asp Glu Lys Ala His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn 850 855 860

    Leu Leu Tyr Tyr Ser Ile Ile Asp Arg Ser Gly Lys Ile Ile Asp Gln 865 870 875 880

    Gln Ser Leu Asn Val Ile Asp Gly Phe Asp Tyr Arg Glu Lys Leu Asn 885 890 895

    Gln Arg Glu Ile Glu Met Lys Asp Ala Arg Gln Ser Trp Asn Ala Ile 900 905 910

    Gly Lys Ile Lys Asp Leu Lys Glu Gly Tyr Leu Ser Lys Ala Val His 915 920 925

    Glu Ile Thr Lys Met Ala Ile Gln Tyr Asn Ala Ile Val Val Met Glu 930 935 940

    Glu Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln 945 950 955 960

    Ile Tyr Gln Lys Phe Glu Asn Met Leu Ile Asp Lys Met Asn Tyr Leu 965 970 975

    Val Phe Lys Asp Ala Pro Asp Glu Ser Pro Gly Gly Val Leu Asn Ala 980 985 990

    Tyr Gln Leu Thr Asn Pro Leu Glu Ser Phe Ala Lys Leu Gly Lys Gln 995 1000 1005

    Thr Gly Ile Leu Phe Tyr Val Pro Ala Ala Tyr Thr Ser Lys Ile 1010 1015 1020

    Asp Pro Thr Thr Gly Phe Val Asn Leu Phe Asn Thr Ser Ser Lys 1025 1030 1035

    Thr Asn Ala Gln Glu Arg Lys Glu Phe Leu Gln Lys Phe Glu Ser 1040 1045 1050

    Ile Ser Tyr Ser Ala Lys Asp Gly Gly Ile Phe Ala Phe Ala Phe 1055 1060 1065

    Asp Tyr Arg Lys Phe Gly Thr Ser Lys Thr Asp His Lys Asn Val 1070 1075 1080

    Trp Thr Ala Tyr Thr Asn Gly Glu Arg Met Arg Tyr Ile Lys Glu 1085 1090 1095

    Lys Lys Arg Asn Glu Leu Phe Asp Pro Ser Lys Glu Ile Lys Glu 1100 1105 1110

    Ala Leu Thr Ser Ser Gly Ile Lys Tyr Asp Gly Gly Gln Asn Ile 1115 1120 1125

    Leu Pro Asp Ile Leu Arg Ser Asn Asn Asn Gly Leu Ile Tyr Thr

    1130

    1135

    1140

    Met Tyr Ser Ser Phe Ile Ala Ala Ile Gln Met Arg Val Tyr Asp 1145 1150 1155

    Gly Lys Glu Asp Tyr Ile Ile Ser Pro Ile Lys Asn Ser Lys Gly 1160 1165 1170

    Glu Phe Phe Arg Thr Asp Pro Lys Arg Arg Glu Leu Pro Ile Asp 1175 1180 1185

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Arg Gly Glu Leu 1190 1195 1200

    Thr Met Arg Ala Ile Ala Glu Lys Phe Asp Pro Asp Ser Glu Lys 1205 1210 1215

    Met Ala Lys Leu Glu Leu Lys His Lys Asp Trp Phe Glu Phe Met 1220 1225 1230

    Gln Thr Arg Gly Asp 1235 <210> 1161 <211> 1227 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 1161

    Met Asp Ala Lys Glu Phe Thr Gly Gln Tyr Pro Leu Ser Lys Thr Leu

    1 5 10 15

    Arg Phe Glu Leu Arg Pro Ile Gly Arg Thr Trp Asp Asn Leu Glu Ala 20 25 30

    Ser Gly Tyr Leu Ala Glu Asp Arg His Arg Ala Glu Cys Tyr Pro Arg 35 40 45

    Ala Lys Glu Leu Leu Asp Asp Asn His Arg Ala Phe Leu Asn Arg Val 50 55 60

    Leu Pro Gln Ile Asp Met Asp Trp His Pro Ile Ala Glu Ala Phe Cys 65 70 75 80

    Lys Val His Lys Asn Pro Gly Asn Lys Glu Leu Ala Gln Asp Tyr Asn 85 90 95

    Leu Gln Leu Ser Lys Arg Arg Lys Glu Ile Ser Ala Tyr Leu Gln Asp 100 105 110

    Ala Asp Gly Tyr Lys Gly Leu Phe Ala Lys Pro Ala Leu Asp Glu Ala 115 120 125

    Met Lys Ile Ala Lys Glu Asn Gly Asn Glu Ser Asp Ile Glu Val Leu 130 135 140

    Glu Ala Phe Asn Gly Phe Ser Val Tyr Phe Thr Gly Tyr His Glu Ser 145 150 155 160

    Arg Glu Asn Ile Tyr Ser Asp Glu Asp Met Val Ser Val Ala Tyr Arg 165 170 175

    Ile Thr Glu Asp Asn Phe Pro Arg Phe Val Ser Asn Ala Leu Ile Phe 180 185 190

    Asp Lys Leu Asn Glu Ser His Pro Asp Ile Ile Ser Glu Val Ser Gly

    195

    200

    205

    Asn Leu Gly Val Asp Asp Ile Gly Lys Tyr Phe Asp Val Ser Asn Tyr 210 215 220

    Asn Asn Phe Leu Ser Gln Ala Gly Ile Asp Asp Tyr Asn His Ile Ile 225 230 235 240

    Gly Gly His Thr Thr Glu Asp Gly Leu Ile Gln Ala Phe Asn Val Val 245 250 255

    Leu Asn Leu Arg His Gln Lys Asp Pro Gly Phe Glu Lys Ile Gln Phe 260 265 270

    Lys Gln Leu Tyr Lys Gln Ile Leu Ser Val Arg Thr Ser Lys Ser Tyr 275 280 285

    Ile Pro Lys Gln Phe Asp Asn Ser Lys Glu Met Val Asp Cys Ile Cys 290 295 300

    Asp Tyr Val Ser Lys Ile Glu Lys Ser Glu Thr Val Glu Arg Ala Leu 305 310 315 320

    Lys Leu Val Arg Asn Ile Ser Ser Phe Asp Leu Arg Gly Ile Phe Val 325 330 335

    Asn Lys Lys Asn Leu Arg Ile Leu Ser Asn Lys Leu Ile Gly Asp Trp 340 345 350

    Asp Ala Ile Glu Thr Ala Leu Met His Ser Ser Ser Ser Glu Asn Asp 355 360 365

    Lys Lys Ser Val Tyr Asp Ser Ala Glu Ala Phe Thr Leu Asp Asp Ile 370 375 380

    Phe Ser Ser Val Lys Lys Phe Ser Asp Ala Ser Ala Glu Asp Ile Gly 385 390 395 400

    Asn Arg Ala Glu Asp Ile Cys Arg Val Ile Ser Glu Thr Ala Pro Phe 405 410 415

    Ile Asn Asp Leu Arg Ala Val Asp Leu Asp Ser Leu Asn Asp Asp Gly 420 425 430

    Tyr Glu Ala Ala Val Ser Lys Ile Arg Glu Ser Leu Glu Pro Tyr Met 435 440 445

    Asp Leu Phe His Glu Leu Glu Ile Phe Ser Val Gly Asp Glu Phe Pro 450 455 460

    Lys Cys Ala Ala Phe Tyr Ser Glu Leu Glu Glu Val Ser Glu Gln Leu 465 470 475 480

    Ile Glu Ile Ile Pro Leu Phe Asn Lys Ala Arg Ser Phe Cys Thr Arg 485 490 495

    Lys Arg Tyr Ser Thr Asp Lys Ile Lys Val Asn Leu Lys Phe Pro Thr 500 505 510

    Leu Ala Asp Gly Trp Asp Leu Asn Lys Glu Arg Asp Asn Lys Ala Ala 515 520 525

    Ile Leu Arg Lys Asp Gly Lys Tyr Tyr Leu Ala Ile Leu Asp Met Lys 530 535 540

    Lys Asp Leu Ser Ser Ile Arg Thr Ser Asp Glu Asp Glu Ser Ser Phe 545 550 555 560

    Glu Lys Met Glu Tyr Lys Leu Leu Pro Ser Pro Val Lys Met Leu Pro 565 570 575

    Lys Ile Phe Val Lys Ser Lys Ala Ala Lys Glu Lys Tyr Gly Leu Thr 580 585 590

    Asp Arg Met Leu Glu Cys Tyr Asp Lys Gly Met His Lys Ser Gly Ser 595 600 605

    Ala Phe Asp Leu Gly Phe Cys His Glu Leu Ile Asp Tyr Tyr Lys Arg 610 615 620

    Cys Ile Ala Glu Tyr Pro Gly Trp Asp Val Phe Asp Phe Lys Phe Arg 625 630 635 640

    Glu Thr Ser Asp Tyr Gly Ser Met Lys Glu Phe Asn Glu Asp Val Ala 645 650 655

    Gly Ala Gly Tyr Tyr Met Ser Leu Arg Lys Ile Pro Cys Ser Glu Val 660 665 670

    Tyr Arg Leu Leu Asp Glu Lys Ser Ile Tyr Leu Phe Gln Ile Tyr Asn 675 680 685

    Lys Asp Tyr Ser Glu Asn Ala His Gly Asn Lys Asn Met His Thr Met 690 695 700

    Tyr Trp Glu Gly Leu Phe Ser Pro Gln Asn Leu Glu Ser Pro Val Phe 705 710 715 720

    Lys Leu Ser Gly Gly Ala Glu Leu Phe Phe Arg Lys Ser Ser Ile Pro 725 730 735

    Asn Asp Ala Lys Thr Val His Pro Lys Gly Ser Val Leu Val Pro Arg 740 745 750

    Asn Asp Val Asn Gly Arg Arg Ile Pro Asp Ser Ile Tyr Arg Glu Leu 755 760 765

    Thr Arg Tyr Phe Asn Arg Gly Asp Cys Arg Ile Ser Asp Glu Ala Lys 770 775 780

    Ser Tyr Leu Asp Lys Val Lys Thr Lys Lys Ala Asp His Asp Ile Val 785 790 795 800

    Lys Asp Arg Arg Phe Thr Val Asp Lys Met Met Phe His Val Pro Ile 805 810 815

    Ala Met Asn Phe Lys Ala Ile Ser Lys Pro Asn Leu Asn Lys Lys Val 820 825 830

    Ile Asp Gly Ile Ile Asp Asp Gln Asp Leu Lys Ile Ile Gly Ile Asp 835 840 845

    Arg Gly Glu Arg Asn Leu Ile Tyr Val Thr Met Val Asp Arg Lys Gly 850 855 860

    Asn Ile Leu Tyr Gln Asp Ser Leu Asn Ile Leu Asn Gly Tyr Asp Tyr 865 870 875 880

    Arg Lys Ala Leu Asp Val Arg Glu Tyr Asp Asn Lys Glu Ala Arg Arg 885 890 895

    Asn Trp Thr Lys Val Glu Gly Ile Arg Lys Met Lys Glu Gly Tyr Leu 900 905 910

    Ser Leu Ala Val Ser Lys Leu Ala Asp Met Ile Ile Glu Asn Asn Ala

    915

    920

    925

    Ile Ile Val Met Glu Asp Leu Asn His Gly Phe Lys Ala Gly Arg Ser 930 935 940

    Lys Ile Glu Lys Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 945 950 955 960

    Lys Leu Gly Tyr Met Val Leu Lys Asp Lys Ser Ile Asp Gln Ser Gly 965 970 975

    Gly Ala Leu His Gly Tyr Gln Leu Ala Asn His Val Thr Thr Leu Ala 980 985 990

    Ser Val Gly Lys Gln Cys Gly Val Ile Phe Tyr Ile Pro Ala Ala Phe 995 1000 1005

    Thr Ser Lys Ile Asp Pro Thr Thr Gly Phe Ala Asp Leu Phe Ala 1010 1015 1020

    Leu Ser Asn Val Lys Asn Val Ala Ser Met Arg Glu Phe Phe Ser 1025 1030 1035

    Lys Met Lys Ser Val Ile Tyr Asp Lys Ala Glu Gly Lys Phe Ala 1040 1045 1050

    Phe Thr Phe Asp Tyr Leu Asp Tyr Asn Val Lys Ser Glu Cys Gly 1055 1060 1065

    Arg Thr Leu Trp Thr Val Tyr Thr Val Gly Glu Arg Phe Thr Tyr 1070 1075 1080

    Ser Arg Val Asn Arg Glu Tyr Val Arg Lys Val Pro Thr Asp Ile 1085 1090 1095

    Ile Tyr Asp Ala Leu Gln Lys Ala Gly Ile Ser Val Glu Gly Asp 1100 1105 1110

    Leu Arg Asp Arg Ile Ala Glu Ser Asp Gly Asp Thr Leu Lys Ser 1115 1120 1125

    Ile Phe Tyr Ala Phe Lys Tyr Ala Leu Asp Met Arg Val Glu Asn 1130 1135 1140

    Arg Glu Glu Asp Tyr Ile Gln Ser Pro Val Lys Asn Ala Ser Gly 1145 1150 1155

    Glu Phe Phe Cys Ser Lys Asn Ala Gly Lys Ser Leu Pro Gln Asp 1160 1165 1170

    Ser Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Lys Gly Ile Leu 1175 1180 1185

    Gln Leu Arg Met Leu Ser Glu Gln Tyr Asp Pro Asn Ala Glu Ser 1190 1195 1200

    Ile Arg Leu Pro Leu Ile Thr Asn Lys Ala Trp Leu Thr Phe Met 1205 1210 1215

    Gln Ser Gly Met Lys Thr Trp Lys Asn 1220 1225 <210> 1162 <211> 1334 <212> PRT <213> Succinivibrio dextrinosolvens <400> 1162

    Met Ser Ser Leu Thr Lys Phe Thr Asn Lys Tyr Ser Lys Gln Leu Thr

    Ile Lys Asn Glu Leu Ile Pro Val Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Glu Asn Gly Leu Ile Asp Gly Asp Glu Gln Leu Asn Glu Asn Tyr Gln 35 40 45

    Lys Ala Lys Ile Ile Val Asp Asp Phe Leu Arg Asp Phe Ile Asn Lys 50 55 60

    Ala Leu Asn Asn Thr Gln Ile Gly Asn Trp Arg Glu Leu Ala Asp Ala 65 70 75 80

    Leu Asn Lys Glu Asp Glu Asp Asn Ile Glu Lys Leu Gln Asp Lys Ile 85 90 95

    Arg Gly Ile Ile Val Ser Lys Phe Glu Thr Phe Asp Leu Phe Ser Ser 100 105 110

    Tyr Ser Ile Lys Lys Asp Glu Lys Ile Ile Asp Asp Asp Asn Asp Val 115 120 125

    Glu Glu Glu Glu Leu Asp Leu Gly Lys Lys Thr Ser Ser Phe Lys Tyr 130 135 140

    Ile Phe Lys Lys Asn Leu Phe Lys Leu Val Leu Pro Ser Tyr Leu Lys 145 150 155 160

    Thr Thr Asn Gln Asp Lys Leu Lys Ile Ile Ser Ser Phe Asp Asn Phe 165 170 175

    Ser Thr Tyr Phe Arg Gly Phe Phe Glu Asn Arg Lys Asn Ile Phe Thr 180 185 190

    Lys Lys Pro Ile Ser Thr Ser Ile Ala Tyr Arg Ile Val His Asp Asn 195 200 205

    Phe Pro Lys Phe Leu Asp Asn Ile Arg Cys Phe Asn Val Trp Gln Thr 210 215 220

    Glu Cys Pro Gln Leu Ile Val Lys Ala Asp Asn Tyr Leu Lys Ser Lys 225 230 235 240

    Asn Val Ile Ala Lys Asp Lys Ser Leu Ala Asn Tyr Phe Thr Val Gly 245 250 255

    Ala Tyr Asp Tyr Phe Leu Ser Gln Asn Gly Ile Asp Phe Tyr Asn Asn 260 265 270

    Ile Ile Gly Gly Leu Pro Ala Phe Ala Gly His Glu Lys Ile Gln Gly 275 280 285

    Leu Asn Glu Phe Ile Asn Gln Glu Cys Gln Lys Asp Ser Glu Leu Lys 290 295 300

    Ser Lys Leu Lys Asn Arg His Ala Phe Lys Met Ala Val Leu Phe Lys 305 310 315 320

    Gln Ile Leu Ser Asp Arg Glu Lys Ser Phe Val Ile Asp Glu Phe Glu 325 330 335

    Ser Asp Ala Gln Val Ile Asp Ala Val Lys Asn Phe Tyr Ala Glu Gln 340 345 350

    Cys Lys Asp Asn Asn Val Ile Phe Asn Leu Leu Asn Leu Ile Lys Asn 355 360 365

    Ile Ala Phe Leu Ser Asp Asp Glu Leu Asp Gly Ile Phe Ile Glu Gly 370 375 380

    Lys Tyr Leu Ser Ser Val Ser Gln Lys Leu Tyr Ser Asp Trp Ser Lys 385 390 395 400

    Leu Arg Asn Asp Ile Glu Asp Ser Ala Asn Ser Lys Gln Gly Asn Lys 405 410 415

    Glu Leu Ala Lys Lys Ile Lys Thr Asn Lys Gly Asp Val Glu Lys Ala 420 425 430

    Ile Ser Lys Tyr Glu Phe Ser Leu Ser Glu Leu Asn Ser Ile Val His 435 440 445

    Asp Asn Thr Lys Phe Ser Asp Leu Leu Ser Cys Thr Leu His Lys Val 450 455 460

    Ala Ser Glu Lys Leu Val Lys Val Asn Glu Gly Asp Trp Pro Lys His 465 470 475 480

    Leu Lys Asn Asn Glu Glu Lys Gln Lys Ile Lys Glu Pro Leu Asp Ala 485 490 495

    Leu Leu Glu Ile Tyr Asn Thr Leu Leu Ile Phe Asn Cys Lys Ser Phe 500 505 510

    Asn Lys Asn Gly Asn Phe Tyr Val Asp Tyr Asp Arg Cys Ile Asn Glu 515 520 525

    Leu Ser Ser Val Val Tyr Leu Tyr Asn Lys Thr Arg Asn Tyr Cys Thr 530 535 540

    Lys Lys Pro Tyr Asn Thr Asp Lys Phe Lys Leu Asn Phe Asn Ser Pro 545 550 555 560

    Gln Leu Gly Glu Gly Phe Ser Lys Ser Lys Glu Asn Asp Cys Leu Thr 565 570 575

    Leu Leu Phe Lys Lys Asp Asp Asn Tyr Tyr Val Gly Ile Ile Arg Lys 580 585 590

    Gly Ala Lys Ile Asn Phe Asp Asp Thr Gln Ala Ile Ala Asp Asn Thr 595 600 605

    Asp Asn Cys Ile Phe Lys Met Asn Tyr Phe Leu Leu Lys Asp Ala Lys 610 615 620

    Lys Phe Ile Pro Lys Cys Ser Ile Gln Leu Lys Glu Val Lys Ala His 625 630 635 640

    Phe Lys Lys Ser Glu Asp Asp Tyr Ile Leu Ser Asp Lys Glu Lys Phe 645 650 655

    Ala Ser Pro Leu Val Ile Lys Lys Ser Thr Phe Leu Leu Ala Thr Ala 660 665 670

    His Val Lys Gly Lys Lys Gly Asn Ile Lys Lys Phe Gln Lys Glu Tyr 675 680 685

    Ser Lys Glu Asn Pro Thr Glu Tyr Arg Asn Ser Leu Asn Glu Trp Ile 690 695 700

    Ala Phe Cys Lys Glu Phe Leu Lys Thr Tyr Lys Ala Ala Thr Ile Phe 705 710 715 720

    Asp Ile Thr Thr Leu Lys Lys Ala Glu Glu Tyr Ala Asp Ile Val Glu

    725

    730

    735

    Phe Tyr Lys Asp Val Asp Asn Leu Cys Tyr Lys Leu Glu Phe Cys Pro 740 745 750

    Ile Lys Thr Ser Phe Ile Glu Asn Leu Ile Asp Asn Gly Asp Leu Tyr 755 760 765

    Leu Phe Arg Ile Asn Asn Lys Asp Phe Ser Ser Lys Ser Thr Gly Thr 770 775 780

    Lys Asn Leu His Thr Leu Tyr Leu Gln Ala Ile Phe Asp Glu Arg Asn 785 790 795 800

    Leu Asn Asn Pro Thr Ile Met Leu Asn Gly Gly Ala Glu Leu Phe Tyr 805 810 815

    Arg Lys Glu Ser Ile Glu Gln Lys Asn Arg Ile Thr His Lys Ala Gly 820 825 830

    Ser Ile Leu Val Asn Lys Val Cys Lys Asp Gly Thr Ser Leu Asp Asp 835 840 845

    Lys Ile Arg Asn Glu Ile Tyr Gln Tyr Glu Asn Lys Phe Ile Asp Thr 850 855 860

    Leu Ser Asp Glu Ala Lys Lys Val Leu Pro Asn Val Ile Lys Lys Glu 865 870 875 880

    Ala Thr His Asp Ile Thr Lys Asp Lys Arg Phe Thr Ser Asp Lys Phe 885 890 895

    Phe Phe His Cys Pro Leu Thr Ile Asn Tyr Lys Glu Gly Asp Thr Lys 900 905 910

    Gln Phe Asn Asn Glu Val Leu Ser Phe Leu Arg Gly Asn Pro Asp Ile 915 920 925

    Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Ile Tyr Val Thr 930 935 940

    Val Ile Asn Gln Lys Gly Glu Ile Leu Asp Ser Val Ser Phe Asn Thr 945 950 955 960

    Val Thr Asn Lys Ser Ser Lys Ile Glu Gln Thr Val Asp Tyr Glu Glu 965 970 975

    Lys Leu Ala Val Arg Glu Lys Glu Arg Ile Glu Ala Lys Arg Ser Trp 980 985 990

    Asp Ser Ile Ser Lys Ile Ala Thr Leu Lys Glu Gly Tyr Leu Ser Ala 995 1000 1005

    Ile Val His Glu Ile Cys Leu Leu Met Ile Lys His Asn Ala Ile 1010 1015 1020

    Val Val Leu Glu Asn Leu Asn Ala Gly Phe Lys Arg Ile Arg Gly 1025 1030 1035

    Gly Leu Ser Glu Lys Ser Val Tyr Gln Lys Phe Glu Lys Met Leu 1040 1045 1050

    Ile Asn Lys Leu Asn Tyr Phe Val Ser Lys Lys Glu Ser Asp Trp 1055 1060 1065

    Asn Lys Pro Ser Gly Leu Leu Asn Gly Leu Gln Leu Ser Asp Gln 1070 1075 1080

    Phe Glu Ser Phe Glu Lys Leu Gly Ile Gln Ser Gly Phe Ile Phe 1085 1090 1095

    Tyr Val Pro Ala Ala Tyr Thr Ser Lys Ile Asp Pro Thr Thr Gly 1100 1105 1110

    Phe Ala Asn Val Leu Asn Leu Ser Lys Val Arg Asn Val Asp Ala 1115 1120 1125

    Ile Lys Ser Phe Phe Ser Asn Phe Asn Glu Ile Ser Tyr Ser Lys 1130 1135 1140

    Lys Glu Ala Leu Phe Lys Phe Ser Phe Asp Leu Asp Ser Leu Ser 1145 1150 1155

    Lys Lys Gly Phe Ser Ser Phe Val Lys Phe Ser Lys Ser Lys Trp 1160 1165 1170

    Asn Val Tyr Thr Phe Gly Glu Arg Ile Ile Lys Pro Lys Asn Lys 1175 1180 1185

    Gln Gly Tyr Arg Glu Asp Lys Arg Ile Asn Leu Thr Phe Glu Met

    1190 1195 1200 Lys Lys Leu Leu Asn Glu Tyr Lys Val Ser Phe Asp Leu Glu Asn 1205 1210 1215 Asn Leu Ile Pro Asn Leu Thr Ser Ala Asn Leu Lys Asp Thr Phe 1220 1225 1230 Trp Lys Glu Leu Phe Phe Ile Phe Lys Thr Thr Leu Gln Leu Arg 1235 1240 1245

    Asn Ser Val Thr Asn Gly Lys Glu Asp Val Leu Ile Ser Pro Val 1250 1255 1260

    Lys Asn Ala Lys Gly Glu Phe Phe Val Ser Gly Thr His Asn Lys 1265 1270 1275

    Thr Leu Pro Gln Asp Cys Asp Ala Asn Gly Ala Tyr His Ile Ala 1280 1285 1290

    Leu Lys Gly Leu Met Ile Leu Glu Arg Asn Asn Leu Val Arg Glu 1295 1300 1305

    Glu Lys Asp Thr Lys Lys Ile Met Ala Ile Ser Asn Val Asp Trp 1310 1315 1320

    Phe Glu Tyr Val Gln Lys Arg Arg Gly Val Leu 1325 1330 <210> 1163 <211> 1307 <212> PRT <213> Acidaminococcus sp.

    <400> 1163

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser

    420

    425

    430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln 865 870 875 880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu 930 935 940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly 1025 1030 1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly 1115 1120 1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn

    1130

    1135

    1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu 1205 1210 1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn 1295 1300 1305 <210> 1164 <211> 1310 <212> PRT <213> Helcococcus kunzii <400> 1164

    Met Phe Glu Lys Leu Ser Asn Ile Val Ser Ile Ser Lys Thr Ile Arg 1 5 10 15

    Phe Lys Leu Ile Pro Val Gly Lys Thr Leu Glu Asn Ile Glu Lys Leu 20 25 30

    Gly Lys Leu Glu Lys Asp Phe Glu Arg Ser Asp Phe Tyr Pro Ile Leu 35 40 45

    Lys Asn Ile Ser Asp Asp Tyr Tyr Arg Gln Tyr Ile Lys Glu Lys Leu 50 55 60

    Ser Asp Leu Asn Leu Asp Trp Gln Lys Leu Tyr Asp Ala His Glu Leu 65 70 75 80

    Leu Asp Ser Ser Lys Lys Glu Ser Gln Lys Asn Leu Glu Met Ile Gln 85 90 95

    Ala Gln Tyr Arg Lys Val Leu Phe Asn Ile Leu Ser Gly Glu Leu Asp 100 105 110

    Lys Ser Gly Glu Lys Asn Ser Lys Asp Leu Ile Lys Asn Asn Lys Ala 115 120 125

    Leu Tyr Gly Lys Leu Phe Lys Lys Gln Phe Ile Leu Glu Val Leu Pro 130 135 140

    Asp Phe Val Asn Asn Asn Asp Ser Tyr Ser Glu Glu Asp Leu Glu Gly

    145

    150

    155

    160

    Leu Asn Leu Tyr Ser Lys Phe Thr Thr Arg Leu Lys Asn Phe Trp Glu 165 170 175

    Thr Arg Lys Asn Val Phe Thr Asp Lys Asp Ile Val Thr Ala Ile Pro 180 185 190

    Phe Arg Ala Val Asn Glu Asn Phe Gly Phe Tyr Tyr Asp Asn Ile Lys 195 200 205

    Ile Phe Asn Lys Asn Ile Glu Tyr Leu Glu Asn Lys Ile Pro Asn Leu 210 215 220

    Glu Asn Glu Leu Lys Glu Ala Asp Ile Leu Asp Asp Asn Arg Ser Val 225 230 235 240

    Lys Asp Tyr Phe Thr Pro Asn Gly Phe Asn Tyr Val Ile Thr Gln Asp 245 250 255

    Gly Ile Asp Val Tyr Gln Ala Ile Arg Gly Gly Phe Thr Lys Glu Asn 260 265 270

    Gly Glu Lys Val Gln Gly Ile Asn Glu Ile Leu Asn Leu Thr Gln Gln 275 280 285

    Gln Leu Arg Arg Lys Pro Glu Thr Lys Asn Val Lys Leu Gly Val Leu 290 295 300

    Thr Lys Leu Arg Lys Gln Ile Leu Glu Tyr Ser Glu Ser Thr Ser Phe 305 310 315 320

    Leu Ile Asp Gln Ile Glu Asp Asp Asn Asp Leu Val Asp Arg Ile Asn 325 330 335

    Lys Phe Asn Val Ser Phe Phe Glu Ser Thr Glu Val Ser Pro Ser Leu 340 345 350

    Phe Glu Gln Ile Glu Arg Leu Tyr Asn Ala Leu Lys Ser Ile Lys Lys 355 360 365

    Glu Glu Val Tyr Ile Asp Ala Arg Asn Thr Gln Lys Phe Ser Gln Met 370 375 380

    Leu Phe Gly Gln Trp Asp Val Ile Arg Arg Gly Tyr Thr Val Lys Ile 385 390 395 400

    Thr Glu Gly Ser Lys Glu Glu Lys Lys Lys Tyr Lys Glu Tyr Leu Glu 405 410 415

    Leu Asp Glu Thr Ser Lys Ala Lys Arg Tyr Leu Asn Ile Arg Glu Ile 420 425 430

    Glu Glu Leu Val Asn Leu Val Glu Gly Phe Glu Glu Val Asp Val Phe 435 440 445

    Ser Val Leu Leu Glu Lys Phe Lys Met Asn Asn Ile Glu Arg Ser Glu 450 455 460

    Phe Glu Ala Pro Ile Tyr Gly Ser Pro Ile Lys Leu Glu Ala Ile Lys 465 470 475 480

    Glu Tyr Leu Glu Lys His Leu Glu Glu Tyr His Lys Trp Lys Leu Leu 485 490 495

    Leu Ile Gly Asn Asp Asp Leu Asp Thr Asp Glu Thr Phe Tyr Pro Leu 500 505 510

    Leu Asn Glu Val Ile Ser Asp Tyr Tyr Ile Ile Pro Leu Tyr Asn Leu 515 520 525

    Thr Arg Asn Tyr Leu Thr Arg Lys His Ser Asp Lys Asp Lys Ile Lys 530 535 540

    Val Asn Phe Asp Phe Pro Thr Leu Ala Asp Gly Trp Ser Glu Ser Lys 545 550 555 560

    Ile Ser Asp Asn Arg Ser Ile Ile Leu Arg Lys Gly Gly Tyr Tyr Tyr 565 570 575

    Leu Gly Ile Leu Ile Asp Asn Lys Leu Leu Ile Asn Lys Lys Asn Lys 580 585 590

    Ser Lys Lys Ile Tyr Glu Ile Leu Ile Tyr Asn Gln Ile Pro Glu Phe 595 600 605

    Ser Lys Ser Ile Pro Asn Tyr Pro Phe Thr Lys Lys Val Lys Glu His 610 615 620

    Phe Lys Asn Asn Val Ser Asp Phe Gln Leu Ile Asp Gly Tyr Val Ser 625 630 635 640

    Pro Leu Ile Ile Thr Lys Glu Ile Tyr Asp Ile Lys Lys Glu Lys Lys 645 650 655

    Tyr Lys Lys Asp Phe Tyr Lys Asp Asn Asn Thr Asn Lys Asn Tyr Leu 660 665 670

    Tyr Thr Ile Tyr Lys Trp Ile Glu Phe Cys Lys Gln Phe Leu Tyr Lys 675 680 685

    Tyr Lys Gly Pro Asn Lys Glu Ser Tyr Lys Glu Met Tyr Asp Phe Ser 690 695 700

    Thr Leu Lys Asp Thr Ser Leu Tyr Val Asn Leu Asn Asp Phe Tyr Ala 705 710 715 720

    Asp Val Asn Ser Cys Ala Tyr Arg Val Leu Phe Asn Lys Ile Asp Glu 725 730 735

    Asn Thr Ile Asp Asn Ala Val Glu Asp Gly Lys Leu Leu Leu Phe Gln 740 745 750

    Ile Tyr Asn Lys Asp Phe Ser Pro Glu Ser Lys Gly Lys Lys Asn Leu 755 760 765

    His Thr Leu Tyr Trp Leu Ser Met Phe Ser Glu Glu Asn Leu Arg Thr 770 775 780

    Arg Lys Leu Lys Leu Asn Gly Gln Ala Glu Ile Phe Tyr Arg Lys Lys 785 790 795 800

    Leu Glu Lys Lys Pro Ile Ile His Lys Glu Gly Ser Ile Leu Leu Asn 805 810 815

    Lys Ile Asp Lys Glu Gly Asn Thr Ile Pro Glu Asn Ile Tyr His Glu 820 825 830

    Cys Tyr Arg Tyr Leu Asn Lys Lys Ile Gly Arg Glu Asp Leu Ser Asp 835 840 845

    Glu Ala Ile Ala Leu Phe Asn Lys Asp Val Leu Lys Tyr Lys Glu Ala 850 855 860

    Arg Phe Asp Ile Ile Lys Asp Arg Arg Tyr Ser Glu Ser Gln Phe Phe

    865

    870

    875

    880

    Phe His Val Pro Ile Thr Phe Asn Trp Asp Ile Lys Thr Asn Lys Asn 885 890 895

    Val Asn Gln Ile Val Gln Gly Met Ile Lys Asp Gly Glu Ile Lys His 900 905 910

    Ile Ile Gly Ile Asp Arg Gly Glu Arg His Leu Leu Tyr Tyr Ser Val 915 920 925

    Ile Asp Leu Glu Gly Asn Ile Val Glu Gln Gly Ser Leu Asn Thr Leu 930 935 940

    Glu Gln Asn Arg Phe Asp Asn Ser Thr Val Lys Val Asp Tyr Gln Asn 945 950 955 960

    Lys Leu Arg Thr Arg Glu Glu Asp Arg Asp Arg Ala Arg Lys Asn Trp 965 970 975

    Thr Asn Ile Asn Lys Ile Lys Glu Leu Lys Asp Gly Tyr Leu Ser His 980 985 990

    Val Val His Lys Leu Ser Arg Leu Ile Ile Lys Tyr Glu Ala Ile Val 995 1000 1005

    Ile Met Glu Asn Leu Asn Gln Gly Phe Lys Arg Gly Arg Phe Lys 1010 1015 1020

    Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Leu Ala Leu Met Asn 1025 1030 1035

    Lys Leu Ser Ala Leu Ser Phe Lys Glu Lys Tyr Asp Glu Arg Lys 1040 1045 1050

    Asn Leu Glu Pro Ser Gly Ile Leu Asn Pro Ile Gln Ala Cys Tyr 1055 1060 1065

    Pro Val Asp Ala Tyr Gln Glu

    Leu Gln Gly Gln Asn Gly Ile Val

    1070 1075 1080

    Phe Tyr Leu Pro Ala Ala Tyr Thr Ser Val Ile Asp Pro Val Thr 1085 1090 1095

    Gly Phe Thr Asn Leu Phe Arg Leu Lys Ser Ile Asn Ser Ser Lys 1100 1105 1110

    Tyr Glu Glu Phe Ile Lys Lys Phe Lys Asn Ile Tyr Phe Asp Asn 1115 1120 1125

    Glu Glu Glu Asp Phe Lys Phe Ile Phe Asn Tyr Lys Asp Phe Ala 1130 1135 1140

    Lys Ala Asn Leu Val Ile Leu Asn Asn Ile Lys Ser Lys Asp Trp 1145 1150 1155

    Lys Ile Ser Thr Arg Gly Glu Arg Ile Ser Tyr Asn Ser Lys Lys 1160 1165 1170

    Lys Glu Tyr Phe Tyr Val Gln Pro Thr Glu Phe Leu Ile Asn Lys 1175 1180 1185

    Leu Lys Glu Leu Asn Ile Asp Tyr Glu Asn Ile Asp Ile Ile Pro 1190 1195 1200

    Leu Ile Asp Asn Leu Glu Glu Lys Ala Lys Arg Lys Ile Leu Lys 1205 1210 1215

    Ala Leu Phe Asp Thr Phe Lys Tyr Ser Val Gln Leu Arg Asn Tyr

    1220 1225 1230 Asp Phe Glu Asn Asp Tyr Ile Ile Ser Pro Thr Ala Asp Asp Asn 1235 1240 1245 Gly Asn Tyr Tyr Asn Ser Asn Glu Ile Asp Ile Asp Lys Thr Asn 1250 1255 1260

    Leu Pro Asn Asn Gly Asp Ala Asn Gly Ala Phe Asn Ile Ala Arg 1265 1270 1275

    Lys Gly Leu Leu Leu Lys Asp Arg Ile Val Asn Ser Asn Glu Ser 1280 1285 1290

    Lys Val Asp Leu Lys Ile Lys Asn Glu Asp Trp Ile Asn Phe Ile 1295 1300 1305

    Ile Ser 1310 <210> 1165 <211> 1255 <212> PRT <213> Butyrivibrio proteoclasticus <400> 1165

    Met Leu Leu Tyr Glu Asn Tyr Thr Lys Arg Asn Gln Ile Thr Lys Ser 1 5 10 15

    Leu Arg Leu Glu Leu Arg Pro Gln Gly Lys Thr Leu Arg Asn Ile Lys 20 25 30

    Glu Leu Asn Leu Leu Glu Gln Asp Lys Ala Ile Tyr Ala Leu Leu Glu 35 40 45

    Arg Leu Lys Pro Val Ile Asp Glu Gly Ile Lys Asp Ile Ala Arg Asp 50 55 60

    Thr Leu Lys Asn Cys Glu Leu Ser Phe Glu Lys Leu Tyr Glu His Phe 65 70 75 80

    Leu Ser Gly Asp Lys Lys Ala Tyr Ala Lys Glu Ser Glu Arg Leu Lys 85 90 95

    Lys Glu Ile Val Lys Thr Leu Ile Lys Asn Leu Pro Glu Gly Ile Gly 100 105 110

    Lys Ile Ser Glu Ile Asn Ser Ala Lys Tyr Leu Asn Gly Val Leu Tyr 115 120 125

    Asp Phe Ile Asp Lys Thr His Lys Asp Ser Glu Glu Lys Gln Asn Ile 130 135 140

    Leu Ser Asp Ile Leu Glu Thr Lys Gly Tyr Leu Ala Leu Phe Ser Lys 145 150 155 160

    Phe Leu Thr Ser Arg Ile Thr Thr Leu Glu Gln Ser Met Pro Lys Arg 165 170 175

    Val Ile Glu Asn Phe Glu Ile Tyr Ala Ala Asn Ile Pro Lys Met Gln 180 185 190

    Asp Ala Leu Glu Arg Gly Ala Val Ser Phe Ala Ile Glu Tyr Glu Ser 195 200 205

    Ile Cys Ser Val Asp Tyr Tyr Asn Gln Ile Leu Ser Gln Glu Asp Ile 210 215 220

    Asp Ser Tyr Asn Arg Leu Ile Ser Gly Ile Met Asp Glu Asp Gly Ala 225 230 235 240

    Lys Glu Lys Gly Ile Asn Gln Thr Ile Ser Glu Leu Met Gln Arg Phe 245 250 255

    Leu Thr Thr Arg Ile Thr Ala Leu Thr Lys Asn Ile Lys Ile Lys Ser 260 265 270

    Glu His Leu Glu Glu Lys Pro Phe Arg Ile Leu Lys Gln Leu His Lys 275 280 285

    Gln Ile Leu Glu Glu Arg Glu Lys Ala Phe Thr Ile Asp His Ile Asp 290 295 300

    Ser Asp Glu Glu Val Val Gln Val Thr Lys Glu Ala Phe Glu Gln Thr 305 310 315 320

    Lys Glu Gln Trp Glu Asn Ile Lys Lys Ile Asn Gly Phe Tyr Ala Lys 325 330 335

    Asp Pro Gly Asp Ile Thr Leu Phe Ile Val Val Gly Pro Asn Gln Thr 340 345 350

    His Val Leu Ser Gln Leu Ile Tyr Gly Glu His Asp Arg Ile Arg Leu 355 360 365

    Leu Leu Glu Glu Tyr Glu Lys Asn Thr Leu Glu Val Leu Pro Arg Arg 370 375 380

    Thr Lys Ser Glu Lys Ala Arg Tyr Asp Lys Phe Val Asn Ala Val Pro 385 390 395 400

    Lys Lys Val Ala Lys Glu Ser His Thr Phe Asp Gly Leu Gln Lys Met 405 410 415

    Thr Gly Asp Asp Arg Leu Phe Ile Leu Tyr Arg Asp Glu Leu Ala Arg 420 425 430

    Asn Tyr Met Arg Ile Lys Glu Ala Tyr Gly Thr Phe Glu Arg Asp Ile 435 440 445

    Leu Lys Ser Arg Arg Gly Ile Lys Gly Asn Arg Asp Val Gln Glu Ser 450 455 460

    Leu Val Ser Phe Tyr Asp Glu Leu Thr Lys Phe Arg Ser Ala Leu Arg 465 470 475 480

    Ile Ile Asn Ser Gly Asn Asp Glu Lys Ala Asp Pro Ile Phe Tyr Asn 485 490 495

    Thr Phe Asp Gly Ile Phe Glu Lys Ala Asn Arg Thr Tyr Lys Ala Glu 500 505 510

    Asn Leu Cys Arg Asn Tyr Val Thr Lys Ser Pro Ala Asp Asp Ala Arg 515 520 525

    Ile Met Ala Ser Cys Leu Gly Thr Pro Ala Arg Leu Arg Thr His Trp 530 535 540

    Trp Asn Gly Glu Glu Asn Phe Ala Ile Asn Asp Val Ala Met Ile Arg 545 550 555 560

    Arg Gly Asp Glu Tyr Tyr Tyr Phe Val Leu Thr Pro Asp Val Lys Pro 565 570 575

    Val Asp Leu Lys Thr Lys Asp Glu Thr Asp Ala Gln Ile Phe Val Gln

    580

    585

    590

    Arg Lys Gly Ala Lys Ser Phe Leu Gly Leu Pro Lys Ala Leu Phe Lys 595 600 605

    Cys Ile Leu Glu Pro Tyr Phe Glu Ser Pro Glu His Lys Asn Asp Lys 610 615 620

    Asn Cys Val Ile Glu Glu Tyr Val Ser Lys Pro Leu Thr Ile Asp Arg 625 630 635 640

    Arg Ala Tyr Asp Ile Phe Lys Asn Gly Thr Phe Lys Lys Thr Asn Ile 645 650 655

    Gly Ile Asp Gly Leu Thr Glu Glu Lys Phe Lys Asp Asp Cys Arg Tyr 660 665 670

    Leu Ile Asp Val Tyr Lys Glu Phe Ile Ala Val Tyr Thr Arg Tyr Ser 675 680 685

    Cys Phe Asn Met Ser Gly Leu Lys Arg Ala Asp Glu Tyr Asn Asp Ile 690 695 700

    Gly Glu Phe Phe Ser Asp Val Asp Thr Arg Leu Cys Thr Met Glu Trp 705 710 715 720

    Ile Pro Val Ser Phe Glu Arg Ile Asn Asp Met Val Asp Lys Lys Glu 725 730 735

    Gly Leu Leu Phe Leu Val Arg Ser Met Phe Leu Tyr Asn Arg Pro Arg 740 745 750

    Lys Pro Tyr Glu Arg Thr Phe Ile Gln Leu Phe Ser Asp Ser Asn Met 755 760 765

    Glu His Thr Ser Met Leu Leu Asn Ser Arg Ala Met Ile Gln Tyr Arg 770 775 780

    Ala Ala Ser Leu Pro Arg Arg Val Thr His Lys Lys Gly Ser Ile Leu 785 790 795 800

    Val Ala Leu Arg Asp Ser Asn Gly Glu His Ile Pro Met His Ile Arg 805 810 815

    Glu Ala Ile Tyr Lys Met Lys Asn Asn Phe Asp Ile Ser Ser Glu Asp 820 825 830

    Phe Ile Met Ala Lys Ala Tyr Leu Ala Glu His Asp Val Ala Ile Lys 835 840 845

    Lys Ala Asn Glu Asp Ile Ile Arg Asn Arg Arg Tyr Thr Glu Asp Lys 850 855 860

    Phe Phe Leu Ser Leu Ser Tyr Thr Lys Asn Ala Asp Ile Ser Ala Arg 865 870 875 880

    Thr Leu Asp Tyr Ile Asn Asp Lys Val Glu Glu Asp Thr Gln Asp Ser 885 890 895

    Arg Met Ala Val Ile Val Thr Arg Asn Leu Lys Asp Leu Thr Tyr Val 900 905 910

    Ala Val Val Asp Glu Lys Asn Asn Val Leu Glu Glu Lys Ser Leu Asn 915 920 925

    Glu Ile Asp Gly Val Asn Tyr Arg Glu Leu Leu Lys Glu Arg Thr Lys 930 935 940

    Ile Lys Tyr His Asp Lys Thr Arg Leu Trp Gln Tyr Asp Val Ser Ser 945 950 955 960

    Lys Gly Leu Lys Glu Ala Tyr Val Glu Leu Ala Val Thr Gln Ile Ser 965 970 975

    Lys Leu Ala Thr Lys Tyr Asn Ala Val Val Val Val Glu Ser Met Ser 980 985 990

    Ser Thr Phe Lys Asp Lys Phe Ser Phe Leu Asp Glu Gln Ile Phe Lys 995 1000 1005

    Ala Phe Glu Ala Arg Leu Cys Ala Arg Met Ser Asp Leu Ser Phe 1010 1015 1020

    Asn Thr Ile Lys Glu Gly Glu Ala Gly Ser Ile Ser Asn Pro Ile 1025 1030 1035

    Gln Val Ser Asn Asn Asn Gly Asn Ser Tyr Gln Asp Gly Val Ile 1040 1045 1050

    Tyr Phe Leu Asn Asn Ala Tyr Thr Arg Thr Leu Cys Pro Asp Thr 1055 1060 1065

    Gly Phe Val Asp Val Phe Asp Lys Thr Arg Leu Ile Thr Met Gln 1070 1075 1080

    Ser Lys Arg Gln Phe Phe Ala Lys Met Lys Asp Ile Arg Ile Asp 1085 1090 1095

    Asp Gly Glu Met Leu Phe Thr Phe Asn Leu Glu Glu Tyr Pro Thr 1100 1105 1110

    Lys Arg Leu Leu Asp Arg Lys Glu Trp Thr Val Lys Ile Ala Gly 1115 1120 1125

    Asp Gly Ser Tyr Phe Asp Lys Asp Lys Gly Glu Tyr Val Tyr Val 1130 1135 1140

    Asn Asp Ile Val Arg Glu Gln Ile Ile Pro Ala Leu Leu Glu Asp 1145 1150 1155

    Lys Ala Val Phe Asp Gly Asn Met Ala Glu Lys Phe Leu Asp Lys 1160 1165 1170

    Thr Ala Ile Ser Gly Lys Ser Val Glu Leu Ile Tyr Lys Trp Phe 1175 1180 1185

    Ala Asn Ala Leu Tyr Gly Ile Ile Thr Lys Lys Asp Gly Glu Lys 1190 1195 1200

    Ile Tyr Arg Ser Pro Ile Thr Gly Thr Glu Ile Asp Val Ser Lys 1205 1210 1215

    Asn Thr Thr Tyr Asn Phe Gly 1220 1225

    Lys Lys Phe Met Phe Lys Gln Glu 1230

    Tyr Arg Gly Asp Gly Asp Phe 1235 1240

    Leu Asp Ala Phe Leu Asn Tyr Met 1245

    Gln Ala Gln Asp Ile Ala Val 1250 1255 <210> 1166 <211> 1219 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1166

    Met Asp Tyr Gly Asn Gly Gln Phe Glu Arg Arg Ala Pro Leu Thr Lys 1 5 10 15

    Thr Ile Thr Leu Arg Leu Lys Pro Ile Gly Glu Thr Arg Glu Thr Ile 20 25 30

    Arg Glu Gln Lys Leu Leu Glu Gln Asp Ala Ala Phe Arg Lys Leu Val 35 40 45

    Glu Thr Val Thr Pro Ile Val Asp Asp Cys Ile Arg Lys Ile Ala Asp 50 55 60

    Asn Ala Leu Cys His Phe Gly Thr Glu Tyr Asp Phe Ser Cys Leu Gly 65 70 75 80

    Asn Ala Ile Ser Lys Asn Asp Ser Lys Ala Ile Lys Lys Glu Thr Glu 85 90 95

    Lys Val Glu Lys Leu Leu Ala Lys Val Leu Thr Glu Asn Leu Pro Asp 100 105 110

    Gly Leu Arg Lys Val Asn Asp Ile Asn Ser Ala Ala Phe Ile Gln Asp 115 120 125

    Thr Leu Thr Ser Phe Val Gln Asp Asp Ala Asp Lys Arg Val Leu Ile 130 135 140

    Gln Glu Leu Lys Gly Lys Thr Val Val Trp Leu Pro Asp Arg Val Phe 145 150 155 160

    Glu Asn Phe Asn Ile Phe Ile Glu Asn Ala Glu Lys Met Arg Ile Leu 165 170 175

    Leu Asp Ser Pro Leu Asn Glu Lys Ile Met Lys Phe Asp Pro Asp Ala 180 185 190

    Glu Gln Tyr Ala Ser Leu Glu Phe Tyr Gly Gln Cys Leu Ser Gln Lys 195 200 205

    Asp Ile Asp Ser Tyr Asn Leu Ile Ile Ser Gly Ile Tyr Ala Asp Asp 210 215 220

    Glu Val Lys Asn Pro Gly Ile Asn Glu Ile Val Lys Glu Tyr Asn Gln 225 230 235 240

    Gln Ile Arg Gly Asp Lys Asp Glu Ser Pro Leu Pro Lys Leu Lys Lys 245 250 255

    Leu His Lys Gln Ile Leu Met Pro Val Glu Lys Ala Phe Phe Val Arg 260 265 270

    Val Leu Ser Asn Asp Ser Asp Ala Arg Ser Ile Leu Glu Lys Ile Leu 275 280 285

    Lys Asp Thr Glu Met Leu Pro Ser Lys Ile Ile Glu Ala Met Lys Glu 290 295 300

    Ala Asp Ala Gly Asp Ile Ala Val Tyr Gly Ser Arg Leu His Glu Leu 305 310 315 320

    Ser His Val Ile Tyr Gly Asp His Gly Lys Leu Ser Gln Ile Ile Tyr 325 330 335

    Asp Lys Glu Ser Lys Arg Ile Ser Glu Leu Met Glu Thr Leu Ser Pro

    340

    345

    350

    Lys Glu Arg Lys Glu Ser Lys Lys Arg Leu Glu Gly Leu Glu Glu His 355 360 365

    Ile Arg Lys Ser Thr Tyr Thr Phe Asp Glu Leu Asn Arg Tyr Ala Glu 370 375 380

    Lys Asn Val Met Ala Ala Tyr Ile Ala Ala Val Glu Glu Ser Cys Ala 385 390 395 400

    Glu Ile Met Arg Lys Glu Lys Asp Leu Arg Thr Leu Leu Ser Lys Glu 405 410 415

    Asp Val Lys Ile Arg Gly Asn Arg His Asn Thr Leu Ile Val Lys Asn 420 425 430

    Tyr Phe Asn Ala Trp Thr Val Phe Arg Asn Leu Ile Arg Ile Leu Arg 435 440 445

    Arg Lys Ser Glu Ala Glu Ile Asp Ser Asp Phe Tyr Asp Val Leu Asp 450 455 460

    Asp Ser Val Glu Val Leu Ser Leu Thr Tyr Lys Gly Glu Asn Leu Cys 465 470 475 480

    Arg Ser Tyr Ile Thr Lys Lys Ile Gly Ser Asp Leu Lys Pro Glu Ile 485 490 495

    Ala Thr Tyr Gly Ser Ala Leu Arg Pro Asn Ser Arg Trp Trp Ser Pro 500 505 510

    Gly Glu Lys Phe Asn Val Lys Phe His Thr Ile Val Arg Arg Asp Gly 515 520 525

    Arg Leu Tyr Tyr Phe Ile Leu Pro Lys Gly Ala Lys Pro Val Glu Leu 530 535 540

    Glu Asp Met Asp Gly Asp Ile Glu Cys Leu Gln Met Arg Lys Ile Pro 545 550 555 560

    Asn Pro Thr Ile Phe Leu Pro Lys Leu Val Phe Lys Asp Pro Glu Ala 565 570 575

    Phe Phe Arg Asp Asn Pro Glu Ala Asp Glu Phe Val Phe Leu Ser Gly 580 585 590

    Met Lys Ala Pro Val Thr Ile Thr Arg Glu Thr Tyr Glu Ala Tyr Arg 595 600 605

    Tyr Lys Leu Tyr Thr Val Gly Lys Leu Arg Asp Gly Glu Val Ser Glu 610 615 620

    Glu Glu Tyr Lys Arg Ala Leu Leu Gln Val Leu Thr Ala Tyr Lys Glu 625 630 635 640

    Phe Leu Glu Asn Arg Met Ile Tyr Ala Asp Leu Asn Phe Gly Phe Lys 645 650 655

    Asp Leu Glu Glu Tyr Lys Asp Ser Ser Glu Phe Ile Lys Gln Val Glu 660 665 670

    Thr His Asn Thr Phe Met Cys Trp Ala Lys Val Ser Ser Ser Gln Leu 675 680 685

    Asp Asp Leu Val Lys Ser Gly Asn Gly Leu Leu Phe Glu Ile Trp Ser 690 695 700

    Glu Arg Leu Glu Ser Tyr Tyr Lys Tyr Gly Asn Glu Lys Val Leu Arg 705 710 715 720

    Gly Tyr Glu Gly Val Leu Leu Ser Ile Leu Lys Asp Glu Asn Leu Val 725 730 735

    Ser Met Arg Thr Leu Leu Asn Ser Arg Pro Met Leu Val Tyr Arg Pro 740 745 750

    Lys Glu Ser Ser Lys Pro Met Val Val His Arg Asp Gly Ser Arg Val 755 760 765

    Val Asp Arg Phe Asp Lys Asp Gly Lys Tyr Ile Pro Pro Glu Val His 770 775 780

    Asp Glu Leu Tyr Arg Phe Phe Asn Asn Leu Leu Ile Lys Glu Lys Leu 785 790 795 800

    Gly Glu Lys Ala Arg Lys Ile Leu Asp Asn Lys Lys Val Lys Val Lys 805 810 815

    Val Leu Glu Ser Glu Arg Val Lys Trp Ser Lys Phe Tyr Asp Glu Gln 820 825 830

    Phe Ala Val Thr Phe Ser Val Lys Lys Asn Ala Asp Cys Leu Asp Thr 835 840 845

    Thr Lys Asp Leu Asn Ala Glu Val Met Glu Gln Tyr Ser Glu Ser Asn 850 855 860

    Arg Leu Ile Leu Ile Arg Asn Thr Thr Asp Ile Leu Tyr Tyr Leu Val 865 870 875 880

    Leu Asp Lys Asn Gly Lys Val Leu Lys Gln Arg Ser Leu Asn Ile Ile 885 890 895

    Asn Asp Gly Ala Arg Asp Val Asp Trp Lys Glu Arg Phe Arg Gln Val 900 905 910

    Thr Lys Asp Arg Asn Glu Gly Tyr Asn Glu Trp Asp Tyr Ser Arg Thr 915 920 925

    Ser Asn Asp Leu Lys Glu Val Tyr Leu Asn Tyr Ala Leu Lys Glu Ile 930 935 940

    Ala Glu Ala Val Ile Glu Tyr Asn Ala Ile Leu Ile Ile Glu Lys Met 945 950 955 960

    Ser Asn Ala Phe Lys Asp Lys Tyr Ser Phe Leu Asp Asp Val Thr Phe 965 970 975

    Lys Gly Phe Glu Thr Lys Leu Leu Ala Lys Leu Ser Asp Leu His Phe 980 985 990

    Arg Gly Ile Lys Asp Gly Glu Pro Cys Ser Phe Thr Asn Pro Leu Gln 995 1000 1005

    Leu Cys Gln Asn Asp Ser Asn Lys Ile Leu Gln Asp Gly Val Ile 1010 1015 1020

    Phe Met Val Pro Asn Ser Met Thr Arg Ser Leu Asp Pro Asp Thr 1025 1030 1035

    Gly Phe Ile Phe Ala Ile Asn Asp His Asn Ile Arg Thr Lys Lys 1040 1045 1050

    Ala Lys Leu Asn Phe Leu Ser Lys Phe Asp Gln Leu Lys Val Ser

    1055 1060 1065

    Ser Glu Gly Cys Leu Ile Met Lys Tyr Ser Gly Asp Ser Leu Pro 1070 1075 1080

    Thr His Asn Thr Asp Asn Arg Val Trp Asn Cys Cys Cys Asn His 1085 1090 1095

    Pro Ile Thr Asn Tyr Asp Arg Glu Thr Lys Lys Val Glu Phe Ile 1100 1105 1110

    Glu Glu Pro Val Glu Glu Leu Ser Arg Val Leu Glu Glu Asn Gly 1115 1120 1125

    Ile Glu Thr Asp Thr Glu Leu Asn Lys Leu Asn Glu Arg Glu Asn 1130 1135 1140

    Val Pro Gly Lys Val Val Asp Ala Ile Tyr Ser Leu Val Leu Asn 1145 1150 1155

    Tyr Leu Arg Gly Thr Val Ser Gly Val Ala Gly Gln Arg Ala Val 1160 1165 1170

    Tyr Tyr Ser Pro Val Thr Gly Lys Lys Tyr Asp Ile Ser Phe Ile 1175 1180 1185

    Gln Ala Met Asn Leu Asn Arg Lys Cys Asp Tyr Tyr Arg Ile Gly 1190 1195 1200

    Ser Lys Glu Arg Gly Glu Trp Thr Asp Phe Val Ala Gln Leu Ile

    1205 1210 1215

    Asn <210> 1167 <211> 10715 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1167 gaattccgga tgagcattca tcaggcgggc aagaatgtga ataaaggccg gataaaactt 60 gtgcttattt ttctttacgg tctttaaaaa ggccgtaata tccagctgaa cggtctggtt 120 ataggtacat tgagcaactg actgaaatgc ctcaaaatgt tctttacgat gccattggga 180 tatatcaacg gtggtatatc cagtgatttt tttctccatt ttagcttcct tagctcctga 240 aaatctcgat aactcaaaaa atacgcccgg tagtgatctt atttcattat ggtgaaagtt 300 ggaacctctt acgtgccgat caacgtctca ttttcgccaa aagttggccc agggcttccc 360 ggtatcaaca gggacaccag gatttattta ttctgcgaag tgatcttccg tcacaggtat 420 ttattcggcg caaagtgcgt cgggtgatgc tgccaactta ctgatttagt gtatgatggt 480 gtttttgagg tgctccagtg gcttctgttt ctatcagctg tccctcctgt tcagctactg 540 acggggtggt gcgtaacggc aaaagcaccg ccggacatca gcgctagcgg agtgtatact 600 ggcttactat gttggcactg atgagggtgt cagtgaagtg cttcatgtgg caggagaaaa 660 aaggctgcac cggtgcgtca gcagaatatg tgatacagga tatattccgc ttcctcgctc 720 actgactcgc tacgctcggt cgttcgactg cggcgagcgg aaatggctta cgaacggggc 780 ggagatttcc tggaagatgc caggaagata cttaacaggg aagtgagagg gccgcggcaa 840 agccgttttt ccataggctc cgcccccctg acaagcatca cgaaatctga cgctcaaatc 900 agtggtggcg aaacccgaca ggactataaa gataccaggc gtttccccct ggcggctccc 960 tcgtgcgctc tcctgttcct gcctttcggt ttaccggtgt cattccgctg ttatggccgc 1020 gtttgtctca ttccacgcct gacactcagt tccgggtagg cagttcgctc caagctggac 1080 tgtatgcacg aaccccccgt tcagtccgac cgctgcgcct tatccggtaa ctatcgtctt 1140 gagtccaacc cggaaagaca tgcaaaagca ccactggcag cagccactgg taattgattt 1200 agaggagtta gtcttgaagt catgcgccgg ttaaggctaa actgaaagga caagttttgg 1260 tgactgcgct cctccaagcc agttacctcg gttcaaagag ttggtagctc agagaacctt 1320 cgaaaaaccg ccctgcaagg cggttttttc gttttcagag caagagatta cgcgcagacc 1380 aaaacgatct caagaagatc atcttattaa tcagataaaa tatttcatca aggaattggt 1440 tctaagctta tagaagcaat gattaaggaa gccaaaaaaa ataatattga tgcaatattt 1500 gtcttaggtc atccaagtta ttatccaaaa tttggtttta aaccagccac agaatatcag 1560 ataaaatgtg aatatgatgt cccagcggat gtttttatgg tactagattt gtcagctaaa 1620 ctagctagtt taaaaggaca aactgtctac tatgccgatg agtttggcaa aattttttag 1680 atctacaaaa ttataaacta aataaagatt cttataataa ctttatatat aatcgaaatg 1740 tagagaattt tataaggagt ctttatcatg tcaatttatc aagaatttgt taataaatat 1800 agtttaagta aaactctaag atttgagtta atcccacagg gtaaaacact tgaaaacata 1860 aaagcaagag gtttgatttt agatgatgag aaaagagcta aagactacaa aaaggctaaa 1920 caaataattg ataaatatca tcagtttttt atagaggaga tattaagttc ggtttgtatt 1980 agcgaagatt tattacaaaa ctattctgat gtttatttta aacttaaaaa gagtgatgat 2040 gataatctac aaaaagattt taaaagtgca aaagatacga taaagaaaca aatatctgaa 2100 tatataaagg actcagagaa atttaagaat ttgtttaatc aaaaccttat cgatgctaaa 2160 aaagggcaag agtcagattt aattctatgg ctaaagcaat ctaaggataa tggtatagaa 2220 ctatttaaag ccaatagtga tatcacagat atagatgagg cgttagaaat aatcaaatct 2280 tttaaaggtt ggacaactta ttttaagggt tttcatgaaa atagaaaaaa tgtttatagt 2340 agcaatgata ttcctacatc tattatttat aggatagtag atgataattt gcctaaattt 2400 ctagaaaata aagctaagta tgagagttta aaagacaaag ctccagaagc tataaactat 2460 gaacaaatta aaaaagattt ggcagaagag ctaacctttg atattgacta caaaacatct 2520 gaagttaatc aaagagtttt ttcacttgat gaagtttttg agatagcaaa ctttaataat 2580 tatctaaatc aaagtggtat tactaaattt aatactatta ttggtggtaa atttgtaaat 2640 ggtgaaaata caaagagaaa aggtataaat gaatatataa atctatactc acagcaaata 2700 aatgataaaa cactcaaaaa atataaaatg agtgttttat ttaagcaaat tttaagtgat 2760 acagaatcta aatcttttgt aattgataag ttagaagatg atagtgatgt agttacaacg 2820 atgcaaagtt tttatgagca aatagcagct tttaaaacag tagaagaaaa atctattaaa 2880 gaaacactat ctttattatt tgatgattta aaagctcaaa aacttgattt gagtaaaatt 2940 tattttaaaa atgataaatc tcttactgat ctatcacaac aagtttttga tgattatagt 3000 gttattggta cagcggtact agaatatata actcaacaaa tagcacctaa aaatcttgat 3060 aaccctagta agaaagagca agaattaata gccaaaaaaa ctgaaaaagc aaaatactta 3120 tctctagaaa ctataaagct tgccttagaa gaatttaata agcatagaga tatagataaa 3180 cagtgtaggt ttgaagaaat acttgcaaac tttgcggcta ttccgatgat atttgatgaa 3240 atagctcaaa acaaagacaa tttggcacag atatctatca aatatcaaaa tcaaggtaaa 3300 aaagacctac ttcaagctag tgcggaagat gatgttaaag ctatcaagga tcttttagat 3360 caaactaata atctcttaca taaactaaaa atatttcata ttagtcagtc agaagataag 3420 gcaaatattt tagacaagga tgagcatttt tatctagtat ttgaggagtg ctactttgag 3480 ctagcgaata tagtgcctct ttataacaaa attagaaact atataactca aaagccatat 3540 agtgatgaga aatttaagct caattttgag aactcgactt tggctaatgg ttgggataaa 3600 aataaagagc ctgacaatac ggcaatttta tttatcaaag atgataaata ttatctgggt 3660 gtgatgaata agaaaaataa caaaatattt gatgataaag ctatcaaaga aaataaaggc 3720 gagggttata aaaaaattgt ttataaactt ttacctggcg caaataaaat gttacctaag 3780 gttttctttt ctgctaaatc tataaaattt tataatccta gtgaagatat acttagaata 3840 agaaatcatt ccacacatac aaaaaatggt agtcctcaaa aaggatatga aaaatttgag 3900 tttaatattg aagattgccg aaaatttata gatttttata aacagtctat aagtaagcat 3960 ccggagtgga aagattttgg atttagattt tctgatactc aaagatataa ttctatagat 4020 gaattttata gagaagttga aaatcaaggc tacaaactaa cttttgaaaa tatatcagag 4080 agctatattg atagcgtagt taatcagggt aaattgtacc tattccaaat ctataataaa 4140 gatttttcag cttatagcaa agggcgacca aatctacata ctttatattg gaaagcgctg 4200 tttgatgaga gaaatcttca agatgtggtt tataagctaa atggtgaggc agagcttttt 4260 tatcgtaaac aatcaatacc taaaaaaatc actcacccag ctaaagaggc aatagctaat 4320 aaaaacaaag ataatcctaa aaaagagagt gtttttgaat atgatttaat caaagataaa 4380 cgctttactg aagataagtt tttctttcac tgtcctatta caatcaattt taaatctagt 4440 ggagctaata agtttaatga tgaaatcaat ttattgctaa aagaaaaagc aaatgatgtt 4500 catatattaa gtatagatag aggtgaaaga catttagctt actatacttt ggtagatggt 4560 aaaggcaata tcatcaaaca agatactttc aacatcattg gtaatgatag aatgaaaaca 4620 aactaccatg ataagcttgc tgcaatagag aaagataggg attcagctag gaaagactgg 4680 aaaaagataa ataacatcaa agagatgaaa gagggctatc tatctcaggt agttcatgaa 4740 atagctaagc tagttataga gtataatgct attgtggttt ttgaggattt aaattttgga 4800 tttaaaagag ggcgtttcaa ggtagagaag caggtctatc aaaagttaga aaaaatgcta 4860 attgagaaac taaactatct agttttcaaa gataatgagt ttgataaaac tgggggagtg 4920 cttagagctt atcagctaac agcacctttt gagactttta aaaagatggg taaacaaaca 4980 ggtattatct actatgtacc agctggtttt acttcaaaaa tttgtcctgt aactggtttt 5040 gtaaatcagt tatatcctaa gtatgaaagt gtcagcaaat ctcaagagtt ctttagtaag 5100 tttgacaaga tttgttataa ccttgataag ggctattttg agtttagttt tgattataaa 5160 aactttggtg acaaggctgc caaaggcaag tggactatag ctagctttgg gagtagattg 5220 attaacttta gaaattcaga taaaaatcat aattgggata ctcgagaagt ttatccaact 5280 aaagagttgg agaaattgct aaaagattat tctatcgaat atgggcatgg cgaatgtatc 5340 aaagcagcta tttgcggtga gagcgacaaa aagttttttg ctaagctaac tagtgtccta 5400 aatactatct tacaaatgcg taactcaaaa acaggtactg agttagatta tctaatttca 5460 ccagtagcag atgtaaatgg caatttcttt gattcgcgac aggcgccaaa aaatatgcct 5520 caagatgctg atgccaatgg tgcttatcat attgggctaa aaggtctgat gctactaggt 5580 aggatcaaaa ataatcaaga gggcaaaaaa ctcaatttgg ttatcaaaaa tgaagagtat 5640 tttgagttcg tgcagaatag gaataactaa ttcattcaag aatatattac cctgtcagtt 5700 tagcgactat tacctcttta ataatttgca ggggaattat tttagtaata gtaatataca 5760 caagagttat tgattatatg gaaaattata tttagataac atggttaaat gattttatat 5820 tctgtcctta ctcgatatat ttgcataata tctatagtaa tgcctcagat actacatact 5880 attcatctag ccaaacaaaa gggcgcgatg ctcataaaag tatcgataaa ggaatctata 5940 gtaccaaaaa agatgacctg atcggtatcg atgttattaa ccataaatat ggtttggttg 6000 gtaaaattga tgtttttcat aaagataagg gcttacttgt ggagagaaaa aggcaaatca 6060 agactatcta tgatggctat aaatatcagc tttatgcgca atatttttgt ctccaagaga 6120 tgggctatga tgtcaaagcc attaaatttt attcgatggt tgataataaa tcatacccaa 6180 tagctatacc aacttcagct gagttagaaa agtttgaaaa acatattcaa acaatcaagc 6240 aatataatcc aatggataac tcatttaggc aaaatattga aaagtgtaaa ttttgtatat 6300 atgcaaactt atgtgataaa acggacttgt agattatgtt tagtaaaaat gatattgaat 6360 caaagaatat agtttttgtt aatatttttg atggagtgaa acttagtcta tcattgggga 6420 atatagttat aaaagataaa gaaactgatg aggtgaaaac taagctttct gttcataaag 6480 ttcttgcatt gtttatcgta ggtaatatga cgatgacctc gcaactttta gagacctgta 6540 agaaaaatgc tatacagcta gtttttatga aaaatagctt tagaccatat ctatgttttg 6600 gtgatattgc tgaggctaat tttttagcta gatataagca atatagtgta gttgagcaag 6660 atataagttt agcaaggatt tttataacat caaagatacg caatcaacat aacttagtca 6720 aaagcctaag agataaaact ccagagcagc aagagatagt caaaaagaat aaacagctaa 6780 tagcagagtt agaaaataca acaagcctag cggagctaat gggtatagag ggcaatgttg 6840 ccaaaaattt cttcaaagga ttctatggac atttagatag ttggcaaggg cgcaaaccta 6900 gaataaaaca ggatccatat aatgttgttt tagacttggg ctatagtatg ttgtttaatt 6960 ttgtagagtg ttttttgcga ctttttggct ttgatttata caagggcttt tgtcatcaga 7020 cttggtataa gcgtaaatcc ctagtttgtg actttgttga gccatttaga tgtatagtgg 7080 ataaccaagt tagaaaatca tggaatctcg ggcaattttc tgtagaggat tttggttgca 7140 aaaatgagca gttttatata aaaaaagata aaacaaaaga ctactcaaaa atactttttg 7200 ccgagattat cagctacaag ctagagatat ttgaatatgt aagagaattt tatcgtgcct 7260 ttatgcgagg caaagaaatt gcagagtatc caatattttg ttatgaaact aggagggtgt 7320 atgttgatag tcagttatga ttttagtaat aataaagtac gtgcaaagtt tgccaaattt 7380 ctagaaagtt atggtgtacg tttacaatat tcggtatttg agctcaaata tagcaagaga 7440 atgttagact tgattttagc tgagatagaa aataactatg taccactatt tacaaatgct 7500 gatagtgttt taatctttaa tgctccagat aaagatgtga taaaatatgg ttatgcgatt 7560 catagagaac aagaggttgt ttttatagac taaaaattgc aaaccttagt ctttatgtta 7620 aaataactac taagttctta gagatattta aaaatatgac tgttgttata tatcaaaatg 7680 ctaaaaaaat catagatttt aggtcttttt ttgctgattt aggcaaaaac gggtctaaga 7740 actttaaata atttctactg ttgtagatga gaagtcattt aataaggcca ctgttaaaag 7800 tctaagaact ttaaataatt tctactgttg tagatgctac tattcctgtg ccttcagata 7860 attcagtcta agaactttaa ataatttcta ctgttgtaga tgtctagagc cttttgtatt 7920 agtagccggt ctaagaactt taaataattt ctactgttgt agattagcga tttatgaagg 7980 tcattttttt gtctagcttt aatgcggtag tttatcacag ttaaattgct aacgcagtca 8040 ggcaccgtgt atgaaatcta acaatgcgct catcgtcatc ctcggcaccg tcaccctgga 8100 tgctgtaggc ataggcttgg ttatgccggt actgccgggc ctcttgcggg atatcgtcca 8160 ttccgacagc atcgccagtc actatggcgt gctgctagcg ctatatgcgt tgatgcaatt 8220 tctatgcgca cccgttctcg gagcactgtc cgaccgcttt ggccgccgcc cagtcctgct 8280 cgcttcgcta cttggagcca ctatcgacta cgcgatcatg gcgaccacac ccgtcctgtg 8340 gatcctctac gccggacgca tcgtggccgg catcaccggc gccacaggtg cggttgctgg 8400 cgcctatatc gccgacatca ccgatgggga agatcgggct cgccacttcg ggctcatgag 8460 cgcttgtttc ggcgtgggta tggtggcagg ccccgtggcc gggggactgt tgggcgccat 8520 ctccttgcat gcaccattcc ttgcggcggc ggtgctcaac ggcctcaacc tactactggg 8580 ctgcttccta atgcaggagt cgcataaggg agagcgtcga ccgatgccct tgagagcctt 8640 caacccagtc agctccttcc ggtgggcgcg gggcatgact atcgtcgccg cacttatgac 8700 tgtcttcttt atcatgcaac tcgtaggaca ggtgccggca gcgctctggg tcattttcgg 8760 cgaggaccgc tttcgctgga gcgcgacgat gatcggcctg tcgcttgcgg tattcggaat 8820 cttgcacgcc ctcgctcaag ccttcgtcac tggtcccgcc accaaacgtt tcggcgagaa 8880 gcaggccatt atcgccggca tggcggccga cgcgctgggc tacgtcttgc tggcgttcgc 8940 gacgcgaggc tggatggcct tccccattat gattcttctc gcttccggcg gcatcgggat 9000 gcccgcgttg caggccatgc tgtccaggca ggtagatgac gaccatcagg gacagcttca 9060 aggatcgctc gcggctctta ccagcctaac ttcgatcatt ggaccgctga tcgtcacggc 9120 gatttatgcc gcctcggcga gcacatggaa cgggttggca tggattgtag gcgccgccct 9180 ataccttgtc tgcctccccg cgttgcgtcg cggtgcatgg agccgggcca cctcgacctg 9240 aatggaagcc ggcggcacct cgctaacgga ttcaccactc caagaattgg agccaatcaa 9300 ttcttgcgga gaactgtgaa tgcgcaaacc aacccttggc agaacatatc catcgcgtcc 9360 gccatctcca gcagccgcac gcggcgcatc tcgggcagcg ttgggtcctg gccacgggtg 9420 cgcatgatcg tgctcctgtc gttgaggacc cggctaggct ggcggggttg ccttactggt 9480 tagcagaatg aatcaccgat acgcgagcga acgtgaagcg actgctgctg caaaacgtct 9540 gcgacctgag caacaacatg aatggtcttc ggtttccgtg tttcgtaaag tctggaaacg 9600 cggaagtccc ctacgtgctg ctgaagttgc ccgcaacaga gagtggaacc aaccggtgat 9660 accacgatac tatgactgag agtcaacgcc atgagcggcc tcatttctta ttctgagtta 9720 caacagtccg caccgctgtc cggtagctcc ttccggtggg cgcggggcat gactatcgtc 9780 gccgcactta tgactgtctt ctttatcatg caactcgtag gacaggtgcc ggcagcgccc 9840 aacagtcccc cggccacggg gcctgccacc atacccacgc cgaaacaagc gccctgcacc 9900 attatgttcc ggatctgcat cgcaggatgc tgctggctac cctgtggaac acctacatct 9960 gtattaacga agcgctaacc gtttttatca ggctctggga ggcagaataa atgatcatat 10020 cgtcaattat tacctccacg gggagagcct gagcaaactg gcctcaggca tttgagaagc 10080 acacggtcac actgcttccg gtagtcaata aaccggtaaa ccagcaatag acataagcgg 10140 ctatttaacg accctgccct gaaccgacga ccgggtcgaa tttgctttcg aatttctgcc 10200 attcatccgc ttattatcac ttattcaggc gtagcaccag gcgtttaagg gcaccaataa 10260 ctgccttaaa aaaattacgc cccgccctgc cactcatcgc agtactgttg taattcatta 10320 agcattctgc cgacatggaa gccatcacag acggcatgat gaacctgaat cgccagcggc 10380 atcagcacct tgtcgccttg cgtataatat ttgcccatgg tgaaaacggg ggcgaagaag 10440 ttgtccatat tggccacgtt taaatcaaaa ctggtgaaac tcacccaggg attggctgag 10500 acgaaaaaca tattctcaat aaacccttta gggaaatagg ccaggttttc accgtaacac gccacatctt gcgaatatat gtgtagaaac tgccggaaat cgtcgtggta ttcactccag agcgatgaaa acgtttcagt ttgctcatgg aaaacggtgt aacaagggtg aacactatcc catatcacca gctcaccgtc tttcattgcc atacg 10715 <210> 1168 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1168 gccctgcaag gcggtttttt 20 <210> 1169 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1169 catcaaggaa ttgagcttat agaagccata gc 32 <210> 1170 <211> 29 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide

    10560

    10620

    10680 <400> 1170 tgatgctcca agtgatgcaa tcatccaag <210> 1171 <211> 29 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1171 aaccatgtga accagccaca taaaatgtg 29 <210> 1172 <211> 48 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1172 atgtcaattt atcaagaata aatatagttt aagtaaaatg tcagtaaa <210> 1173 <211> 33 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1173 aggagatatt aagttcggtt tgtattagcg aag 33 <210> 1174 <211> 31 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1174 tcgctaatac aaaccgaact taatatctcc t <210> 1175 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1175 taatactatt attggtggta aatttgtaaa tggtg <210> 1176 <211> 26 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1176 tgaggagtgc tactttgagc tagcga <210> 1177 <211> 44 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1177 gattataaaa accttaggat tataaaattt aaagaaaacc ttag <210> 1178 <211> 41 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1178 tatgttcata tgtgtggaat gattttctaa gtatatcttc a <210> 1179 <211> 40 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1179 tgaagatata cttagaaatc attccacaca tatgaacata <210> 1180 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1180 ggtaaaggtg aggcagtatc gtaaa <210> 1181 <211> 26 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1181 ctgggggagt gcttagagct tatcag 26 <210> 1182 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1182 tgccaatggt tcatattggg tggg 24 <210> 1183 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1183 ttagttattc actcaaaata cttagttaaa aatac <210> 1184 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1184 atttttgtct ccaagagatg ggctatga 28 <210> 1185 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1185 taaaaacaga ggttctctac ccgatact 28 <210> 1186 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1186 ggcaagggca cctagaag 18 <210> 1187 <211> 29 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1187 ggttatgcga ttcatagaga acaagaggt <210> 1188 <211> 29 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1188 agacaaaaaa atgaccttca taaatcgct 29 <210> 1189 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1189 tcatacacgg ttgactgcgt t 21 <210> 1190 <211> 3912 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <220>

    <221> CDS <222> (1)..(3909) <400> 1190 gcc acc atg aac atc aaa aac ttt acc ggg ctc tac ccc ctc agc aaa

    Ala Thr Met Asn Ile Lys Asn Phe Thr Gly Leu Tyr Pro Leu Ser Lys

    1 5 10 15 act ttg cgc ttt gaa ctc aag cct att ggc aaa acc aag gaa aac atc 96 Thr Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Lys Glu Asn Ile

    20 25 30 gag aaa aat ggc atc ctg acc aag gac gag caa cgg gct aaa gac tac 144

    Glu Lys Asn Gly Ile Leu Thr Lys Asp Glu Gln Arg Ala Lys Asp Tyr

    35 40 45 ctc ata gtc aaa ggc ttt att gac gag tat cac aag cag ttc atc aaa 192

    Leu Ile Val Lys Gly Phe Ile Asp Glu Tyr His Lys Gln Phe Ile Lys

    50 55 60 gac agg ctt tgg gac ttt aaa ttg cct ctc gaa agt gag ggg gag aag 240 Asp Arg Leu Trp Asp Phe Lys Leu Pro Leu Glu Ser Glu Gly Glu Lys 65 70 75 80 aac agt ctc gaa gaa tac cag gaa ctg tac gag ctc act aag cgc aac 288 Asn Ser Leu Glu Glu Tyr Gln Glu Leu Tyr Glu Leu Thr Lys Arg Asn

    85 90 95 gat gcc cag gag gcc gac ttc acc gag att aaa gat aac ctt cgc agc 336 Asp Ala Gln Glu Ala Asp Phe Thr Glu Ile Lys Asp Asn Leu Arg Ser

    100 105 110 tct att acc gaa cag ctc acg aag tct gga tct gcg tac gat cgg att 384 Ser Ile Thr Glu Gln Leu Thr Lys Ser Gly Ser Ala Tyr Asp Arg Ile

    115 120 125 ttt aaa aaa gag ttc att aga gaa gac ctg gtc aac ttc ctc gaa gat 432 Phe Lys Lys Glu Phe Ile Arg Glu Asp Leu Val Asn Phe Leu Glu Asp

    130 135 140 gaa aaa gat aaa aat atc gtg aaa cag ttc gag gac ttt act aca tat 480 Glu Lys Asp Lys Asn Ile Val Lys Gln Phe Glu Asp Phe Thr Thr Tyr 145 150 155 160 ttt acg ggt ttt tat gaa aat agg aag aac atg tac tct agc gaa gag 528 Phe Thr Gly Phe Tyr Glu Asn Arg Lys Asn Met Tyr Ser Ser Glu Glu

    165 170 175 aag tcc acg gcc atc gca tac cgg ctt atc cat cag aat ctg cca aaa 576 Lys Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Gln Asn Leu Pro Lys

    180 185 190 ttc atg gac aac atg aga agt ttt gcc aaa att gca aat tcc agt gtt 624 Phe Met Asp Asn Met Arg Ser Phe Ala Lys Ile Ala Asn Ser Ser Val

    195 200 205 tcc gag cac ttt agc gac atc tat gaa agc tgg aag gaa tat ctg aat 672 Ser Glu His Phe Ser Asp Ile Tyr Glu Ser Trp Lys Glu Tyr Leu Asn

    210 215 220 gta aat agc atc gag gaa atc ttc cag ctc gac tat ttt agc gaa acc 720 Val Asn Ser Ile Glu Glu Ile Phe Gln Leu Asp Tyr Phe Ser Glu Thr 225 230 235 240 ttg act cag cca cat att gag gtg tat aac tat att atc ggg aag aaa 768 Leu Thr Gln Pro His Ile Glu Val Tyr Asn Tyr Ile Ile Gly Lys Lys

    245 250 255 gtc ctg gaa gac gga acc gag ata aag ggc atc aac gag tat gtg aac 816 Val Leu Glu Asp Gly Thr Glu Ile Lys Gly Ile Asn Glu Tyr Val Asn

    260 265 270 ctc tac aat cag cag cag aaa gat aag agt aaa cga ctg cct ttc ctg 864 Leu Tyr Asn Gln Gln Gln Lys Asp Lys Ser Lys Arg Leu Pro Phe Leu

    275 280 285 gtg cca ctg tat aag caa att ttg tct gat agg gaa aaa ctc tcc tgg 912 Val Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Lys Leu Ser Trp

    290 295 300 att gct gaa gag ttc gac agc gac aag aag atg ctg agc gct atc acc 960 Ile Ala Glu Glu Phe Asp Ser Asp Lys Lys Met Leu Ser Ala Ile Thr 305 310 315 320 gag tct tac aac cac ctg cac aac gtg ttg atg ggt aac gag aac gaa 1008 Glu Ser Tyr Asn His Leu His Asn Val Leu Met Gly Asn Glu Asn Glu

    325 330 335 agc ctg cga aat ctg ctg ctg aat att aag gac tat aac ctg gag aaa 1056 Ser Leu Arg Asn Leu Leu Leu Asn Ile Lys Asp Tyr Asn Leu Glu Lys

    340 345 350 att aat atc aca aac gac ttg tct ctc acc gaa atc tcc cag aat ctt 1104 Ile Asn Ile Thr Asn Asp Leu Ser Leu Thr Glu Ile Ser Gln Asn Leu

    355 360 365 ttt ggc cga tat gat gta ttc aca aat ggg atc aaa aac aag ctg aga 1152

    Phe Gly Arg Tyr Asp Val Phe Thr Asn Gly Ile Lys Asn Lys Leu Arg 370 375 380 gtg ttg act cca agg aag aaa aag gag acg gac gaa aat ttt gag gac 1200 Val Leu Thr Pro Arg Lys Lys Lys Glu Thr Asp Glu Asn Phe Glu Asp 385 390 395 400 cgc att aac aaa att ttt aag acc cag aag tcc ttc agc atc gct ttt 1248 Arg Ile Asn Lys Ile Phe Lys Thr Gln Lys Ser Phe Ser Ile Ala Phe

    405 410 415 ctg aac aag ctg cct cag ccc gaa atg gag gat ggg aag ccc cgg aac 1296 Leu Asn Lys Leu Pro Gln Pro Glu Met Glu Asp Gly Lys Pro Arg Asn

    420 425 430 att gag gac tat ttc att aca cag ggg gcg att aac acc aaa tct ata 1344

    Ile Glu Asp Tyr Phe Ile Thr Gln Gly Ala Ile Asn Thr Lys Ser Ile

    435 440 445 cag aaa gaa gat atc ttc gcc caa att gag aat gca tac gag gat gca 1392

    Gln Lys Glu Asp Ile Phe Ala Gln Ile Glu Asn Ala Tyr Glu Asp Ala

    450 455 460 cag gtg ttc ctg caa att aag gac acc gac aac aaa ctt agc cag aac 1440 Gln Val Phe Leu Gln Ile Lys Asp Thr Asp Asn Lys Leu Ser Gln Asn 465 470 475 480 aag acg gcg gtg gaa aag atc aaa act ttg ctg gac gcc ttg aag gaa 1488 Lys Thr Ala Val Glu Lys Ile Lys Thr Leu Leu Asp Ala Leu Lys Glu

    485 490 495 ctc cag cac ttc atc aaa ccg ctg ctg ggc tct ggg gag gag aac gag 1536 Leu Gln His Phe Ile Lys Pro Leu Leu Gly Ser Gly Glu Glu Asn Glu

    500 505 510 aaa gac gaa ctg ttc tac ggt tcc ttc ctg gcc atc tgg gac gaa ctg 1584 Lys Asp Glu Leu Phe Tyr Gly Ser Phe Leu Ala Ile Trp Asp Glu Leu

    515 520 525 gac acc att aca cca ctt tat aac aaa gtg aga aat tgg ctg acc cga 1632 Asp Thr Ile Thr Pro Leu Tyr Asn Lys Val Arg Asn Trp Leu Thr Arg

    530 535 540 aaa cca tat tca aca gaa aaa atc aaa ttg aat ttc gac aac gct cag 1680 Lys Pro Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Asp Asn Ala Gln

    545

    550

    555

    560 ctg ctg gga ggg tgg gat gtc aat aaa gaa cac gac tgt gca ggt atc 1728 Leu Leu Gly Gly Trp Asp Val Asn Lys Glu His Asp Cys Ala Gly Ile

    565 570 575 ttg ttg cgg aaa aac gat agc tac tat ctc gga att atc aat aag aaa 1776 Leu Leu Arg Lys Asn Asp Ser Tyr Tyr Leu Gly Ile Ile Asn Lys Lys

    580 585 590 acc aac cac atc ttt gat acg gat att acg cca tca gat ggc gag tgc 1824 Thr Asn His Ile Phe Asp Thr Asp Ile Thr Pro Ser Asp Gly Glu Cys

    595 600 605 tat gac aaa atc gac tac aag ctc ctt ccc ggg gcg aac aaa atg ctt 1872 Tyr Asp Lys Ile Asp Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu

    610 615 620 cca aag gtg ttt ttt agt aag tcc cga atc aaa gag ttc gag cca tca 1920 Pro Lys Val Phe Phe Ser Lys Ser Arg Ile Lys Glu Phe Glu Pro Ser 625 630 635 640 gag gcc ata atc aat tgc tat aag aag ggg aca cac aaa aaa gga aaa 1968 Glu Ala Ile Ile Asn Cys Tyr Lys Lys Gly Thr His Lys Lys Gly Lys

    645 650 655 aac ttt aac ctg acg gac tgt cac cgc ctg atc aac ttt ttt aag acc 2016 Asn Phe Asn Leu Thr Asp Cys His Arg Leu Ile Asn Phe Phe Lys Thr

    660 665 670 tca atc gag aaa cac gag gat tgg tca aaa ttc gga ttc aag ttc tcc 2064 Ser Ile Glu Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser

    675 680 685 gat acc gaa acg tat gag gat att agc ggt ttt tat aga gag gtc gag 2112 Asp Thr Glu Thr Tyr Glu Asp Ile Ser Gly Phe Tyr Arg Glu Val Glu

    690 695 700 cag cag gga tac agg ctg acg agc cat cca gtc agt gcc agc tat ata 2160

    Gln Gln Gly Tyr Arg Leu Thr Ser His Pro Val Ser Ala Ser Tyr Ile 705 710 715 720 cat agt ctg gtc aag gaa gga aaa ctg tac ctc ttc caa atc tgg aac 2208

    His Ser Leu Val Lys Glu Gly Lys Leu Tyr Leu Phe Gln Ile Trp Asn

    725 730 735 aag gac ttt tct caa ttc tcc aag ggg acc cct aac ttg cac act ctc 2256 Lys Asp Phe Ser Gln Phe Ser Lys Gly Thr Pro Asn Leu His Thr Leu

    740 745 750 tat tgg aag atg ctg ttt gac aaa cgg aat ctt agc gat gtg gtt tat 2304 Tyr Trp Lys Met Leu Phe Asp Lys Arg Asn Leu Ser Asp Val Val Tyr

    755 760 765 aag ctg aat ggc cag gct gaa gtg ttc tat aga aag agc tcc att gaa 2352 Lys Leu Asn Gly Gln Ala Glu Val Phe Tyr Arg Lys Ser Ser Ile Glu

    770 775 780 cac cag aac cga att atc cac ccc gct cag cat ccc atc aca aat aag 2400

    His Gln Asn Arg Ile Ile His Pro Ala Gln His Pro Ile Thr Asn Lys 785 790 795 800 aat gag ctt aac aaa aag cac act agc acc ttc aaa tac gat atc atc 2448 Asn Glu Leu Asn Lys Lys His Thr Ser Thr Phe Lys Tyr Asp Ile Ile

    805 810 815 aaa gat cgc aga tac acg gtg gat aaa ttc cag ttc cat gtg ccc att 2496 Lys Asp Arg Arg Tyr Thr Val Asp Lys Phe Gln Phe His Val Pro Ile

    820 825 830 act ata aat ttt aag gcg acc ggg cag aac aac atc aac cca atc gtc 2544 Thr Ile Asn Phe Lys Ala Thr Gly Gln Asn Asn Ile Asn Pro Ile Val

    835 840 845 caa gag gtg att cgc caa aac ggt atc acc cac atc ata ggc atc gat 2592

    Gln Glu Val Ile Arg Gln Asn Gly Ile Thr His Ile Ile Gly Ile Asp

    850 855 860 cga ggt gaa cgc cat ctt ctg tac ctc tct ctc atc gat ttg aaa ggc 2640 Arg Gly Glu Arg His Leu Leu Tyr Leu Ser Leu Ile Asp Leu Lys Gly

    865 870 875 880 aac atc atc aag cag atg act ctc aac gaa att att aat gag tat aag 2688

    Asn Ile Ile Lys Gln Met Thr Leu Asn Glu Ile Ile Asn Glu Tyr Lys

    885 890 895 ggt gtg acc tat aag acc aac tac cat aac ctc ctg gag aag agg gag 2736 Gly Val Thr Tyr Lys Thr Asn Tyr His Asn Leu Leu Glu Lys Arg Glu

    900 905 910 aag gag cgg acc gag gcc aga cac tcc tgg agt agt att gaa agc ata 2784

    Lys Glu Arg Thr Glu Ala Arg His Ser Trp Ser Ser Ile Glu Ser Ile

    915 920 925 aaa gaa ctg aag gat gga tac atg tca cag gtg att cac aaa att acg 2832

    Lys Glu Leu Lys Asp Gly Tyr Met Ser Gln Val Ile His Lys Ile Thr

    930 935 940 gac atg atg gtt aag tac aat gcg att gtg gtc ctg gag gac ctc aac 2880 Asp Met Met Val Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 945 950 955 960 ggg ggg ttt atg cga ggc cgc cag aag gtc gag aag cag gtg tac cag 2928 Gly Gly Phe Met Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln

    965 970 975 aaa ttt gaa aaa aag ttg atc gac aag ctg aac tat ctc gtt gac aag 2976 Lys Phe Glu Lys Lys Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys

    980 985 990 aaa ctc gac gct aac gag gtc ggc gga gta ctg aat gct tat cag ctg 3024 Lys Leu Asp Ala Asn Glu Val Gly Gly Val Leu Asn Ala Tyr Gln Leu

    995 1000 1005 acc aac aag ttc gag tct ttc aag aag att ggg aaa caa agc gga 3069 Thr Asn Lys Phe Glu Ser Phe Lys Lys Ile Gly Lys Gln Ser Gly

    1010 1015 1020 ttt ttg ttc tac atc ccc gcc tgg aac aca agc aaa atc gat cct 3114 Phe Leu Phe Tyr Ile Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro

    1025 1030 1035 ata aca ggg ttc gtt aat ctg ttc aac acc agg tac gag tct atc 3159 Ile Thr Gly Phe Val Asn Leu Phe Asn Thr Arg Tyr Glu Ser Ile

    1040 1045 1050 aag gag aca aaa gtt ttt tgg tct aag ttt gat att atc cga tac 3204 Lys Glu Thr Lys Val Phe Trp Ser Lys Phe Asp Ile Ile Arg Tyr

    1055 1060 1065 aat aaa gag aag aat tgg ttc gag ttc gtc ttc gat tac aat acc 3249 Asn Lys Glu Lys Asn Trp Phe Glu Phe Val Phe Asp Tyr Asn Thr

    1070 1075 1080 ttt acg act aaa gcg gag gga aca cgc act aag tgg act ctg tgc 3294

    Phe Thr Thr Lys Ala Glu Gly Thr Arg Thr Lys Trp Thr Leu Cys 1085 1090 1095 acc cac ggc act cgc atc cag aca ttc cgg aac cca gaa aag aat 3339 Thr His Gly Thr Arg Ile Gln Thr Phe Arg Asn Pro Glu Lys Asn

    1100 1105 1110 gcc cag tgg gac aat aaa gag atc aat ttg act gag tcc ttc aaa 3384 Ala Gln Trp Asp Asn Lys Glu Ile Asn Leu Thr Glu Ser Phe Lys

    1115 1120 1125 gct ctg ttt gaa aag tac aag atc gat atc acc agt aat ctc aag 3429 Ala Leu Phe Glu Lys Tyr Lys Ile Asp Ile Thr Ser Asn Leu Lys

    1130 1135 1140 gaa tcc atc atg cag gaa acc gag aag aag ttc ttc cag gaa ctg 3474 Glu Ser Ile Met Gln Glu Thr Glu Lys Lys Phe Phe Gln Glu Leu

    1145 1150 1155 cat aat ctg ctc cac ctg acc ctg cag atg agg aat agc gtt act 3519 His Asn Leu Leu His Leu Thr Leu Gln Met Arg Asn Ser Val Thr

    1160 1165 1170 gga acc gac ata gac tat ttg atc agc ccc gtt gcc gat gag gat 3564 Gly Thr Asp Ile Asp Tyr Leu Ile Ser Pro Val Ala Asp Glu Asp

    1175 1180 1185 gga aat ttc tat gat agt cgc ata aat ggc aaa aat ttt ccg gag 3609 Gly Asn Phe Tyr Asp Ser Arg Ile Asn Gly Lys Asn Phe Pro Glu

    1190 1195 1200 aat gcc gat gcc aat ggc gcg tac aac atc gca cga aag ggt ctg 3654 Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu

    1205 1210 1215 atg ctt att cgg cag atc aag caa gca gat cca cag aag aaa ttc 3699 Met Leu Ile Arg Gln Ile Lys Gln Ala Asp Pro Gln Lys Lys Phe

    1220 1225 1230 aag ttt gag aca atc acc aat aaa gac tgg ctg aaa ttc gcc caa 3744 Lys Phe Glu Thr Ile Thr Asn Lys Asp Trp Leu Lys Phe Ala Gln

    1235 1240 1245 gac aag ccc tat ctt aaa gat ggc agc ggg aaa agg ccg gcg gcc 3789 Asp Lys Pro Tyr Leu Lys Asp Gly Ser Gly Lys Arg Pro Ala Ala

    1250

    1255

    1260 acg aaa aag gcc ggc cag gca aaa aag aaa aag gga tcc tac cca 3834 Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro

    1265 1270 1275 tac gat gtt cca gat tac gct tat ccc tac gac gtg cct gat tat 3879 Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr

    1280 1285 1290 gca tac cca tac gat gtc ccc gac tat gcc taa 3912

    Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala

    1295 1300 <210> 1191 <211> 1303 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1191

    Ala Thr Met Asn Ile Lys Asn Phe Thr Gly Leu Tyr Pro Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Lys Glu Asn Ile 20 25 30

    Glu Lys Asn Gly Ile Leu Thr Lys Asp Glu Gln Arg Ala Lys Asp Tyr 35 40 45

    Leu Ile Val Lys Gly Phe Ile Asp Glu Tyr His Lys Gln Phe Ile Lys 50 55 60

    Asp Arg Leu Trp Asp Phe Lys Leu Pro Leu Glu Ser Glu Gly Glu Lys 65 70 75 80

    Asn Ser Leu Glu Glu Tyr Gln Glu Leu Tyr Glu Leu Thr Lys Arg Asn 85 90 95

    Asp Ala Gln Glu Ala Asp Phe Thr Glu Ile Lys Asp Asn Leu Arg Ser 100 105 110

    Ser Ile Thr Glu Gln Leu Thr Lys Ser Gly Ser Ala Tyr Asp Arg Ile 115 120 125

    Phe Lys Lys Glu Phe Ile Arg Glu Asp Leu Val Asn Phe Leu Glu Asp 130 135 140

    Glu Lys Asp Lys Asn Ile Val Lys Gln Phe Glu Asp Phe Thr Thr Tyr 145 150 155 160

    Phe Thr Gly Phe Tyr Glu Asn Arg Lys Asn Met Tyr Ser Ser Glu Glu 165 170 175

    Lys Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Gln Asn Leu Pro Lys 180 185 190

    Phe Met Asp Asn Met Arg Ser Phe Ala Lys Ile Ala Asn Ser Ser Val 195 200 205

    Ser Glu His Phe Ser Asp Ile Tyr Glu Ser Trp Lys Glu Tyr Leu Asn 210 215 220

    Val Asn Ser Ile Glu Glu Ile Phe Gln Leu Asp Tyr Phe Ser Glu Thr 225 230 235 240

    Leu Thr Gln Pro His Ile Glu Val Tyr Asn Tyr Ile Ile Gly Lys Lys 245 250 255

    Val Leu Glu Asp Gly Thr Glu Ile Lys Gly Ile Asn Glu Tyr Val Asn

    260

    265

    270

    Leu Tyr Asn Gln Gln Gln Lys Asp Lys Ser Lys Arg Leu Pro Phe Leu 275 280 285

    Val Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Lys Leu Ser Trp 290 295 300

    Ile Ala Glu Glu Phe Asp Ser Asp Lys Lys Met Leu Ser Ala Ile Thr 305 310 315 320

    Glu Ser Tyr Asn His Leu His Asn Val Leu Met Gly Asn Glu Asn Glu 325 330 335

    Ser Leu Arg Asn Leu Leu Leu Asn Ile Lys Asp Tyr Asn Leu Glu Lys 340 345 350

    Ile Asn Ile Thr Asn Asp Leu Ser Leu Thr Glu Ile Ser Gln Asn Leu 355 360 365

    Phe Gly Arg Tyr Asp Val Phe Thr Asn Gly Ile Lys Asn Lys Leu Arg 370 375 380

    Val Leu Thr Pro Arg Lys Lys Lys Glu Thr Asp Glu Asn Phe Glu Asp 385 390 395 400

    Arg Ile Asn Lys Ile Phe Lys Thr Gln Lys Ser Phe Ser Ile Ala Phe 405 410 415

    Leu Asn Lys Leu Pro Gln Pro Glu Met Glu Asp Gly Lys Pro Arg Asn 420 425 430

    Ile Glu Asp Tyr Phe Ile Thr Gln Gly Ala Ile Asn Thr Lys Ser Ile 435 440 445

    Gln Lys Glu Asp Ile Phe Ala Gln Ile Glu Asn Ala Tyr Glu Asp Ala 450 455 460

    Gln Val Phe Leu Gln Ile Lys Asp Thr Asp Asn Lys Leu Ser Gln Asn 465 470 475 480

    Lys Thr Ala Val Glu Lys Ile Lys Thr Leu Leu Asp Ala Leu Lys Glu 485 490 495

    Leu Gln His Phe Ile Lys Pro Leu Leu Gly Ser Gly Glu Glu Asn Glu 500 505 510

    Lys Asp Glu Leu Phe Tyr Gly Ser Phe Leu Ala Ile Trp Asp Glu Leu 515 520 525

    Asp Thr Ile Thr Pro Leu Tyr Asn Lys Val Arg Asn Trp Leu Thr Arg 530 535 540

    Lys Pro Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Asp Asn Ala Gln 545 550 555 560

    Leu Leu Gly Gly Trp Asp Val Asn Lys Glu His Asp Cys Ala Gly Ile 565 570 575

    Leu Leu Arg Lys Asn Asp Ser Tyr Tyr Leu Gly Ile Ile Asn Lys Lys 580 585 590

    Thr Asn His Ile Phe Asp Thr Asp Ile Thr Pro Ser Asp Gly Glu Cys 595 600 605

    Tyr Asp Lys Ile Asp Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu 610 615 620

    Pro Lys Val Phe Phe Ser Lys Ser Arg Ile Lys Glu Phe Glu Pro Ser 625 630 635 640

    Glu Ala Ile Ile Asn Cys Tyr Lys Lys Gly Thr His Lys Lys Gly Lys 645 650 655

    Asn Phe Asn Leu Thr Asp Cys His Arg Leu Ile Asn Phe Phe Lys Thr 660 665 670

    Ser Ile Glu Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser 675 680 685

    Asp Thr Glu Thr Tyr Glu Asp Ile Ser Gly Phe Tyr Arg Glu Val Glu 690 695 700

    Gln Gln Gly Tyr Arg Leu Thr Ser His Pro Val Ser Ala Ser Tyr Ile 705 710 715 720

    His Ser Leu Val Lys Glu Gly Lys Leu Tyr Leu Phe Gln Ile Trp Asn 725 730 735

    Lys Asp Phe Ser Gln Phe Ser Lys Gly Thr Pro Asn Leu His Thr Leu 740 745 750

    Tyr Trp Lys Met Leu Phe Asp Lys Arg Asn Leu Ser Asp Val Val Tyr 755 760 765

    Lys Leu Asn Gly Gln Ala Glu Val Phe Tyr Arg Lys Ser Ser Ile Glu 770 775 780

    His Gln Asn Arg Ile Ile His Pro Ala Gln His Pro Ile Thr Asn Lys 785 790 795 800

    Asn Glu Leu Asn Lys Lys His Thr Ser Thr Phe Lys Tyr Asp Ile Ile 805 810 815

    Lys Asp Arg Arg Tyr Thr Val Asp Lys Phe Gln Phe His Val Pro Ile 820 825 830

    Thr Ile Asn Phe Lys Ala Thr Gly Gln Asn Asn Ile Asn Pro Ile Val 835 840 845

    Gln Glu Val Ile Arg Gln Asn Gly Ile Thr His Ile Ile Gly Ile Asp 850 855 860

    Arg Gly Glu Arg His Leu Leu Tyr Leu Ser Leu Ile Asp Leu Lys Gly 865 870 875 880

    Asn Ile Ile Lys Gln Met Thr Leu Asn Glu Ile Ile Asn Glu Tyr Lys 885 890 895

    Gly Val Thr Tyr Lys Thr Asn Tyr His Asn Leu Leu Glu Lys Arg Glu 900 905 910

    Lys Glu Arg Thr Glu Ala Arg His Ser Trp Ser Ser Ile Glu Ser Ile 915 920 925

    Lys Glu Leu Lys Asp Gly Tyr Met Ser Gln Val Ile His Lys Ile Thr 930 935 940

    Asp Met Met Val Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 945 950 955 960

    Gly Gly Phe Met Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln 965 970 975

    Lys Phe Glu Lys Lys Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys

    980

    985

    990

    Lys Leu Asp Ala Asn Glu Val Gly Gly Val Leu Asn Ala Tyr Gln Leu 995 1000 1005

    Thr Asn Lys Phe Glu Ser Phe Lys Lys Ile Gly Lys Gln Ser Gly 1010 1015 1020

    Phe Leu Phe Tyr Ile Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro 1025 1030 1035

    Ile Thr Gly Phe Val Asn Leu Phe Asn Thr Arg Tyr Glu Ser Ile 1040 1045 1050

    Lys Glu Thr Lys Val Phe Trp Ser Lys Phe Asp Ile Ile Arg Tyr 1055 1060 1065

    Asn Lys Glu Lys Asn Trp Phe Glu Phe Val Phe Asp Tyr Asn Thr 1070 1075 1080

    Phe Thr Thr Lys Ala Glu Gly Thr Arg Thr Lys Trp Thr Leu Cys 1085 1090 1095

    Thr His Gly Thr Arg Ile Gln Thr Phe Arg Asn Pro Glu Lys Asn 1100 1105 1110

    Ala Gln Trp Asp Asn Lys Glu Ile Asn Leu Thr Glu Ser Phe Lys 1115 1120 1125

    Ala Leu Phe Glu Lys Tyr Lys Ile Asp Ile Thr Ser Asn Leu Lys 1130 1135 1140

    Glu Ser Ile Met Gln Glu Thr Glu Lys Lys Phe Phe Gln Glu Leu 1145 1150 1155

    His Asn Leu Leu His Leu Thr Leu Gln Met Arg Asn Ser Val Thr 1160 1165 1170

    Gly Thr Asp Ile Asp Tyr Leu Ile Ser Pro Val Ala Asp Glu Asp 1175 1180 1185

    Gly Asn Phe Tyr Asp Ser Arg Ile Asn Gly Lys Asn Phe Pro Glu 1190 1195 1200

    Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1205 1210 1215

    Met Leu Ile Arg Gln Ile Lys Gln Ala Asp Pro Gln Lys Lys Phe 1220 1225 1230

    Lys Phe Glu Thr Ile Thr Asn Lys Asp Trp Leu Lys Phe Ala Gln 1235 1240 1245

    Asp Lys Pro Tyr Leu Lys Asp Gly Ser Gly Lys Arg Pro Ala Ala 1250 1255 1260

    Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gly Ser Tyr Pro 1265 1270 1275

    Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp Tyr 1280 1285 1290

    Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1295 1300 <210> 1192 <211> 112 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <220>

    <221> modified_base <222> (30)..(37) <223> a, c, t, g, unknown or other <400> 1192 ggccagtgaa ttcgagctcg gtacccgggn nnnnnnngag aagtcattta ataaggccac tgttaaaaag cttggcgtaa tcatggtcat agctgtttcc tgtgtgaaat tg 112 <210> 1193 <211> 112 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <220>

    <221> modified_base <222> (61)..(68) <223> a, c, t, g, unknown or other <400> 1193 ggccagtgaa ttcgagctcg gtacccgggg agaagtcatt taataaggcc actgttaaaa nnnnnnnnag cttggcgtaa tcatggtcat agctgtttcc tgtgtgaaat tg 112 <210> 1194 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1194 ggccagtgaa ttcgagctcg g 21 <210> 1195 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1195 caatttcaca caggaaacag ctatgacc 28 <210> 1196 <211> 81 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1196 aaguucuuag agauauuuaa aaauaugacu guuguuauau aucaaaaugc uaaaaaaauc auagauuuua ggucuuuuuu u 81 <210> 1197 <211> 111 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1197 aattttttag atctacaaaa ttataaacta aataaagatt cttataataa ctttatatat 60 aatcgaaatg tagagaattt tataaggagt ctttatcatg tcaatttatc a 111 <210> 1198 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1198 aaaattataa actaaataaa gattcttata ataactttat atataatcga aatgtagaga attttataag gagtctt 77 <210> 1199 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1199 aaaattataa actaaataaa gattcttata ataactttat atataatcga aatgtagaga attttataag gagtctt 77 <210> 1200 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1200 aaaattataa actaaataaa gattcttata ataactttat atataatcga aatgtagaga 60 attttataag gagtctt <210> 1201 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1201 aaattataaa ctaaataaag attcttataa taactttata tataatcgaa atgtagagaa ttttataagg agtcttt 77 <210> 1202 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1202 aattttttag atct 14 <210> 1203 <211> 77 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1203 aaaauuauaa acuaaauaaa gauucuuaua auaacuuuau auauaaucga auguagagaa 60 auuuuauaag gagucuu <210> 1204 <211> 44 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <220>

    <221> MOD_RES <222> (16)..(16) <223> Any amino acid <400> 1204

    Pro Tyr Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Lys Xaa 1 5 10 15

    Leu Phe Ser Glu Arg Asn Leu Lys Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Ile Phe Tyr Arg Lys Lys Ser Ile Lys 35 40 <210> 1205 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1205 actttaaata atttctactg ttgtagatga gaagtcattt aataaggcca ctgttaaaag tctaagaact ttaaata <210> 1206 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1206 ctactattcc tgtgccttca gataattcag tctaagaact ttaaataatt tctactgttg tagatgtcta gagcctt 77 <210> 1207 <211> 103 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1207 gtctaagaac tttaaataat ttctactgtt gtagatgaga agtcatttaa taaggccact gttaaaagtc taagaacttt aaataatttc tactgttgta gat 103 <210> 1208 <211> 149 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1208 ctgatttagg caaaaacggg tctaagaact ttaaataatt tctactgttg tagatgagaa gtcatttaat aaggccactg ttaaaagtct aagaacttta aataatttct actgttgtag 120 atgctactat tcctgtgcct tcagataat

    149 <210> 1209 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1209 ttagagaagt catttaataa ggccactgtt aaaa 34 <210> 1210 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1210 acuuuaaaua auuucuacug uuguagau 28 <210> 1211 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1211 gagaagucau uuaauaaggc cacuguuaaa aagcu <210> 1212 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1212 gucuaagaac uuuaaau 17 <210> 1213 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1213 acuuuaaaua auuucuacug uuguagau <210> 1214 <211> 31 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1214 gagaagucau uuaauaaggc cacuguuaaa a <210> 1215 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1215 gucuaagaac uuuaaau <210> 1216 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1216 acuuuaaaua auuucuacug uuguagau <210> 1217 <211> 30 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1217 gagaagucau uuaauaaggc cacuguuaaa <210> 1218 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1218 gucuaagaac uuuaaau 17 <210> 1219 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1219 acuuuaaaua auuucuacug uuguagau <210> 1220 <211> 27 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1220 gagaagucau uuaauaaggccacuguu <210> 1221 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1221 gucuaagaac uuuaaau 17 <210> 1222 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1222 acuuuaaaua auuucuacug uuguagau <210> 1223 <211> 24 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1223 gagaagucau uuaauaaggc cacu 24 <210> 1224 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1224 gucuaagaac uuuaaau 17 <210> 1225 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1225 acuuuaaaua auuucuacug uuguagau <210> 1226 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1226 gagaagucau uuaauaaggc 20 <210> 1227 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1227 gucuaagaac uuuaaau 17 <210> 1228 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1228 acuuuaaaua auuucuacug uuguagau <210> 1229 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1229 gagaagucau uuaauaa 17 <210> 1230 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1230 gucuaagaac uuuaaau 17 <210> 1231 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1231 acuuuaaaua auuucuacug uuguagau <210> 1232 <211> 14 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1232 gagaagucau uuaa <210> 1233 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1233 gucuaagaac uuuaaau 17 <210> 1234 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1234 acuuuaaaua auuucuacug uuguagau <210> 1235 <211> 27 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1235 agucauuuaa uaaggccacu guuaaaa <210> 1236 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1236 gucuaagaac uuuaaau 17 <210> 1237 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1237 acuuuaaaua auuucuacug uuguagau 28 <210> 1238 <211> 24 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1238 cauuuaauaa ggccacuguu aaaa 24 <210> 1239 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1239 gucuaagaac uuuaaau <210> 1240 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1240 acuuuaaaua auuucuacug uuguagau <210> 1241 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1241 uaauaaggcc acuguuaaaa 20 <210> 1242 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1242 gucuaagaac uuuaaau 17 <210> 1243 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1243 acuuuaaaua auuucuacug uuguagau <210> 1244 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1244 uaaggccacu guuaaaa 17 <210> 1245 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1245 gucuaagaac uuuaaau 17 <210> 1246 <211> 28 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1246 acuuuaaaua auuucuacug uuguagau <210> 1247 <211> 14 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1247 ggccacuguu aaaa 14 <210> 1248 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1248 gucuaagaac uuuaaau 17 <210> 1249 <211> 103 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1249 gtctaagaac tttaaataat ttctactgtt gtagatgaga agtcatttaa taaggccact gttaaaagtc taagaacttt aaataatttc tactgttgta gat 103 <210> 1250 <211> 3849 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1250 ggtaccatgg attacggcaa cggccagttt gagcggagag cccccctgac caagacaatc 60 accctgcgcc tgaagcctat cggcgagaca cgggagacaa tccgcgagca gaagctgctg 120 gagcaggacg ccgccttcag aaagctggtg gagacagtga cccctatcgt ggacgattgt 180 atcaggaaga tcgccgataa cgccctgtgc cactttggca ccgagtatga cttcagctgt 240 ctgggcaacg ccatctctaa gaatgacagc aaggccatca agaaggagac agagaaggtg 300 gagaagctgc tggccaaggt gctgaccgag aatctgccag atggcctgcg caaggtgaac 360 gacatcaatt ccgccgcctt tatccaggat acactgacct ctttcgtgca ggacgatgcc 420 gacaagcggg tgctgatcca ggagctgaag ggcaagaccg tgctgatgca gcggttcctg 480 accacacgga tcacagccct gaccgtgtgg ctgcccgaca gagtgttcga gaactttaat 540 atcttcatcg agaacgccga gaagatgaga atcctgctgg actcccctct gaatgagaag 600 atcatgaagt ttgacccaga tgccgagcag tacgcctctc tggagttcta tggccagtgc 660 ctgtctcaga aggacatcga tagctacaac ctgatcatct ccggcatcta tgccgacgat 720 gaggtgaaga accctggcat caatgagatc gtgaaggagt acaatcagca gatccggggc 780 gacaaggatg agtccccact gcccaagctg aagaagctgc acaagcagat cctgatgcca 840 gtggagaagg ccttctttgt gcgcgtgctg tctaacgaca gcgatgcccg gagcatcctg 900 gagaagatcc tgaaggacac agagatgctg ccctccaaga tcatcgaggc catgaaggag 960 gcagatgcag gcgacatcgc cgtgtacggc agccggctgc acgagctgag ccacgtgatc 1020 tacggcgatc acggcaagct gtcccagatc atctatgaca aggagtccaa gaggatctct 1080 gagctgatgg agacactgtc tccaaaggag cgcaaggaga gcaagaagcg gctggagggc 1140 ctggaggagc acatcagaaa gtctacatac accttcgacg agctgaacag gtatgccgag 1200 aagaatgtga tggcagcata catcgcagca gtggaggagt cttgtgccga gatcatgaga 1260 aaggagaagg atctgaggac cctgctgagc aaggaggacg tgaagatccg gggcaacaga 1320 cacaatacac tgatcgtgaa gaactacttt aatgcctgga ccgtgttccg gaacctgatc 1380 agaatcctga ggcgcaagtc cgaggccgag atcgactctg acttctacga tgtgctggac 1440 gattccgtgg aggtgctgtc tctgacatac aagggcgaga atctgtgccg cagctatatc 1500 accaagaaga tcggctccga cctgaagccc gagatcgcca catacggcag cgccctgagg 1560 cctaacagcc gctggtggtc cccaggagag aagtttaatg tgaagttcca caccatcgtg 1620 cggagagatg gccggctgta ctatttcatc ctgcccaagg gcgccaagcc tgtggagctg 1680 gaggacatgg atggcgacat cgagtgtctg cagatgagaa agatccctaa cccaacaatc 1740 tttctgccca agctggtgtt caaggaccct gaggccttct ttagggataa tccagaggcc 1800 gacgagttcg tgtttctgag cggcatgaag gcccccgtga caatcaccag agagacatac 1860 gaggcctaca ggtataagct gtataccgtg ggcaagctgc gcgatggcga ggtgtccgaa 1920 gaggagtaca agcgggccct gctgcaggtg ctgaccgcct acaaggagtt tctggagaac 1980 agaatgatct atgccgacct gaatttcggc tttaaggatc tggaggagta taaggacagc 2040 tccgagttta tcaagcaggt ggagacacac aacaccttca tgtgctgggc caaggtgtct 2100 agctcccagc tggacgatct ggtgaagtct ggcaacggcc tgctgttcga gatctggagc 2160 gagcgcctgg agtcctacta taagtacggc aatgagaagg tgctgcgggg ctatgagggc 2220 gtgctgctga gcatcctgaa ggatgagaac ctggtgtcca tgcggaccct gctgaacagc 2280 cggcccatgc tggtgtaccg gccaaaggag tctagcaagc ctatggtggt gcaccgggat 2340 ggcagcagag tggtggacag gtttgataag gacggcaagt acatcccccc tgaggtgcac 2400 gacgagctgt atcgcttctt taacaatctg ctgatcaagg agaagctggg cgagaaggcc 2460 cggaagatcc tggacaacaa gaaggtgaag gtgaaggtgc tggagagcga gagagtgaag 2520 tggtccaagt tctacgatga gcagtttgcc gtgaccttca gcgtgaagaa gaacgccgat 2580 tgtctggaca ccacaaagga cctgaatgcc gaagtgatgg agcagtatag cgagtccaac 2640 agactgatcc tgatcaggaa taccacagat atcctgtact atctggtgct ggacaagaat 2700 ggcaaggtgc tgaagcagag atccctgaac atcatcaatg acggcgccag ggatgtggac 2760 tggaaggaga ggttccgcca ggtgacaaag gatagaaacg agggctacaa tgagtgggat 2820 tattccagga cctctaacga cctgaaggag gtgtacctga attatgccct gaaggagatc 2880 gccgaggccg tgatcgagta caacgccatc ctgatcatcg agaagatgtc taatgccttt 2940 aaggacaagt atagcttcct ggacgacgtg accttcaagg gcttcgagac aaagctgctg 3000 gccaagctga gcgatctgca ctttaggggc atcaaggacg gcgagccatg ttccttcaca 3060 aaccccctgc agctgtgcca gaacgattct aataagatcc tgcaggacgg cgtgatcttt 3120 atggtgccaa attctatgac acggagcctg gaccccgaca ccggcttcat ctttgccatc 3180 aacgaccaca atatcaggac caagaaggcc aagctgaact ttctgagcaa gttcgatcag 3240 ctgaaggtgt cctctgaggg ctgcctgatc atgaagtaca gcggcgattc cctgcctaca 3300 cacaacaccg acaatcgcgt gtggaactgc tgttgcaatc acccaatcac aaactatgac 3360 cgggagacaa agaaggtgga gttcatcgag gagcccgtgg aggagctgtc ccgcgtgctg 3420 gaggagaatg gcatcgagac agacaccgag ctgaacaagc tgaatgagcg ggagaacgtg 3480 cctggcaagg tggtggatgc catctactct ctggtgctga attatctgcg cggcacagtg 3540 agcggagtgg caggacagag ggccgtgtac tatagccctg tgaccggcaa gaagtacgat 3600 atctccttta tccaggccat gaacctgaat aggaagtgtg actactatag gatcggctcc 3660 aaggagaggg gagagtggac cgatttcgtg gcccagctga tcaacaaaag gccggcggcc 3720 acgaaaaagg ccggccaggc aaaaaagaaa aagggatcct acccatacga tgttccagat 3780 tacgcttatc cctacgacgt gcctgattat gcatacccat atgatgtccc cgactatgcc 3840 taagaattc

    3849 <210> 1251 <211> 1233 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1251

    Met Asp Tyr Gly Asn Gly Gln Phe Glu Arg Arg Ala Pro Leu Thr Lys 1 5 10 15

    Thr Ile Thr Leu Arg Leu Lys Pro Ile Gly Glu Thr Arg Glu Thr Ile 20 25 30

    Arg Glu Gln Lys Leu Leu Glu Gln Asp Ala Ala Phe Arg Lys Leu Val 35 40 45

    Glu Thr Val Thr Pro Ile Val Asp Asp Cys Ile Arg Lys Ile Ala Asp 50 55 60

    Asn Ala Leu Cys His Phe Gly Thr Glu Tyr Asp Phe Ser Cys Leu Gly 65 70 75 80

    Asn Ala Ile Ser Lys Asn Asp Ser Lys Ala Ile Lys Lys Glu Thr Glu 85 90 95

    Lys Val Glu Lys Leu Leu Ala Lys Val Leu Thr Glu Asn Leu Pro Asp 100 105 110

    Gly Leu Arg Lys Val Asn Asp Ile Asn Ser Ala Ala Phe Ile Gln Asp 115 120 125

    Thr Leu Thr Ser Phe Val Gln Asp Asp Ala Asp Lys Arg Val Leu Ile 130 135 140

    Gln Glu Leu Lys Gly Lys Thr Val Leu Met Gln Arg Phe Leu Thr Thr 145 150 155 160

    Arg Ile Thr Ala Leu Thr Val Trp Leu Pro Asp Arg Val Phe Glu Asn 165 170 175

    Phe Asn Ile Phe Ile Glu Asn Ala Glu Lys Met Arg Ile Leu Leu Asp 180 185 190

    Ser Pro Leu Asn Glu Lys Ile Met Lys Phe Asp Pro Asp Ala Glu Gln 195 200 205

    Tyr Ala Ser Leu Glu Phe Tyr Gly Gln Cys Leu Ser Gln Lys Asp Ile 210 215 220

    Asp Ser Tyr Asn Leu Ile Ile Ser Gly Ile Tyr Ala Asp Asp Glu Val 225 230 235 240

    Lys Asn Pro Gly Ile Asn Glu Ile Val Lys Glu Tyr Asn Gln Gln Ile 245 250 255

    Arg Gly Asp Lys Asp Glu Ser Pro Leu Pro Lys Leu Lys Lys Leu His 260 265 270

    Lys Gln Ile Leu Met Pro Val Glu Lys Ala Phe Phe Val Arg Val Leu 275 280 285

    Ser Asn Asp Ser Asp Ala Arg Ser Ile Leu Glu Lys Ile Leu Lys Asp 290 295 300

    Thr Glu Met Leu Pro Ser Lys Ile Ile Glu Ala Met Lys Glu Ala Asp 305 310 315 320

    Ala Gly Asp Ile Ala Val Tyr Gly Ser Arg Leu His Glu Leu Ser His 325 330 335

    Val Ile Tyr Gly Asp His Gly Lys Leu Ser Gln Ile Ile Tyr Asp Lys 340 345 350

    Glu Ser Lys Arg Ile Ser Glu Leu Met Glu Thr Leu Ser Pro Lys Glu 355 360 365

    Arg Lys Glu Ser Lys Lys Arg Leu Glu Gly Leu Glu Glu His Ile Arg 370 375 380

    Lys Ser Thr Tyr Thr Phe Asp Glu Leu Asn Arg Tyr Ala Glu Lys Asn 385 390 395 400

    Val Met Ala Ala Tyr Ile Ala Ala Val Glu Glu Ser Cys Ala Glu Ile 405 410 415

    Met Arg Lys Glu Lys Asp Leu Arg Thr Leu Leu Ser Lys Glu Asp Val 420 425 430

    Lys Ile Arg Gly Asn Arg His Asn Thr Leu Ile Val Lys Asn Tyr Phe 435 440 445

    Asn Ala Trp Thr Val Phe Arg Asn Leu Ile Arg Ile Leu Arg Arg Lys 450 455 460

    Ser Glu Ala Glu Ile Asp Ser Asp Phe Tyr Asp Val Leu Asp Asp Ser 465 470 475 480

    Val Glu Val Leu Ser Leu Thr Tyr Lys Gly Glu Asn Leu Cys Arg Ser

    485

    490

    495

    Tyr Ile Thr Lys Lys Ile Gly Ser Asp Leu Lys Pro Glu Ile Ala Thr 500 505 510

    Tyr Gly Ser Ala Leu Arg Pro Asn Ser Arg Trp Trp Ser Pro Gly Glu 515 520 525

    Lys Phe Asn Val Lys Phe His Thr Ile Val Arg Arg Asp Gly Arg Leu 530 535 540

    Tyr Tyr Phe Ile Leu Pro Lys Gly Ala Lys Pro Val Glu Leu Glu Asp 545 550 555 560

    Met Asp Gly Asp Ile Glu Cys Leu Gln Met Arg Lys Ile Pro Asn Pro 565 570 575

    Thr Ile Phe Leu Pro Lys Leu Val Phe Lys Asp Pro Glu Ala Phe Phe 580 585 590

    Arg Asp Asn Pro Glu Ala Asp Glu Phe Val Phe Leu Ser Gly Met Lys 595 600 605

    Ala Pro Val Thr Ile Thr Arg Glu Thr Tyr Glu Ala Tyr Arg Tyr Lys 610 615 620

    Leu Tyr Thr Val Gly Lys Leu Arg Asp Gly Glu Val Ser Glu Glu Glu 625 630 635 640

    Tyr Lys Arg Ala Leu Leu Gln Val Leu Thr Ala Tyr Lys Glu Phe Leu 645 650 655

    Glu Asn Arg Met Ile Tyr Ala Asp Leu Asn Phe Gly Phe Lys Asp Leu 660 665 670

    Glu Glu Tyr Lys Asp Ser Ser Glu Phe Ile Lys Gln Val Glu Thr His 675 680 685

    Asn Thr Phe Met Cys Trp Ala Lys Val Ser Ser Ser Gln Leu Asp Asp 690 695 700

    Leu Val Lys Ser Gly Asn Gly Leu Leu Phe Glu Ile Trp Ser Glu Arg 705 710 715 720

    Leu Glu Ser Tyr Tyr Lys Tyr Gly Asn Glu Lys Val Leu Arg Gly Tyr 725 730 735

    Glu Gly Val Leu Leu Ser Ile Leu Lys Asp Glu Asn Leu Val Ser Met 740 745 750

    Arg Thr Leu Leu Asn Ser Arg Pro Met Leu Val Tyr Arg Pro Lys Glu 755 760 765

    Ser Ser Lys Pro Met Val Val His Arg Asp Gly Ser Arg Val Val Asp 770 775 780

    Arg Phe Asp Lys Asp Gly Lys Tyr Ile Pro Pro Glu Val His Asp Glu 785 790 795 800

    Leu Tyr Arg Phe Phe Asn Asn Leu Leu Ile Lys Glu Lys Leu Gly Glu 805 810 815

    Lys Ala Arg Lys Ile Leu Asp Asn Lys Lys Val Lys Val Lys Val Leu 820 825 830

    Glu Ser Glu Arg Val Lys Trp Ser Lys Phe Tyr Asp Glu Gln Phe Ala 835 840 845

    Val Thr Phe Ser Val Lys Lys Asn Ala Asp Cys Leu Asp Thr Thr Lys 850 855 860

    Asp Leu Asn Ala Glu Val Met Glu Gln Tyr Ser Glu Ser Asn Arg Leu 865 870 875 880

    Ile Leu Ile Arg Asn Thr Thr Asp Ile Leu Tyr Tyr Leu Val Leu Asp 885 890 895

    Lys Asn Gly Lys Val Leu Lys Gln Arg Ser Leu Asn Ile Ile Asn Asp 900 905 910

    Gly Ala Arg Asp Val Asp Trp Lys Glu Arg Phe Arg Gln Val Thr Lys 915 920 925

    Asp Arg Asn Glu Gly Tyr Asn Glu Trp Asp Tyr Ser Arg Thr Ser Asn 930 935 940

    Asp Leu Lys Glu Val Tyr Leu Asn Tyr Ala Leu Lys Glu Ile Ala Glu 945 950 955 960

    Ala Val Ile Glu Tyr Asn Ala Ile Leu Ile Ile Glu Lys Met Ser Asn 965 970 975

    Ala Phe Lys Asp Lys Tyr Ser Phe Leu Asp Asp Val Thr Phe Lys Gly 980 985 990

    Phe Glu Thr Lys Leu Leu Ala Lys Leu Ser Asp Leu His Phe Arg Gly 995 1000 1005

    Ile Lys Asp Gly Glu Pro Cys Ser Phe Thr Asn Pro Leu Gln Leu 1010 1015 1020

    Cys Gln Asn Asp Ser Asn Lys Ile Leu Gln Asp Gly Val Ile Phe 1025 1030 1035

    Met Val Pro Asn Ser Met Thr Arg Ser Leu Asp Pro Asp Thr Gly 1040 1045 1050

    Phe Ile Phe Ala Ile Asn Asp His Asn Ile Arg Thr Lys Lys Ala 1055 1060 1065

    Lys Leu Asn Phe Leu Ser Lys Phe Asp Gln Leu Lys Val Ser Ser 1070 1075 1080

    Glu Gly Cys Leu Ile Met Lys Tyr Ser Gly Asp Ser Leu Pro Thr 1085 1090 1095

    His Asn Thr Asp Asn Arg Val Trp Asn Cys Cys Cys Asn His Pro 1100 1105 1110

    Ile Thr Asn Tyr Asp Arg Glu Thr Lys Lys Val Glu Phe Ile Glu 1115 1120 1125

    Glu Pro Val Glu Glu Leu Ser Arg Val Leu Glu Glu Asn Gly Ile 1130 1135 1140

    Glu Thr Asp Thr Glu Leu Asn Lys Leu Asn Glu Arg Glu Asn Val 1145 1150 1155

    Pro Gly Lys Val Val Asp Ala Ile Tyr Ser Leu Val Leu Asn Tyr 1160 1165 1170

    Leu Arg Gly Thr Val Ser Gly Val Ala Gly Gln Arg Ala Val Tyr 1175 1180 1185

    Tyr Ser Pro Val Thr Gly Lys Lys Tyr Asp Ile Ser Phe Ile Gln

    1190

    1195

    1200

    Ala Met Asn Leu Asn Arg Lys Cys Asp Tyr Tyr Arg Ile Gly Ser 1205 1210 1215

    Lys Glu Arg Gly Glu Trp Thr Asp Phe Val Ala Gln Leu Ile Asn 1220 1225 1230 <210> 1252 <211> 3873 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1252 ggtaccatgc tgctgtatga gaactacacc aagcggaatc agatcacaaa gagcctgagg 60 ctggagctgc gccctcaggg caagaccctg agaaacatca aggagctgaa tctgctggag 120 caggacaagg ccatctacgc cctgctggag cggctgaagc cagtgatcga tgagggcatc 180 aaggacatcg ccagagatac cctgaagaac tgcgagctgt cttttgagaa gctgtacgag 240 cacttcctga gcggcgacaa gaaggcctat gccaaggagt ccgagcggct gaagaaggag 300 atcgtgaaaa ccctgatcaa gaacctgccc gagggcatcg gcaagatctc tgagatcaac 360 agcgccaagt atctgaatgg cgtgctgtac gacttcatcg ataagacaca caaggactct 420 gaggagaagc agaatatcct gagcgatatc ctggagacaa agggctacct ggccctgttc 480 tccaagtttc tgacatctcg gatcaccaca ctggagcagt ccatgcctaa gagagtgatc 540 gagaacttcg agatctatgc cgccaatatc ccaaagatgc aggacgccct ggagagggga 600 gccgtgtctt ttgccatcga gtacgagagc atctgttccg tggattacta taaccagatc 660 ctgtcccagg aggacatcga ttcttataat cgcctgatca gcggcatcat ggacgaggat 720 ggcgccaagg agaagggcat caaccagacc atctccgaga agaatatcaa gatcaagtct 780 gagcacctgg aggagaagcc cttcagaatc ctgaagcagc tgcacaagca gatcctggag 840 gagcgcgaga aggcctttac aatcgaccac atcgacagcg atgaggaggt ggtgcaggtg 900 accaaggagg ccttcgagca gacaaaggag cagtgggaga acatcaagaa gatcaatggc 960 ttctacgcca aggaccccgg cgatatcacc ctgtttatcg tggtgggccc taaccagaca 1020 cacgtgctgt cccagctgat ctacggcgag cacgaccgga tcagactgct gctggaggag 1080 tatgagaaga acaccctgga ggtgctgccc cggagaacaa agtctgagaa ggccagatac 1140 gataagttcg tgaatgccgt gcctaagaag gtggccaagg agagccacac cttcgacggc 1200 ctgcagaaga tgacaggcga cgatcggctg tttatcctgt atagagatga gctggcccgg 1260 aactacatga gaatcaagga ggcctatggc acctttgagc gggacatcct gaagagcagg 1320 cgcggcatca agggcaatcg ggacgtgcag gagtctctgg tgagctttta cgatgagctg 1380 acaaagttca ggagcgccct gcgcatcatc aattccggca acgacgagaa ggccgatcca 1440 atcttctata acacctttga tggcatcttc gagaaggcca ataggacata caaggccgag 1500 aatctgtgcc gcaactatgt gaccaagtct ccagccgacg atgccaggat catggccagc 1560 tgtctgggca ccccagcaag gctgcgcaca cactggtgga atggcgagga gaacttcgcc 1620 atcaatgacg tggccatgat ccggagaggc gatgagtact attactttgt gctgacccca 1680 gacgtgaagc ccgtggacct gaaaaccaag gacgagacag atgcccagat cttcgtgcag 1740 cgcaagggcg ccaagtcctt tctgggcctg ccaaaggccc tgttcaagtg catcctggag 1800 ccttactttg agtccccaga gcacaagaat gacaagaact gcgtgatcga ggagtacgtg 1860 tctaagcccc tgaccatcga caggcgcgcc tatgatatct ttaagaacgg caccttcaag 1920 aaaaccaata tcggcatcga cggcctgacc gaggagaagt tcaaggacga ttgccgctat 1980 ctgatcgacg tgtataagga gttcatcgcc gtgtatacaa ggtacagctg ttttaacatg 2040 tccggcctga agcgcgccga cgagtacaat gatatcggcg agttcttttc tgacgtggat 2100 accaggctgt gcacaatgga gtggattccc gtgagcttcg agcgcatcaa cgacatggtg 2160 gataagaagg agggcctgct gtttctggtg aggagcatgt tcctgtataa ccggcccaga 2220 aagccttatg agcgcacctt tatccagctg ttcagcgact ccaacatgga gcacacatct 2280 atgctgctga atagcagggc catgatccag tacagggcag cctccctgcc acggagagtg 2340 acccacaaga agggcagcat cctggtggcc ctgcgggatt ccaacggcga gcacatcccc 2400 atgcacatca gagaggccat ctacaagatg aagaacaatt ttgacatcag ctccgaggat 2460 ttcatcatgg ccaaggccta tctggccgag cacgacgtgg ccatcaagaa ggccaacgag 2520 gatatcatca ggaataggcg ctacaccgag gacaagttct ttctgtctct gagctatacc 2580 aagaacgccg atatcagcgc ccgcacactg gactacatca atgataaggt ggaggaggac 2640 acacaggatt ccaggatggc cgtgatcgtg acccgcaacc tgaaggacct gacatacgtg 2700 gccgtggtgg atgagaagaa caatgtgctg gaggagaaga gcctgaacga gatcgacggc 2760 gtgaattatc gggagctgct gaaggagaga accaagatca agtaccacga caagacacgg 2820 ctgtggcagt atgacgtgag cagcaagggc ctgaaggagg cctacgtgga gctggccgtg 2880 acccagatct ccaagctggc cacaaagtat aacgccgtgg tggtggtgga gtccatgtcc 2940 tctaccttca aggacaagtt ctcttttctg gatgagcaga tcttcaaggc ctttgaggcc 3000 cggctgtgcg ccagaatgtc cgacctgtct tttaatacaa tcaaggaggg cgaggccggc 3060 tccatctcta accccatcca ggtgtccaac aataacggca attcttatca ggacggcgtg 3120 atctacttcc tgaataacgc ctatacccgg accctgtgcc ctgataccgg ctttgtggac 3180 gtgttcgata agacccggct gatcacaatg cagtctaaga gacagttctt tgccaagatg 3240 aaggacatca gaatcgacga tggcgagatg ctgttcacct ttaacctgga ggagtaccct 3300 acaaagaggc tgctggaccg caaggagtgg accgtgaaga tcgccggcga tggctcctat 3360 ttcgacaagg ataagggcga gtacgtgtac gtgaacgaca tcgtgagaga gcagatcatc 3420 ccagccctgc tggaggacaa ggccgtgttc gatggcaata tggccgagaa gtttctggat 3480 aagaccgcca tcagcggcaa gtccgtggag ctgatctaca agtggttcgc caacgccctg 3540 tatggcatca tcacaaagaa ggacggcgag aagatctacc ggagccccat caccggcaca 3600 gagatcgacg tgagcaagaa caccacatac aacttcggca agaagttcat gttcaagcag 3660 gagtatagag gcgacggcga ttttctggac gccttcctga attacatgca ggcccaggat 3720 atcgccgtga aaaggccggc ggccacgaaa aaggccggcc aggcaaaaaa gaaaaaggga 3780 tcctacccat acgatgttcc agattacgct tatccctacg acgtgcctga ttatgcatac 3840 ccatatgatg tccccgacta tgcctaagaa ttc 3873 <210> 1253 <211> 1241 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1253

    Met Leu Leu Tyr Glu Asn Tyr Thr Lys Arg Asn Gln Ile Thr Lys Ser 1 5 10 15

    Leu Arg Leu Glu Leu Arg Pro Gln Gly Lys Thr Leu Arg Asn Ile Lys 20 25 30

    Glu Leu Asn Leu Leu Glu Gln Asp Lys Ala Ile Tyr Ala Leu Leu Glu 35 40 45

    Thr Leu Lys Asn Cys Glu Leu Ser Phe Glu Lys Leu Tyr Glu His Phe 65 70 75 80

    Arg Leu Lys Pro Val Ile Asp Glu Gly Ile Lys Asp Ile Ala Arg Asp

    50 55 60

    Leu Ser Gly Asp Lys Lys Ala Tyr Ala Lys Glu Ser Glu Arg Leu Lys 85 90 95

    Lys Glu Ile Val Lys Thr Leu Ile Lys Asn Leu Pro Glu Gly Ile Gly 100 105 110

    Lys Ile Ser Glu Ile Asn Ser Ala Lys Tyr Leu Asn Gly Val Leu Tyr 115 120 125

    Asp Phe Ile Asp Lys Thr His Lys Asp Ser Glu Glu Lys Gln Asn Ile 130 135 140

    Leu Ser Asp Ile Leu Glu Thr Lys Gly Tyr Leu Ala Leu Phe Ser Lys 145 150 155 160

    Phe Leu Thr Ser Arg Ile Thr Thr Leu Glu Gln Ser Met Pro Lys Arg 165 170 175

    Val Ile Glu Asn Phe Glu Ile Tyr Ala Ala Asn Ile Pro Lys Met Gln 180 185 190

    Asp Ala Leu Glu Arg Gly Ala Val Ser Phe Ala Ile Glu Tyr Glu Ser 195 200 205

    Ile Cys Ser Val Asp Tyr Tyr Asn Gln Ile Leu Ser Gln Glu Asp Ile 210 215 220

    Asp Ser Tyr Asn Arg Leu Ile Ser Gly Ile Met Asp Glu Asp Gly Ala 225 230 235 240

    Lys Glu Lys Gly Ile Asn Gln Thr Ile Ser Glu Lys Asn Ile Lys Ile 245 250 255

    Lys Ser Glu His Leu Glu Glu Lys Pro Phe Arg Ile Leu Lys Gln Leu 260 265 270

    His Lys Gln Ile Leu Glu Glu Arg Glu Lys Ala Phe Thr Ile Asp His 275 280 285

    Ile Asp Ser Asp Glu Glu Val Val Gln Val Thr Lys Glu Ala Phe Glu 290 295 300

    Gln Thr Lys Glu Gln Trp Glu Asn Ile Lys Lys Ile Asn Gly Phe Tyr 305 310 315 320

    Ala Lys Asp Pro Gly Asp Ile Thr Leu Phe Ile Val Val Gly Pro Asn 325 330 335

    Gln Thr His Val Leu Ser Gln Leu Ile Tyr Gly Glu His Asp Arg Ile 340 345 350

    Arg Leu Leu Leu Glu Glu Tyr Glu Lys Asn Thr Leu Glu Val Leu Pro 355 360 365

    Arg Arg Thr Lys Ser Glu Lys Ala Arg Tyr Asp Lys Phe Val Asn Ala 370 375 380

    Val Pro Lys Lys Val Ala Lys Glu Ser His Thr Phe Asp Gly Leu Gln 385 390 395 400

    Lys Met Thr Gly Asp Asp Arg Leu Phe Ile Leu Tyr Arg Asp Glu Leu 405 410 415

    Ala Arg Asn Tyr Met Arg Ile Lys Glu Ala Tyr Gly Thr Phe Glu Arg 420 425 430

    Asp Ile Leu Lys Ser Arg Arg Gly Ile Lys Gly Asn Arg Asp Val Gln 435 440 445

    Glu Ser Leu Val Ser Phe Tyr Asp Glu Leu Thr Lys Phe Arg Ser Ala 450 455 460

    Leu Arg Ile Ile Asn Ser Gly Asn Asp Glu Lys Ala Asp Pro Ile Phe 465 470 475 480

    Tyr Asn Thr Phe Asp Gly Ile Phe Glu Lys Ala Asn Arg Thr Tyr Lys 485 490 495

    Ala Glu Asn Leu Cys Arg Asn Tyr Val Thr Lys Ser Pro Ala Asp Asp 500 505 510

    Ala Arg Ile Met Ala Ser Cys Leu Gly Thr Pro Ala Arg Leu Arg Thr 515 520 525

    His Trp Trp Asn Gly Glu Glu Asn Phe Ala Ile Asn Asp Val Ala Met 530 535 540

    Ile Arg Arg Gly Asp Glu Tyr Tyr Tyr Phe Val Leu Thr Pro Asp Val 545 550 555 560

    Lys Pro Val Asp Leu Lys Thr Lys Asp Glu Thr Asp Ala Gln Ile Phe 565 570 575

    Val Gln Arg Lys Gly Ala Lys Ser Phe Leu Gly Leu Pro Lys Ala Leu 580 585 590

    Phe Lys Cys Ile Leu Glu Pro Tyr Phe Glu Ser Pro Glu His Lys Asn 595 600 605

    Asp Lys Asn Cys Val Ile Glu Glu Tyr Val Ser Lys Pro Leu Thr Ile

    610

    615

    620

    Asp Arg Arg Ala Tyr Asp Ile Phe Lys Asn Gly Thr Phe Lys Lys Thr 625 630 635 640

    Asn Ile Gly Ile Asp Gly Leu Thr Glu Glu Lys Phe Lys Asp Asp Cys 645 650 655

    Arg Tyr Leu Ile Asp Val Tyr Lys Glu Phe Ile Ala Val Tyr Thr Arg 660 665 670

    Tyr Ser Cys Phe Asn Met Ser Gly Leu Lys Arg Ala Asp Glu Tyr Asn 675 680 685

    Asp Ile Gly Glu Phe Phe Ser Asp Val Asp Thr Arg Leu Cys Thr Met 690 695 700

    Glu Trp Ile Pro Val Ser Phe Glu Arg Ile Asn Asp Met Val Asp Lys 705 710 715 720

    Lys Glu Gly Leu Leu Phe Leu Val Arg Ser Met Phe Leu Tyr Asn Arg 725 730 735

    Pro Arg Lys Pro Tyr Glu Arg Thr Phe Ile Gln Leu Phe Ser Asp Ser 740 745 750

    Asn Met Glu His Thr Ser Met Leu Leu Asn Ser Arg Ala Met Ile Gln 755 760 765

    Tyr Arg Ala Ala Ser Leu Pro Arg Arg Val Thr His Lys Lys Gly Ser 770 775 780

    Ile Leu Val Ala Leu Arg Asp Ser Asn Gly Glu His Ile Pro Met His 785 790 795 800

    Ile Arg Glu Ala Ile Tyr Lys Met Lys Asn Asn Phe Asp Ile Ser Ser 805 810 815

    Glu Asp Phe Ile Met Ala Lys Ala Tyr Leu Ala Glu His Asp Val Ala 820 825 830

    Ile Lys Lys Ala Asn Glu Asp Ile Ile Arg Asn Arg Arg Tyr Thr Glu 835 840 845

    Asp Lys Phe Phe Leu Ser Leu Ser Tyr Thr Lys Asn Ala Asp Ile Ser 850 855 860

    Ala Arg Thr Leu Asp Tyr Ile Asn Asp Lys Val Glu Glu Asp Thr Gln 865 870 875 880

    Asp Ser Arg Met Ala Val Ile Val Thr Arg Asn Leu Lys Asp Leu Thr 885 890 895

    Tyr Val Ala Val Val Asp Glu Lys Asn Asn Val Leu Glu Glu Lys Ser 900 905 910

    Leu Asn Glu Ile Asp Gly Val Asn Tyr Arg Glu Leu Leu Lys Glu Arg 915 920 925

    Thr Lys Ile Lys Tyr His Asp Lys Thr Arg Leu Trp Gln Tyr Asp Val 930 935 940

    Ser Ser Lys Gly Leu Lys Glu Ala Tyr Val Glu Leu Ala Val Thr Gln 945 950 955 960

    Ile Ser Lys Leu Ala Thr Lys Tyr Asn Ala Val Val Val Val Glu Ser 965 970 975

    Met Ser Ser Thr Phe Lys Asp Lys Phe Ser Phe Leu Asp Glu Gln Ile 980 985 990

    Phe Lys Ala Phe Glu Ala Arg Leu Cys Ala Arg Met Ser Asp Leu Ser 995 1000 1005

    Phe Asn Thr Ile Lys Glu Gly Glu Ala Gly Ser Ile Ser Asn Pro 1010 1015 1020

    Ile Gln Val Ser Asn Asn Asn Gly Asn Ser Tyr Gln Asp Gly Val 1025 1030 1035

    Ile Tyr Phe Leu Asn Asn Ala Tyr Thr Arg Thr Leu Cys Pro Asp 1040 1045 1050

    Thr Gly Phe Val Asp Val Phe Asp Lys Thr Arg Leu Ile Thr Met 1055 1060 1065

    Gln Ser Lys Arg Gln Phe Phe Ala Lys Met Lys Asp Ile Arg Ile 1070 1075 1080

    Asp Asp Gly Glu Met Leu Phe Thr Phe Asn Leu Glu Glu Tyr Pro 1085 1090 1095

    Thr Lys Arg Leu Leu Asp Arg Lys Glu Trp Thr Val Lys Ile Ala 1100 1105 1110

    Gly Asp Gly Ser Tyr Phe Asp Lys Asp Lys Gly Glu Tyr Val Tyr 1115 1120 1125

    Val Asn Asp Ile Val Arg Glu Gln Ile Ile Pro Ala Leu Leu Glu 1130 1135 1140

    Asp Lys Ala Val Phe Asp Gly Asn Met Ala Glu Lys Phe Leu Asp 1145 1150 1155

    Lys Thr Ala Ile Ser Gly Lys Ser Val Glu Leu Ile Tyr Lys Trp 1160 1165 1170

    Phe Ala Asn Ala Leu Tyr Gly Ile Ile Thr Lys Lys Asp Gly Glu 1175 1180 1185

    Lys Ile Tyr Arg Ser Pro Ile Thr Gly Thr Glu Ile Asp Val Ser 1190 1195 1200

    Lys Asn Thr Thr Tyr Asn Phe Gly Lys Lys Phe Met Phe Lys Gln 1205 1210 1215

    Glu Tyr Arg Gly Asp Gly Asp Phe Leu Asp Ala Phe Leu Asn Tyr 1220 1225 1230

    Met Gln Ala Gln Asp Ile Ala Val 1235 1240 <210> 1254 <211> 4581 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1254 ggtaccatgt ccaacttctt taagaatttc accaacctgt atgagctgtc caagacactg 60 aggtttgagc tgaagcccgt gggcgacacc ctgacaaaca tgaaggacca cctggagtac 120 gatgagaagc tgcagacctt cctgaaggat cagaatatcg acgatgccta tcaggccctg 180 aagcctcagt tcgacgagat ccacgaggag tttatcacag attctctgga gagcaagaag 240 gccaaggaga tcgacttctc cgagtacctg gatctgtttc aggagaagaa ggagctgaac 300 gactctgaga agaagctgcg caacaagatc ggcgagacat tcaacaaggc cggcgagaag 360 tggaagaagg agaagtaccc tcagtatgag tggaagaagg gctccaagat cgccaatggc 420 gccgacatcc tgtcttgcca ggatatgctg cagtttatca agtataagaa cccagaggat 480 gagaagatca agaattacat cgacgataca ctgaagggct tctttaccta tttcggcggc 540 tttaatcaga acagggccaa ctactatgag acaaagaagg aggcctccac cgcagtggca 600 acaaggatcg tgcacgagaa cctgccaaag ttctgtgaca atgtgatcca gtttaagcac 660 atcatcaagc ggaagaagga tggcaccgtg gagaaaaccg agagaaagac cgagtacctg 720 aacgcctacc agtatctgaa gaacaataac aagatcacac agatcaagga cgccgagaca 780 gagaagatga tcgagtctac acccatcgcc gagaagatct tcgacgtgta ctacttcagc 840 agctgcctga gccagaagca gatcgaggag tacaaccgga tcatcggcca ctataatctg 900 ctgatcaacc tgtataacca ggccaagaga tctgagggca agcacctgag cgccaacgag 960 aagaagtata aggacctgcc taagttcaag accctgtata agcagatcgg ctgcggcaag 1020 aagaaggacc tgttttacac aatcaagtgt gataccgagg aggaggccaa taagtcccgg 1080 aacgagggca aggagtccca ctctgtggag gagatcatca acaaggccca ggaggccatc 1140 aataagtact tcaagtctaa taacgactgt gagaatatca acaccgtgcc cgacttcatc 1200 aactatatcc tgacaaagga gaattacgag ggcgtgtatt ggagcaaggc cgccatgaac 1260 accatctccg acaagtactt cgccaattat cacgacctgc aggatagact gaaggaggcc 1320 aaggtgtttc agaaggccga taagaagtcc gaggacgata tcaagatccc agaggccatc 1380 gagctgtctg gcctgttcgg cgtgctggac agcctggccg attggcagac cacactgttt 1440 aagtctagca tcctgagcaa cgaggacaag ctgaagatca tcacagattc ccagaccccc 1500 tctgaggccc tgctgaagat gatcttcaat gacatcgaga agaacatgga gtcctttctg 1560 aaggagacaa acgatatcat caccctgaag aagtataagg gcaataagga gggcaccgag 1620 aagatcaagc agtggttcga ctatacactg gccatcaacc ggatgctgaa gtactttctg 1680 gtgaaggaga ataagatcaa gggcaactcc ctggatacca atatctctga ggccctgaaa 1740 accctgatct acagcgacga tgccgagtgg ttcaagtggt acgacgccct gagaaactat 1800 ctgacccaga agcctcagga tgaggccaag gagaataagc tgaagctgaa tttcgacaac 1860 ccatctctgg ccggcggctg ggatgtgaac aaggagtgca gcaatttttg cgtgatcctg 1920 aaggacaaga acgagaagaa gtacctggcc atcatgaaga agggcgagaa taccctgttc 1980 cagaaggagt ggacagaggg ccggggcaag aacctgacaa agaagtctaa tccactgttc 2040 gagatcaata actgcgagat cctgagcaag atggagtatg acttttgggc cgacgtgagc 2100 aagatgatcc ccaagtgtag cacccagctg aaggccgtgg tgaaccactt caagcagtcc 2160 gacaatgagt tcatctttcc tatcggctac aaggtgacaa gcggcgagaa gtttagggag 2220 gagtgcaaga tctccaagca ggacttcgag ctgaataaca aggtgtttaa taagaacgag 2280 ctgagcgtga ccgccatgcg ctacgatctg tcctctacac aggagaagca gtatatcaag 2340 gccttccaga aggagtactg ggagctgctg tttaagcagg agaagcggga caccaagctg 2400 acaaataacg agatcttcaa cgagtggatc aatttttgca acaagaagta tagcgagctg 2460 ctgtcctggg agagaaagta caaggatgcc ctgaccaatt ggatcaactt ctgtaagtac 2520 tttctgagca agtatcccaa gaccacactg ttcaactact cttttaagga gagcgagaat 2580 tataactccc tggacgagtt ctaccgggac gtggatatct gttcttacaa gctgaatatc 2640 aacaccacaa tcaataagag catcctggat agactggtgg aggagggcaa gctgtacctg 2700 tttgagatca agaatcagga cagcaacgat ggcaagtcca tcggccacaa gaataacctg 2760 cacaccatct actggaacgc catcttcgag aattttgaca acaggcctaa gctgaatggc 2820 gaggccgaga tcttctatcg caaggccatc tccaaggata agctgggcat cgtgaagggc 2880 aagaaaacca agaacggcac cgagatcatc aagaattaca gattcagcaa ggagaagttt 2940 atcctgcacg tgccaatcac cctgaacttc tgctccaata acgagtatgt gaatgacatc 3000 gtgaacacaa agttctacaa tttttccaac ctgcactttc tgggcatcga taggggcgag 3060 aagcacctgg cctactattc tctggtgaat aagaacggcg agatcgtgga ccagggcaca 3120 ctgaacctgc ctttcaccga caaggatggc aatcagcgca gcatcaagaa ggagaagtac 3180 ttttataaca agcaggagga caagtgggag gccaaggagg tggattgttg gaattataac 3240 gacctgctgg atgccatggc ctctaaccgg gacatggcca gaaagaattg gcagaggatc 3300 ggcaccatca aggaggccaa gaacggctac gtgagcctgg tcatcaggaa gatcgccgat 3360 ctggccgtga ataacgagcg ccccgccttc atcgtgctgg aggacctgaa tacaggcttt 3420 aagcggtcca gacagaagat cgataagagc gtgtaccaga agttcgagct ggccctggcc 3480 aagaagctga actttctggt ggacaagaat gccaagcgcg atgagatcgg ctcccctaca 3540 aaggccctgc agctgacccc ccctgtgaat aactacggcg acattgagaa caagaagcag 3600 gccggcatca tgctgtatac ccgggccaat tatacctctc agacagatcc agccacaggc 3660 tggagaaaga ccatctatct gaaggccggc cccgaggaga caacatacaa gaaggacggc 3720 aagatcaaga acaagagcgt gaaggaccag atcatcgaga cattcaccga tatcggcttt 3780 gacggcaagg attactattt cgagtacgac aagggcgagt ttgtggatga gaaaaccggc 3840 gagatcaagc ccaagaagtg gcggctgtac tccggcgaga atggcaagtc cctggacagg 3900 ttccgcggag agagggagaa ggataagtat gagtggaaga tcgacaagat cgatatcgtg 3960 aagatcctgg acgatctgtt cgtgaatttt gacaagaaca tcagcctgct gaagcagctg 4020 aaggagggcg tggagctgac ccggaataac gagcacggca caggcgagtc cctgagattc 4080 gccatcaacc tgatccagca gatccggaat accggcaata acgagagaga caacgatttc 4140 atcctgtccc cagtgaggga cgagaatggc aagcactttg actctcgcga gtactgggat 4200 aaggagacaa agggcgagaa gatcagcatg cccagctccg gcgatgccaa tggcgccttc 4260 aacatcgccc ggaagggcat catcatgaac gcccacatcc tggccaatag cgactccaag 4320 gatctgtccc tgttcgtgtc tgacgaggag tgggatctgc acctgaataa caagaccgag 4380 tggaagaagc agctgaacat cttttctagc aggaaggcca tggccaagcg caagaagaaa 4440 aggccggcgg ccacgaaaaa ggccggccag gcaaaaaaga aaaagggatc ctacccatac 4500 gatgttccag attacgctta tccctacgac gtgcctgatt atgcataccc atatgatgtc 4560 cccgactatg cctaagaatt c 4581 <210> 1255 <211> 1477 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1255

    Met Ser Asn Phe Phe Lys Asn Phe Thr Asn Leu Tyr Glu Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Asp Thr Leu Thr Asn Met 20 25 30

    Lys Asp His Leu Glu Tyr Asp Glu Lys Leu Gln Thr Phe Leu Lys Asp 35 40 45

    Gln Asn Ile Asp Asp Ala Tyr Gln Ala Leu Lys Pro Gln Phe Asp Glu 50 55 60

    Glu Ile Asp Phe Ser Glu Tyr Leu Asp Leu Phe Gln Glu Lys Lys Glu 85 90 95

    Ile His Glu Glu Phe Ile Thr Asp Ser Leu Glu Ser Lys Lys Ala Lys

    65 70 75 80

    Leu Asn Asp Ser Glu Lys Lys Leu Arg Asn Lys Ile Gly Glu Thr Phe 100 105 110

    Asn Lys Ala Gly Glu Lys Trp Lys Lys Glu Lys Tyr Pro Gln Tyr Glu 115 120 125

    Trp Lys Lys Gly Ser Lys Ile Ala Asn Gly Ala Asp Ile Leu Ser Cys 130 135 140

    Gln Asp Met Leu Gln Phe Ile Lys Tyr Lys Asn Pro Glu Asp Glu Lys 145 150 155 160

    Ile Lys Asn Tyr Ile Asp Asp Thr Leu Lys Gly Phe Phe Thr Tyr Phe 165 170 175

    Gly Gly Phe Asn Gln Asn Arg Ala Asn Tyr Tyr Glu Thr Lys Lys Glu 180 185 190

    Ala Ser Thr Ala Val Ala Thr Arg Ile Val His Glu Asn Leu Pro Lys 195 200 205

    Phe Cys Asp Asn Val Ile Gln Phe Lys His Ile Ile Lys Arg Lys Lys 210 215 220

    Asp Gly Thr Val Glu Lys Thr Glu Arg Lys Thr Glu Tyr Leu Asn Ala 225 230 235 240

    Tyr Gln Tyr Leu Lys Asn Asn Asn Lys Ile Thr Gln Ile Lys Asp Ala 245 250 255

    Glu Thr Glu Lys Met Ile Glu Ser Thr Pro Ile Ala Glu Lys Ile Phe 260 265 270

    Asp Val Tyr Tyr Phe Ser Ser Cys Leu Ser Gln Lys Gln Ile Glu Glu 275 280 285

    Tyr Asn Arg Ile Ile Gly His Tyr Asn Leu Leu Ile Asn Leu Tyr Asn 290 295 300

    Gln Ala Lys Arg Ser Glu Gly Lys His Leu Ser Ala Asn Glu Lys Lys 305 310 315 320

    Tyr Lys Asp Leu Pro Lys Phe Lys Thr Leu Tyr Lys Gln Ile Gly Cys 325 330 335

    Gly Lys Lys Lys Asp Leu Phe Tyr Thr Ile Lys Cys Asp Thr Glu Glu 340 345 350

    Glu Ala Asn Lys Ser Arg Asn Glu Gly Lys Glu Ser His Ser Val Glu 355 360 365

    Glu Ile Ile Asn Lys Ala Gln Glu Ala Ile Asn Lys Tyr Phe Lys Ser 370 375 380

    Asn Asn Asp Cys Glu Asn Ile Asn Thr Val Pro Asp Phe Ile Asn Tyr 385 390 395 400

    Ile Leu Thr Lys Glu Asn Tyr Glu Gly Val Tyr Trp Ser Lys Ala Ala 405 410 415

    Met Asn Thr Ile Ser Asp Lys Tyr Phe Ala Asn Tyr His Asp Leu Gln 420 425 430

    Asp Arg Leu Lys Glu Ala Lys Val Phe Gln Lys Ala Asp Lys Lys Ser 435 440 445

    Glu Asp Asp Ile Lys Ile Pro Glu Ala Ile Glu Leu Ser Gly Leu Phe 450 455 460

    Gly Val Leu Asp Ser Leu Ala Asp Trp Gln Thr Thr Leu Phe Lys Ser 465 470 475 480

    Ser Ile Leu Ser Asn Glu Asp Lys Leu Lys Ile Ile Thr Asp Ser Gln 485 490 495

    Thr Pro Ser Glu Ala Leu Leu Lys Met Ile Phe Asn Asp Ile Glu Lys 500 505 510

    Asn Met Glu Ser Phe Leu Lys Glu Thr Asn Asp Ile Ile Thr Leu Lys 515 520 525

    Lys Tyr Lys Gly Asn Lys Glu Gly Thr Glu Lys Ile Lys Gln Trp Phe 530 535 540

    Asp Tyr Thr Leu Ala Ile Asn Arg Met Leu Lys Tyr Phe Leu Val Lys 545 550 555 560

    Glu Asn Lys Ile Lys Gly Asn Ser Leu Asp Thr Asn Ile Ser Glu Ala 565 570 575

    Leu Lys Thr Leu Ile Tyr Ser Asp Asp Ala Glu Trp Phe Lys Trp Tyr 580 585 590

    Asp Ala Leu Arg Asn Tyr Leu Thr Gln Lys Pro Gln Asp Glu Ala Lys 595 600 605

    Glu Asn Lys Leu Lys Leu Asn Phe Asp Asn Pro Ser Leu Ala Gly Gly 610 615 620

    Trp Asp Val Asn Lys Glu Cys Ser Asn Phe Cys Val Ile Leu Lys Asp

    625

    630

    635

    640

    Lys Asn Glu Lys Lys Tyr Leu Ala Ile Met Lys Lys Gly Glu Asn Thr 645 650 655

    Leu Phe Gln Lys Glu Trp Thr Glu Gly Arg Gly Lys Asn Leu Thr Lys 660 665 670

    Lys Ser Asn Pro Leu Phe Glu Ile Asn Asn Cys Glu Ile Leu Ser Lys 675 680 685

    Met Glu Tyr Asp Phe Trp Ala Asp Val Ser Lys Met Ile Pro Lys Cys 690 695 700

    Ser Thr Gln Leu Lys Ala Val Val Asn His Phe Lys Gln Ser Asp Asn 705 710 715 720

    Glu Phe Ile Phe Pro Ile Gly Tyr Lys Val Thr Ser Gly Glu Lys Phe 725 730 735

    Arg Glu Glu Cys Lys Ile Ser Lys Gln Asp Phe Glu Leu Asn Asn Lys 740 745 750

    Val Phe Asn Lys Asn Glu Leu Ser Val Thr Ala Met Arg Tyr Asp Leu 755 760 765

    Ser Ser Thr Gln Glu Lys Gln Tyr Ile Lys Ala Phe Gln Lys Glu Tyr 770 775 780

    Trp Glu Leu Leu Phe Lys Gln Glu Lys Arg Asp Thr Lys Leu Thr Asn 785 790 795 800

    Asn Glu Ile Phe Asn Glu Trp Ile Asn Phe Cys Asn Lys Lys Tyr Ser 805 810 815

    Glu Leu Leu Ser Trp Glu Arg Lys Tyr Lys Asp Ala Leu Thr Asn Trp 820 825 830

    Ile Asn Phe Cys Lys Tyr Phe Leu Ser Lys Tyr Pro Lys Thr Thr Leu 835 840 845

    Phe Asn Tyr Ser Phe Lys Glu Ser Glu Asn Tyr Asn Ser Leu Asp Glu 850 855 860

    Phe Tyr Arg Asp Val Asp Ile Cys Ser Tyr Lys Leu Asn Ile Asn Thr 865 870 875 880

    Thr Ile Asn Lys Ser Ile Leu Asp Arg Leu Val Glu Glu Gly Lys Leu 885 890 895

    Tyr Leu Phe Glu Ile Lys Asn Gln Asp Ser Asn Asp Gly Lys Ser Ile 900 905 910

    Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp Asn Ala Ile Phe Glu 915 920 925

    Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu Ala Glu Ile Phe Tyr 930 935 940

    Arg Lys Ala Ile Ser Lys Asp Lys Leu Gly Ile Val Lys Gly Lys Lys 945 950 955 960

    Thr Lys Asn Gly Thr Glu Ile Ile Lys Asn Tyr Arg Phe Ser Lys Glu 965 970 975

    Lys Phe Ile Leu His Val Pro Ile Thr Leu Asn Phe Cys Ser Asn Asn 980 985 990

    Glu Tyr Val Asn Asp Ile Val Asn Thr Lys Phe Tyr Asn Phe Ser Asn 995 1000 1005

    Leu His Phe Leu Gly Ile Asp Arg Gly Glu Lys His Leu Ala Tyr 1010 1015 1020

    Tyr Ser Leu Val Asn Lys Asn Gly Glu Ile Val Asp Gln Gly Thr 1025 1030 1035

    Leu Asn Leu Pro Phe Thr Asp Lys Asp Gly Asn Gln Arg Ser Ile 1040 1045 1050

    Lys Lys Glu Lys Tyr Phe Tyr Asn Lys Gln Glu Asp Lys Trp Glu 1055 1060 1065

    Ala Lys Glu Val Asp Cys Trp Asn Tyr Asn Asp Leu Leu Asp Ala 1070 1075 1080

    Met Ala Ser Asn Arg Asp Met Ala Arg Lys Asn Trp Gln Arg Ile 1085 1090 1095

    Gly Thr Ile Lys Glu Ala Lys Asn Gly Tyr Val Ser Leu Val Ile 1100 1105 1110

    Arg Lys Ile Ala Asp Leu Ala Val Asn Asn Glu Arg Pro Ala Phe 1115 1120 1125

    Ile Val Leu Glu Asp Leu Asn Thr Gly Phe Lys Arg Ser Arg Gln 1130 1135 1140

    Lys Ile Asp Lys Ser Val Tyr Gln Lys Phe Glu Leu Ala Leu Ala 1145 1150 1155

    Lys Lys Leu Asn Phe Leu Val Asp Lys Asn Ala Lys Arg Asp Glu 1160 1165 1170

    Ile Gly Ser Pro Thr Lys Ala Leu Gln Leu Thr Pro Pro Val Asn 1175 1180 1185

    Asn Tyr Gly Asp Ile Glu Asn Lys Lys Gln Ala Gly Ile Met Leu 1190 1195 1200

    Tyr Thr Arg Ala Asn Tyr Thr Ser Gln Thr Asp Pro Ala Thr Gly 1205 1210 1215

    Trp Arg Lys Thr Ile Tyr Leu Lys Ala Gly Pro Glu Glu Thr Thr 1220 1225 1230 Tyr Lys Lys Asp Gly Lys Ile Lys Asn Lys Ser Val Lys Asp Gln 1235 1240 1245 Ile Ile Glu Thr Phe Thr Asp Ile Gly Phe Asp Gly Lys Asp Tyr 1250 1255 1260

    Tyr Phe Glu Tyr Asp Lys Gly Glu Phe Val Asp Glu Lys Thr Gly 1265 1270 1275

    Glu Ile Lys Pro Lys Lys Trp Arg Leu Tyr Ser Gly Glu Asn Gly 1280 1285 1290

    Lys Ser Leu Asp Arg Phe Arg Gly Glu Arg Glu Lys Asp Lys Tyr 1295 1300 1305

    Glu Trp Lys Ile Asp Lys Ile Asp Ile Val Lys Ile Leu Asp Asp 1310 1315 1320

    Leu Phe Val Asn Phe Asp Lys Asn Ile Ser Leu Leu Lys Gln Leu

    1325

    1330

    1335

    Lys Glu Gly Val Glu Leu Thr Arg Asn Asn Glu His Gly Thr Gly 1340 1345 1350

    Glu Ser Leu Arg Phe Ala Ile Asn Leu Ile Gln Gln Ile Arg Asn 1355 1360 1365

    Thr Gly Asn Asn Glu Arg Asp Asn Asp Phe Ile Leu Ser Pro Val 1370 1375 1380

    Arg Asp Glu Asn Gly Lys His Phe Asp Ser Arg Glu Tyr Trp Asp 1385 1390 1395

    Lys Glu Thr Lys Gly Glu Lys Ile Ser Met Pro Ser Ser Gly Asp 1400 1405 1410

    Ala Asn Gly Ala Phe Asn Ile Ala Arg Lys Gly Ile Ile Met Asn 1415 1420 1425

    Ala His Ile Leu Ala Asn Ser Asp Ser Lys Asp Leu Ser Leu Phe 1430 1435 1440

    Val Ser Asp Glu Glu Trp Asp Leu His Leu Asn Asn Lys Thr Glu 1445 1450 1455

    Trp Lys Lys Gln Leu Asn Ile Phe Ser Ser Arg Lys Ala Met Ala 1460 1465 1470

    Lys Arg Lys Lys 1475 <210> 1256 <211> 4206 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1256 ggtaccatgg agaacatctt cgaccagttt atcggcaagt acagcctgtc caagaccctg 60 agattcgagc tgaagcccgt gggcaagaca gaggacttcc tgaagatcaa caaggtgttt 120 gagaaggatc agaccatcga cgatagctac aatcaggcca agttctattt tgattccctg 180 caccagaagt ttatcgacgc cgccctggcc tccgataaga catccgagct gtctttccag 240 aactttgccg acgtgctgga gaagcagaat aagatcatcc tggataagaa gagagagatg 300 ggcgccctga ggaagcgcga caagaacgcc gtgggcatcg ataggctgca gaaggagatc 360 aatgacgccg aggatatcat ccagaaggag aaggagaaga tctacaagga cgtgcgcacc 420 ctgttcgata acgaggccga gtcttggaaa acctactatc aggagcggga ggtggacggc 480 aagaagatca ccttcagcaa ggccgacctg aagcagaagg gcgccgattt tctgacagcc 540 gccggcatcc tgaaggtgct gaagtatgag ttccccgagg agaaggagaa ggagtttcag 600 gccaagaacc agccctccct gttcgtggag gagaaggaga atcctggcca gaagaggtac 660 atcttcgact cttttgataa gttcgccggc tatctgacca agtttcagca gacaaagaag 720 aatctgtacg cagcagacgg caccagcaca gcagtggcca cccgcatcgc cgataacttt 780 atcatcttcc accagaatac caaggtgttc cgggacaagt acaagaacaa tcacacagac 840 ctgggcttcg atgaggagaa catctttgag atcgagaggt ataagaattg cctgctgcag 900 cgcgagatcg agcacatcaa gaatgagaat agctacaaca agatcatcgg ccggatcaat 960 aagaagatca aggagtatcg ggaccagaag gccaaggata ccaagctgac aaagtccgac 1020 ttccctttct ttaagaacct ggataagcag atcctgggcg aggtggagaa ggagaagcag 1080 ctgatcgaga aaacccggga gaaaaccgag gaggacgtgc tgatcgagcg gttcaaggag 1140 ttcatcgaga acaatgagga gaggttcacc gccgccaaga agctgatgaa tgccttctgt 1200 aacggcgagt ttgagtccga gtacgagggc atctatctga agaataaggc catcaacaca 1260 atctcccgga gatggttcgt gtctgacaga gattttgagc tgaagctgcc tcagcagaag 1320 tccaagaaca agtctgagaa gaatgagcca aaggtgaaga agttcatctc catcgccgag 1380 atcaagaacg ccgtggagga gctggacggc gatatcttta aggccgtgtt ctacgacaag 1440 aagatcatcg cccagggcgg ctctaagctg gagcagttcc tggtcatctg gaagtacgag 1500 tttgagtatc tgttccggga catcgagaga gagaacggcg agaagctgct gggctatgat 1560 agctgcctga agatcgccaa gcagctgggc atcttcccac aggagaagga ggcccgcgag 1620 aaggcaaccg ccgtgatcaa gaattacgcc gacgccggcc tgggcatctt ccagatgatg 1680 aagtattttt ctctggacga taaggatcgg aagaacaccc ccggccagct gagcacaaat 1740 ttctacgccg agtatgacgg ctactacaag gatttcgagt ttatcaagta ctacaacgag 1800 tttaggaact tcatcaccaa gaagcctttc gacgaggata agatcaagct gaactttgag 1860 aatggcgccc tgctgaaggg ctgggacgag aacaaggagt acgatttcat gggcgtgatc 1920 ctgaagaagg agggccgcct gtatctgggc atcatgcaca agaaccaccg gaagctgttt 1980 cagtccatgg gcaatgccaa gggcgacaac gccaatagat accagaagat gatctataag 2040 cagatcgccg acgcctctaa ggatgtgccc aggctgctgc tgaccagcaa gaaggccatg 2100 gagaagttca agccttccca ggagatcctg agaatcaaga aggagaaaac cttcaagcgg 2160 gagagcaaga acttttccct gagagatctg cacgccctga tcgagtacta taggaactgc 2220 atccctcagt acagcaattg gtccttttat gacttccagt ttcaggatac cggcaagtac 2280 cagaatatca aggagttcac agacgatgtg cagaagtacg gctataagat ctcctttcgc 2340 gacatcgacg atgagtatat caatcaggcc ctgaacgagg gcaagatgta cctgttcgag 2400 gtggtgaaca aggatatcta taacaccaag aatggctcca agaatctgca cacactgtac 2460 tttgagcaca tcctgtctgc cgagaacctg aatgacccag tgttcaagct gtctggcatg 2520 gccgagatct ttcagcggca gcccagcgtg aacgaaagag agaagatcac cacacagaag 2580 aatcagtgta tcctggacaa gggcgataga gcctacaagt ataggcgcta caccgagaag 2640 aagatcatgt tccacatgag cctggtgctg aacacaggca agggcgagat caagcaggtg 2700 cagtttaata agatcatcaa ccagaggatc agctcctctg acaacgagat gagggtgaat 2760 gtgatcggca tcgatcgcgg cgagaagaac ctgctgtact atagcgtggt gaagcagaat 2820 ggcgagatca tcgagcaggc ctccctgaac gagatcaatg gcgtgaacta ccgggacaag 2880 ctgatcgaga gggagaagga gcgcctgaag aaccggcaga gctggaagcc tgtggtgaag 2940 atcaaggatc tgaagaaggg ctacatctcc cacgtgatcc acaagatctg ccagctgatc 3000 gagaagtatt ctgccatcgt ggtgctggag gacctgaata tgagattcaa gcagatcagg 3060 ggaggaatcg agcggagcgt gtaccagcag ttcgagaagg ccctgatcga taagctgggc 3120 tatctggtgt ttaaggacaa cagggatctg agggcaccag gaggcgtgct gaatggctac 3180 cagctgtctg ccccctttgt gagcttcgag aagatgcgca agcagaccgg catcctgttc 3240 tacacacagg ccgagtatac cagcaagaca gacccaatca ccggctttcg gaagaacgtg 3300 tatatctcta atagcgcctc cctggataag atcaaggagg ccgtgaagaa gttcgacgcc 3360 atcggctggg atggcaagga gcagtcttac ttctttaagt acaaccctta caacctggcc 3420 gacgagaagt ataagaactc taccgtgagc aaggagtggg ccatctttgc cagcgcccca 3480 agaatccgga gacagaaggg cgaggacggc tactggaagt atgatagggt gaaagtgaat 3540 gaggagttcg agaagctgct gaaggtctgg aattttgtga acccaaaggc cacagatatc 3600 aagcaggaga tcatcaagaa ggagaaggca ggcgacctgc agggagagaa ggagctggat 3660 ggccggctga gaaacttttg gcactctttc atctacctgt ttaacctggt gctggagctg 3720 cgcaattctt tcagcctgca gatcaagatc aaggcaggag aagtgatcgc agtggacgag 3780 ggcgtggact tcatcgccag cccagtgaag cccttcttta ccacacccaa cccttacatc 3840 ccctccaacc tgtgctggct ggccgtggag aatgcagacg caaacggagc ctataatatc 3900 gccaggaagg gcgtgatgat cctgaagaag atccgcgagc acgccaagaa ggaccccgag 3960 ttcaagaagc tgccaaacct gtttatcagc aatgcagagt gggacgaggc agcccgggat 4020 tggggcaagt acgcaggcac cacagccctg aacctggacc acaaaaggcc ggcggccacg 4080 aaaaaggccg gccaggcaaa aaagaaaaag ggatcctacc catacgatgt tccagattac 4140 gcttatccct acgacgtgcc tgattatgca tacccatatg atgtccccga ctatgcctaa 4200 gaattc 4206 <210> 1257 <211> 1352 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1257

    Met Glu Asn Ile Phe Asp Gln Phe Ile Gly Lys Tyr Ser Leu Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Glu Asp Phe Leu 20 25 30

    Lys Ile Asn Lys Val Phe Glu Lys Asp Gln Thr Ile Asp Asp Ser Tyr 35 40 45

    Asn Gln Ala Lys Phe Tyr Phe Asp Ser Leu His Gln Lys Phe Ile Asp 50 55 60

    Ala Ala Leu Ala Ser Asp Lys Thr Ser Glu Leu Ser Phe Gln Asn Phe 65 70 75 80

    Ala Asp Val Leu Glu Lys Gln Asn Lys Ile Ile Leu Asp Lys Lys Arg 85 90 95

    Glu Met Gly Ala Leu Arg Lys Arg Asp Lys Asn Ala Val Gly Ile Asp 100 105 110

    Arg Leu Gln Lys Glu Ile Asn Asp Ala Glu Asp Ile Ile Gln Lys Glu 115 120 125

    Lys Glu Lys Ile Tyr Lys Asp Val Arg Thr Leu Phe Asp Asn Glu Ala 130 135 140

    Glu Ser Trp Lys Thr Tyr Tyr Gln Glu Arg Glu Val Asp Gly Lys Lys 145 150 155 160

    Ile Thr Phe Ser Lys Ala Asp Leu Lys Gln Lys Gly Ala Asp Phe Leu 165 170 175

    Thr Ala Ala Gly Ile Leu Lys Val Leu Lys Tyr Glu Phe Pro Glu Glu 180 185 190

    Lys Glu Lys Glu Phe Gln Ala Lys Asn Gln Pro Ser Leu Phe Val Glu 195 200 205

    Glu Lys Glu Asn Pro Gly Gln Lys Arg Tyr Ile Phe Asp Ser Phe Asp 210 215 220

    Lys Phe Ala Gly Tyr Leu Thr Lys Phe Gln Gln Thr Lys Lys Asn Leu 225 230 235 240

    Tyr Ala Ala Asp Gly Thr Ser Thr Ala Val Ala Thr Arg Ile Ala Asp 245 250 255

    Asn Phe Ile Ile Phe His Gln Asn Thr Lys Val Phe Arg Asp Lys Tyr 260 265 270

    Lys Asn Asn His Thr Asp Leu Gly Phe Asp Glu Glu Asn Ile Phe Glu 275 280 285

    Ile Glu Arg Tyr Lys Asn Cys Leu Leu Gln Arg Glu Ile Glu His Ile 290 295 300

    Lys Asn Glu Asn Ser Tyr Asn Lys Ile Ile Gly Arg Ile Asn Lys Lys 305 310 315 320

    Ile Lys Glu Tyr Arg Asp Gln Lys Ala Lys Asp Thr Lys Leu Thr Lys 325 330 335

    Ser Asp Phe Pro Phe Phe Lys Asn Leu Asp Lys Gln Ile Leu Gly Glu 340 345 350

    Val Glu Lys Glu Lys Gln Leu Ile Glu Lys Thr Arg Glu Lys Thr Glu 355 360 365

    Glu Asp Val Leu Ile Glu Arg Phe Lys Glu Phe Ile Glu Asn Asn Glu 370 375 380

    Glu Arg Phe Thr Ala Ala Lys Lys Leu Met Asn Ala Phe Cys Asn Gly 385 390 395 400

    Glu Phe Glu Ser Glu Tyr Glu Gly Ile Tyr Leu Lys Asn Lys Ala Ile 405 410 415

    Asn Thr Ile Ser Arg Arg Trp Phe Val Ser Asp Arg Asp Phe Glu Leu 420 425 430

    Lys Leu Pro Gln Gln Lys Ser Lys Asn Lys Ser Glu Lys Asn Glu Pro

    435

    440

    445

    Lys Val Lys Lys Phe Ile Ser Ile Ala Glu Ile Lys Asn Ala Val Glu 450 455 460

    Glu Leu Asp Gly Asp Ile Phe Lys Ala Val Phe Tyr Asp Lys Lys Ile 465 470 475 480

    Ile Ala Gln Gly Gly Ser Lys Leu Glu Gln Phe Leu Val Ile Trp Lys 485 490 495

    Tyr Glu Phe Glu Tyr Leu Phe Arg Asp Ile Glu Arg Glu Asn Gly Glu 500 505 510

    Lys Leu Leu Gly Tyr Asp Ser Cys Leu Lys Ile Ala Lys Gln Leu Gly 515 520 525

    Ile Phe Pro Gln Glu Lys Glu Ala Arg Glu Lys Ala Thr Ala Val Ile 530 535 540

    Lys Asn Tyr Ala Asp Ala Gly Leu Gly Ile Phe Gln Met Met Lys Tyr 545 550 555 560

    Phe Ser Leu Asp Asp Lys Asp Arg Lys Asn Thr Pro Gly Gln Leu Ser 565 570 575

    Thr Asn Phe Tyr Ala Glu Tyr Asp Gly Tyr Tyr Lys Asp Phe Glu Phe 580 585 590

    Ile Lys Tyr Tyr Asn Glu Phe Arg Asn Phe Ile Thr Lys Lys Pro Phe 595 600 605

    Asp Glu Asp Lys Ile Lys Leu Asn Phe Glu Asn Gly Ala Leu Leu Lys 610 615 620

    Gly Trp Asp Glu Asn Lys Glu Tyr Asp Phe Met Gly Val Ile Leu Lys 625 630 635 640

    Lys Glu Gly Arg Leu Tyr Leu Gly Ile Met His Lys Asn His Arg Lys 645 650 655

    Leu Phe Gln Ser Met Gly Asn Ala Lys Gly Asp Asn Ala Asn Arg Tyr 660 665 670

    Gln Lys Met Ile Tyr Lys Gln Ile Ala Asp Ala Ser Lys Asp Val Pro 675 680 685

    Arg Leu Leu Leu Thr Ser Lys Lys Ala Met Glu Lys Phe Lys Pro Ser 690 695 700

    Gln Glu Ile Leu Arg Ile Lys Lys Glu Lys Thr Phe Lys Arg Glu Ser 705 710 715 720

    Lys Asn Phe Ser Leu Arg Asp Leu His Ala Leu Ile Glu Tyr Tyr Arg 725 730 735

    Asn Cys Ile Pro Gln Tyr Ser Asn Trp Ser Phe Tyr Asp Phe Gln Phe 740 745 750

    Gln Asp Thr Gly Lys Tyr Gln Asn Ile Lys Glu Phe Thr Asp Asp Val 755 760 765

    Gln Lys Tyr Gly Tyr Lys Ile Ser Phe Arg Asp Ile Asp Asp Glu Tyr 770 775 780

    Ile Asn Gln Ala Leu Asn Glu Gly Lys Met Tyr Leu Phe Glu Val Val 785 790 795 800

    Asn Lys Asp Ile Tyr Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr 805 810 815

    Leu Tyr Phe Glu His Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val 820 825 830

    Phe Lys Leu Ser Gly Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val 835 840 845

    Asn Glu Arg Glu Lys Ile Thr Thr Gln Lys Asn Gln Cys Ile Leu Asp 850 855 860

    Lys Gly Asp Arg Ala Tyr Lys Tyr Arg Arg Tyr Thr Glu Lys Lys Ile 865 870 875 880

    Met Phe His Met Ser Leu Val Leu Asn Thr Gly Lys Gly Glu Ile Lys 885 890 895

    Gln Val Gln Phe Asn Lys Ile Ile Asn Gln Arg Ile Ser Ser Ser Asp 900 905 910

    Asn Glu Met Arg Val Asn Val Ile Gly Ile Asp Arg Gly Glu Lys Asn 915 920 925

    Leu Leu Tyr Tyr Ser Val Val Lys Gln Asn Gly Glu Ile Ile Glu Gln 930 935 940

    Ala Ser Leu Asn Glu Ile Asn Gly Val Asn Tyr Arg Asp Lys Leu Ile 945 950 955 960

    Glu Arg Glu Lys Glu Arg Leu Lys Asn Arg Gln Ser Trp Lys Pro Val 965 970 975

    Val Lys Ile Lys Asp Leu Lys Lys Gly Tyr Ile Ser His Val Ile His 980 985 990

    Lys Ile Cys Gln Leu Ile Glu Lys Tyr Ser Ala Ile Val Val Leu Glu 995 1000 1005

    Asp Leu Asn Met Arg Phe Lys Gln Ile Arg Gly Gly Ile Glu Arg 1010 1015 1020

    Ser Val Tyr Gln Gln Phe Glu Lys Ala Leu Ile Asp Lys Leu Gly 1025 1030 1035

    Tyr Leu Val Phe Lys Asp Asn Arg Asp Leu Arg Ala Pro Gly Gly 1040 1045 1050

    Val Leu Asn Gly Tyr Gln Leu Ser Ala Pro Phe Val Ser Phe Glu 1055 1060 1065

    Lys Met Arg Lys Gln Thr Gly Ile Leu Phe Tyr Thr Gln Ala Glu 1070 1075 1080

    Tyr Thr Ser Lys Thr Asp Pro Ile Thr Gly Phe Arg Lys Asn Val 1085 1090 1095

    Tyr Ile Ser Asn Ser Ala Ser Leu Asp Lys Ile Lys Glu Ala Val 1100 1105 1110

    Lys Lys Phe Asp Ala Ile Gly Trp Asp Gly Lys Glu Gln Ser Tyr 1115 1120 1125

    Phe Phe Lys Tyr Asn Pro Tyr Asn Leu Ala Asp Glu Lys Tyr Lys 1130 1135 1140

    Asn Ser Thr Val Ser Lys Glu Trp Ala Ile Phe Ala Ser Ala Pro

    1145

    1150

    1155

    Arg Ile Arg Arg Gln Lys Gly Glu Asp Gly Tyr Trp Lys Tyr Asp 1160 1165 1170

    Arg Val Lys Val Asn Glu Glu Phe Glu Lys Leu Leu Lys Val Trp 1175 1180 1185

    Asn Phe Val Asn Pro Lys Ala Thr Asp Ile Lys Gln Glu Ile Ile 1190 1195 1200

    Lys Lys Glu Lys Ala Gly Asp Leu Gln Gly Glu Lys Glu Leu Asp 1205 1210 1215

    Gly Arg Leu Arg Asn Phe Trp His Ser Phe Ile Tyr Leu Phe Asn 1220 1225 1230

    Leu Val Leu Glu Leu Arg Asn Ser Phe Ser Leu Gln Ile Lys Ile 1235 1240 1245

    Lys Ala Gly Glu Val Ile Ala Val Asp Glu Gly Val Asp Phe Ile 1250 1255 1260

    Ala Ser Pro Val Lys Pro Phe Phe Thr Thr Pro Asn Pro Tyr Ile 1265 1270 1275

    Pro Ser Asn Leu Cys Trp Leu Ala Val Glu Asn Ala Asp Ala Asn 1280 1285 1290

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Val Met Ile Leu Lys Lys 1295 1300 1305

    Ile Arg Glu His Ala Lys Lys Asp Pro Glu Phe Lys Lys Leu Pro 1310 1315 1320

    Asn Leu Phe Ile Ser Asn Ala Glu Trp Asp Glu Ala Ala Arg Asp 1325 1330 1335

    Trp Gly Lys Tyr Ala Gly Thr Thr Ala Leu Asn Leu Asp His 1340 1345 1350 <210> 1258 <211> 3900 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1258 ggtaccatgc agaccctgtt tgagaacttc acaaatcagt acccagtgtc caagaccctg 60 cgctttgagc tgatccccca gggcaagaca aaggacttca tcgagcagaa gggcctgctg 120 aagaaggatg aggaccgggc cgagaagtat aagaaggtga agaacatcat cgatgagtac 180 cacaaggact tcatcgagaa gtctctgaat ggcctgaagc tggacggcct ggagaagtac 240 aagaccctgt atctgaagca ggagaaggac gataaggata agaaggcctt tgacaaggag 300 aaggagaacc tgcgcaagca gatcgccaat gccttccgga acaatgagaa gtttaagaca 360 ctgttcgcca aggagctgat caagaacgat ctgatgtctt tcgcctgcga ggaggacaag 420 aagaatgtga aggagtttga ggccttcacc acatacttca ccggcttcca ccagaaccgc 480 gccaatatgt acgtggccga tgagaagaga acagccatcg ccagcaggct gatccacgag 540 aacctgccaa agtttatcga caatatcaag atcttcgaga agatgaagaa ggaggccccc 600 gagctgctgt ctcctttcaa ccagaccctg aaggatatga aggacgtgat caagggcacc 660 acactggagg agatctttag cctggattat ttcaacaaga ccctgacaca gagcggcatc 720 gacatctaca attccgtgat cggcggcaga acccctgagg agggcaagac aaagatcaag 780 ggcctgaacg agtacatcaa taccgacttc aaccagaagc agacagacaa gaagaagcgg 840 cagccaaagt tcaagcagct gtataagcag atcctgagcg ataggcagag cctgtccttt 900 atcgccgagg ccttcaagaa cgacaccgag atcctggagg ccatcgagaa gttttacgtg 960 aatgagctgc tgcacttcag caatgagggc aagtccacaa acgtgctgga cgccatcaag 1020 aatgccgtgt ctaacctgga gagctttaac ctgaccaaga tgtatttccg ctccggcgcc 1080 tctctgacag acgtgagccg gaaggtgttt ggcgagtgga gcatcatcaa tagagccctg 1140 gacaactact atgccaccac atatccaatc aagcccagag agaagtctga gaagtacgag 1200 gagaggaagg agaagtggct gaagcaggac ttcaacgtga gcctgatcca gaccgccatc 1260 gatgagtacg acaacgagac agtgaagggc aagaacagcg gcaaagtgat cgccgattat 1320 tttgccaagt tctgcgacga taaggagaca gacctgatcc agaaggtgaa cgagggctac 1380 atcgccgtga aggatctgct gaatacaccc tgtcctgaga acgagaagct gggcagcaat 1440 aaggaccagg tgaagcagat caaggccttt atggattcta tcatggacat catgcacttc 1500 gtgcgccccc tgagcctgaa ggataccgac aaggagaagg atgagacatt ctactccctg 1560 ttcacacctc tgtacgacca cctgacccag acaatcgccc tgtataacaa ggtgcggaac 1620 tatctgaccc agaagcctta cagcacagag aagatcaagc tgaacttcga gaacagcacc 1680 ctgctgggcg gctgggatct gaataaggag acagacaaca cagccatcat cctgaggaag 1740 gataacctgt actatctggg catcatggac aagaggcaca atcgcatctt tcggaacgtg 1800 cccaaggccg ataagaagga cttctgctac gagaagatgg tgtataagct gctgcctggc 1860 gccaacaaga tgctgccaaa ggtgttcttt tctcagagca gaatccagga gtttacccct 1920 tccgccaagc tgctggagaa ctacgccaat gagacacaca agaagggcga taatttcaac 1980 ctgaatcact gtcacaagct gatcgatttc tttaaggact ctatcaacaa gcacgaggat 2040 tggaagaatt tcgactttag gttcagcgcc acctccacct acgccgacct gagcggcttt 2100 taccacgagg tggagcacca gggctacaag atctcttttc agagcgtggc cgattccttc 2160 atcgacgatc tggtgaacga gggcaagctg tacctgttcc agatctataa taaggacttt 2220 tccccattct ctaagggcaa gcccaacctg cacaccctgt actggaagat gctgtttgat 2280 gagaacaatc tgaaggacgt ggtgtataag ctgaatggcg aggccgaggt gttctaccgc 2340 aagaagagca ttgccgagaa gaacaccaca atccacaagg ccaatgagtc catcatcaac 2400 aagaatcctg ataacccaaa ggccaccagc accttcaact atgatatcgt gaaggacaag 2460 agatacacca tcgacaagtt tcagttccac atcccaatca caatgaactt taaggccgag 2520 ggcatcttca acatgaatca gagggtgaat cagttcctga aggccaatcc cgatatcaac 2580 atcatcggca tcgacagagg cgagaggcac ctgctgtact atgccctgat caaccagaag 2640 ggcaagatcc tgaagcagga taccctgaat gtgatcgcca acgagaagca gaaggtggac 2700 taccacaatc tgctggataa gaaggagggc gaccgcgcaa ccgcaaggca ggagtggggc 2760 gtgatcgaga caatcaagga gctgaaggag ggctatctgt cccaggtcat ccacaagctg 2820 accgatctga tgatcgagaa caatgccatc atcgtgatgg aggacctgaa ctttggcttc 2880 aagcggggca gacagaaggt ggagaagcag gtgtatcaga agtttgagaa gatgctgatc 2940 gataagctga attacctggt ggacaagaat aagaaggcaa acgagctggg aggcctgctg 3000 aacgcattcc agctggccaa taagtttgag tccttccaga agatgggcaa gcagaacggc 3060 tttatcttct acgtgcccgc ctggaatacc tctaagacag atcctgccac cggctttatc 3120 gacttcctga agccccgcta tgagaacctg aatcaggcca aggatttctt tgagaagttt 3180 gactctatcc ggctgaacag caaggccgat tactttgagt tcgcctttga cttcaagaat 3240 ttcaccgaga aggccgatgg cggcagaacc aagtggacag tgtgcaccac aaacgaggac 3300 agatatgcct ggaatagggc cctgaacaat aacaggggca gccaggagaa gtacgacatc 3360 acagccgagc tgaagtccct gttcgatggc aaggtggact ataagtctgg caaggatctg 3420 aagcagcaga tcgccagcca ggagtccgcc gacttcttta aggccctgat gaagaacctg 3480 tccatcaccc tgtctctgag acacaataac ggcgagaagg gcgataatga gcaggactac 3540 atcctgtccc ctgtggccga ttctaagggc cgcttctttg actcccggaa ggccgacgat 3600 gacatgccaa agaatgccga cgccaacggc gcctatcaca tcgccctgaa gggcctgtgg 3660 tgtctggagc agatcagcaa gaccgatgac ctgaagaagg tgaagctggc catctccaac 3720 aaggagtggc tggagttcgt gcagacactg aagggcaaaa ggccggcggc cacgaaaaag 3780 gccggccagg caaaaaagaa aaagggatcc tacccatacg atgttccaga ttacgcttat 3840 ccctacgacg tgcctgatta tgcataccca tatgatgtcc ccgactatgc ctaagaattc 3900 <210> 1259 <211> 1250 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1259

    Met Gln Thr Leu Phe Glu Asn Phe Thr Asn Gln Tyr Pro Val Ser Lys 1 5 10 15

    Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Lys Asp Phe Ile 20 25 30

    Glu Gln Lys Gly Leu Leu Lys Lys Asp Glu Asp Arg Ala Glu Lys Tyr 35 40 45

    Lys Ser Leu Asn Gly Leu Lys Leu Asp Gly Leu Glu Lys Tyr Lys Thr 65 70 75 80

    Lys Lys Val Lys Asn Ile Ile Asp Glu Tyr His Lys Asp Phe Ile Glu

    50 55 60

    Leu Tyr Leu Lys Gln Glu Lys Asp Asp Lys Asp Lys Lys Ala Phe Asp 85 90 95

    Lys Glu Lys Glu Asn Leu Arg Lys Gln Ile Ala Asn Ala Phe Arg Asn 100 105 110

    Asn Glu Lys Phe Lys Thr Leu Phe Ala Lys Glu Leu Ile Lys Asn Asp 115 120 125

    Leu Met Ser Phe Ala Cys Glu Glu Asp Lys Lys Asn Val Lys Glu Phe 130 135 140

    Glu Ala Phe Thr Thr Tyr Phe Thr Gly Phe His Gln Asn Arg Ala Asn 145 150 155 160

    Met Tyr Val Ala Asp Glu Lys Arg Thr Ala Ile Ala Ser Arg Leu Ile 165 170 175

    His Glu Asn Leu Pro Lys Phe Ile Asp Asn Ile Lys Ile Phe Glu Lys 180 185 190

    Met Lys Lys Glu Ala Pro Glu Leu Leu Ser Pro Phe Asn Gln Thr Leu 195 200 205

    Lys Asp Met Lys Asp Val Ile Lys Gly Thr Thr Leu Glu Glu Ile Phe 210 215 220

    Ser Leu Asp Tyr Phe Asn Lys Thr Leu Thr Gln Ser Gly Ile Asp Ile 225 230 235 240

    Tyr Asn Ser Val Ile Gly Gly Arg Thr Pro Glu Glu Gly Lys Thr Lys 245 250 255

    Ile Lys Gly Leu Asn Glu Tyr Ile Asn Thr Asp Phe Asn Gln Lys Gln 260 265 270

    Thr Asp Lys Lys Lys Arg Gln Pro Lys Phe Lys Gln Leu Tyr Lys Gln 275 280 285

    Ile Leu Ser Asp Arg Gln Ser Leu Ser Phe Ile Ala Glu Ala Phe Lys 290 295 300

    Asn Asp Thr Glu Ile Leu Glu Ala Ile Glu Lys Phe Tyr Val Asn Glu 305 310 315 320

    Leu Leu His Phe Ser Asn Glu Gly Lys Ser Thr Asn Val Leu Asp Ala 325 330 335

    Ile Lys Asn Ala Val Ser Asn Leu Glu Ser Phe Asn Leu Thr Lys Met 340 345 350

    Tyr Phe Arg Ser Gly Ala Ser Leu Thr Asp Val Ser Arg Lys Val Phe 355 360 365

    Gly Glu Trp Ser Ile Ile Asn Arg Ala Leu Asp Asn Tyr Tyr Ala Thr 370 375 380

    Thr Tyr Pro Ile Lys Pro Arg Glu Lys Ser Glu Lys Tyr Glu Glu Arg 385 390 395 400

    Lys Glu Lys Trp Leu Lys Gln Asp Phe Asn Val Ser Leu Ile Gln Thr 405 410 415

    Ala Ile Asp Glu Tyr Asp Asn Glu Thr Val Lys Gly Lys Asn Ser Gly 420 425 430

    Lys Val Ile Ala Asp Tyr Phe Ala Lys Phe Cys Asp Asp Lys Glu Thr

    435

    440

    445

    Asp Leu Ile Gln Lys Val Asn Glu Gly Tyr Ile Ala Val Lys Asp Leu 450 455 460

    Leu Asn Thr Pro Cys Pro Glu Asn Glu Lys Leu Gly Ser Asn Lys Asp 465 470 475 480

    Gln Val Lys Gln Ile Lys Ala Phe Met Asp Ser Ile Met Asp Ile Met 485 490 495

    His Phe Val Arg Pro Leu Ser Leu Lys Asp Thr Asp Lys Glu Lys Asp 500 505 510

    Glu Thr Phe Tyr Ser Leu Phe Thr Pro Leu Tyr Asp His Leu Thr Gln 515 520 525

    Thr Ile Ala Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Gln Lys Pro 530 535 540

    Tyr Ser Thr Glu Lys Ile Lys Leu Asn Phe Glu Asn Ser Thr Leu Leu 545 550 555 560

    Gly Gly Trp Asp Leu Asn Lys Glu Thr Asp Asn Thr Ala Ile Ile Leu 565 570 575

    Arg Lys Asp Asn Leu Tyr Tyr Leu Gly Ile Met Asp Lys Arg His Asn 580 585 590

    Arg Ile Phe Arg Asn Val Pro Lys Ala Asp Lys Lys Asp Phe Cys Tyr 595 600 605

    Glu Lys Met Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro 610 615 620

    Lys Val Phe Phe Ser Gln Ser Arg Ile Gln Glu Phe Thr Pro Ser Ala 625 630 635 640

    Lys Leu Leu Glu Asn Tyr Ala Asn Glu Thr His Lys Lys Gly Asp Asn 645 650 655

    Phe Asn Leu Asn His Cys His Lys Leu Ile Asp Phe Phe Lys Asp Ser 660 665 670

    Ile Asn Lys His Glu Asp Trp Lys Asn Phe Asp Phe Arg Phe Ser Ala 675 680 685

    Thr Ser Thr Tyr Ala Asp Leu Ser Gly Phe Tyr His Glu Val Glu His 690 695 700

    Gln Gly Tyr Lys Ile Ser Phe Gln Ser Val Ala Asp Ser Phe Ile Asp 705 710 715 720

    Asp Leu Val Asn Glu Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 725 730 735

    Asp Phe Ser Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr 740 745 750

    Trp Lys Met Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys 755 760 765

    Leu Asn Gly Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala Glu 770 775 780

    Lys Asn Thr Thr Ile His Lys Ala Asn Glu Ser Ile Ile Asn Lys Asn 785 790 795 800

    Pro Asp Asn Pro Lys Ala Thr Ser Thr Phe Asn Tyr Asp Ile Val Lys 805 810 815

    Asp Lys Arg Tyr Thr Ile Asp Lys Phe Gln Phe His Ile Pro Ile Thr 820 825 830

    Met Asn Phe Lys Ala Glu Gly Ile Phe Asn Met Asn Gln Arg Val Asn 835 840 845

    Gln Phe Leu Lys Ala Asn Pro Asp Ile Asn Ile Ile Gly Ile Asp Arg 850 855 860

    Gly Glu Arg His Leu Leu Tyr Tyr Ala Leu Ile Asn Gln Lys Gly Lys 865 870 875 880

    Ile Leu Lys Gln Asp Thr Leu Asn Val Ile Ala Asn Glu Lys Gln Lys 885 890 895

    Val Asp Tyr His Asn Leu Leu Asp Lys Lys Glu Gly Asp Arg Ala Thr 900 905 910

    Ala Arg Gln Glu Trp Gly Val Ile Glu Thr Ile Lys Glu Leu Lys Glu 915 920 925

    Gly Tyr Leu Ser Gln Val Ile His Lys Leu Thr Asp Leu Met Ile Glu 930 935 940

    Asn Asn Ala Ile Ile Val Met Glu Asp Leu Asn Phe Gly Phe Lys Arg 945 950 955 960

    Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met 965 970 975

    Leu Ile Asp Lys Leu Asn Tyr Leu Val Asp Lys Asn Lys Lys Ala Asn 980 985 990

    Glu Leu Gly Gly Leu Leu Asn Ala Phe Gln Leu Ala Asn Lys Phe Glu 995 1000 1005

    Ser Phe Gln Lys Met Gly Lys Gln Asn Gly Phe Ile Phe Tyr Val 1010 1015 1020

    Pro Ala Trp Asn Thr Ser Lys Thr Asp Pro Ala Thr Gly Phe Ile 1025 1030 1035

    Asp Phe Leu Lys Pro Arg Tyr Glu Asn Leu Asn Gln Ala Lys Asp 1040 1045 1050

    Phe Phe Glu Lys Phe Asp Ser Ile Arg Leu Asn Ser Lys Ala Asp 1055 1060 1065

    Tyr Phe Glu Phe Ala Phe Asp Phe Lys Asn Phe Thr Glu Lys Ala 1070 1075 1080

    Asp Gly Gly Arg Thr Lys Trp Thr Val Cys Thr Thr Asn Glu Asp 1085 1090 1095

    Arg Tyr Ala Trp Asn Arg Ala Leu Asn Asn Asn Arg Gly Ser Gln 1100 1105 1110

    Glu Lys Tyr Asp Ile Thr Ala Glu Leu Lys Ser Leu Phe Asp Gly 1115 1120 1125

    Lys Val Asp Tyr Lys Ser Gly Lys Asp Leu Lys Gln Gln Ile Ala 1130 1135 1140

    Ser Gln Glu Ser Ala Asp Phe Phe Lys Ala Leu Met Lys Asn Leu

    1145

    1150

    1155

    Ser Ile Thr Leu Ser Leu Arg His Asn Asn Gly Glu Lys Gly Asp 1160 1165 1170

    Asn Glu Gln Asp Tyr Ile Leu Ser Pro Val Ala Asp Ser Lys Gly 1175 1180 1185

    Arg Phe Phe Asp Ser Arg Lys Ala Asp Asp Asp Met Pro Lys Asn 1190 1195 1200

    Ala Asp Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Trp 1205 1210 1215

    Cys Leu Glu Gln Ile Ser Lys Thr Asp Asp Leu Lys Lys Val Lys 1220 1225 1230

    Leu Ala Ile Ser Asn Lys Glu Trp Leu Glu Phe Val Gln Thr Leu 1235 1240 1245

    Lys Gly 1250 <210> 1260 <211> 4071 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1260 ggtaccatga cacagttcga gggctttacc aacctgtatc aggtgagcaa gacactgcgg tttgagctga tcccacaggg caagaccctg aagcacatcc aggagcaggg cttcatcgag 120 gaggacaagg cccgcaatga tcactacaag gagctgaagc ccatcatcga tcggatctac 180 aagacctatg ccgaccagtg cctgcagctg gtgcagctgg attgggagaa cctgagcgcc 240 gccatcgact cctatagaaa ggagaaaacc gaggagacaa ggaacgccct gatcgaggag 300 caggccacat atcgcaatgc catccacgac tacttcatcg gccggacaga caacctgacc 360 gatgccatca ataagagaca cgccgagatc tacaagggcc tgttcaaggc cgagctgttt 420 aatggcaagg tgctgaagca gctgggcacc gtgaccacaa ccgagcacga gaacgccctg 480 ctgcggagct tcgacaagtt tacaacctac ttctccggct tttatgagaa caggaagaac 540 gtgttcagcg ccgaggatat cagcacagcc atcccacacc gcatcgtgca ggacaacttc 600 cccaagttta aggagaattg tcacatcttc acacgcctga tcaccgccgt gcccagcctg 660 cgggagcact ttgagaacgt gaagaaggcc atcggcatct tcgtgagcac ctccatcgag 720 gaggtgtttt ccttcccttt ttataaccag ctgctgacac agacccagat cgacctgtat 780 aaccagctgc tgggaggaat ctctcgggag gcaggcaccg agaagatcaa gggcctgaac 840 gaggtgctga atctggccat ccagaagaat gatgagacag cccacatcat cgcctccctg 900 ccacacagat tcatccccct gtttaagcag atcctgtccg ataggaacac cctgtctttc 960 atcctggagg agtttaagag cgacgaggaa gtgatccagt ccttctgcaa gtacaagaca 1020 ctgctgagaa acgagaacgt gctggagaca gccgaggccc tgtttaacga gctgaacagc 1080 atcgacctga cacacatctt catcagccac aagaagctgg agacaatcag cagcgccctg 1140 tgcgaccact gggatacact gaggaatgcc ctgtatgagc ggagaatctc cgagctgaca 1200 ggcaagatca ccaagtctgc caaggagaag gtgcagcgca gcctgaagca cgaggatatc 1260 aacctgcagg agatcatctc tgccgcaggc aaggagctga gcgaggcctt caagcagaaa 1320 accagcgaga tcctgtccca cgcacacgcc gccctggatc agccactgcc tacaaccctg 1380 aagaagcagg aggagaagga gatcctgaag tctcagctgg acagcctgct gggcctgtac 1440 cacctgctgg actggtttgc cgtggatgag tccaacgagg tggaccccga gttctctgcc 1500 cggctgaccg gcatcaagct ggagatggag ccttctctga gcttctacaa caaggccaga 1560 aattatgcca ccaagaagcc ctactccgtg gagaagttca agctgaactt tcagatgcct 1620 acactggcct ctggctggga cgtgaataag gagaagaaca atggcgccat cctgtttgtg 1680 aagaacggcc tgtactatct gggcatcatg ccaaagcaga agggcaggta taaggccctg 1740 agcttcgagc ccacagagaa aaccagcgag ggctttgata agatgtacta tgactacttc 1800 cctgatgccg ccaagatgat cccaaagtgc agcacccagc tgaaggccgt gacagcccac 1860 tttcagaccc acacaacccc catcctgctg tccaacaatt tcatcgagcc tctggagatc 1920 acaaaggaga tctacgacct gaacaatcct gagaaggagc caaagaagtt tcagacagcc 1980 tacgccaaga aaaccggcga ccagaagggc tacagagagg ccctgtgcaa gtggatcgac 2040 ttcacaaggg attttctgtc caagtatacc aagacaacct ctatcgatct gtctagcctg 2100 cggccatcct ctcagtataa ggacctgggc gagtactatg ccgagctgaa tcccctgctg 2160 taccacatca gcttccagag aatcgccgag aaggagatca tggatgccgt ggagacaggc 2220 aagctgtacc tgttccagat ctataacaag gactttgcca agggccacca cggcaagcct 2280 aatctgcaca cactgtattg gaccggcctg ttttctccag agaacctggc caagacaagc 2340 atcaagctga atggccaggc cgagctgttc taccgcccta agtccaggat gaagaggatg 2400 gcacaccggc tgggagagaa gatgctgaac aagaagctga aggatcagaa aaccccaatc 2460 cccgacaccc tgtaccagga gctgtacgac tatgtgaatc acagactgtc ccacgacctg 2520 tctgatgagg ccagggccct gctgcccaac gtgatcacca aggaggtgtc tcacgagatc 2580 atcaaggata ggcgctttac cagcgacaag ttctttttcc acgtgcctat cacactgaac 2640 tatcaggccg ccaattcccc atctaagttc aaccagaggg tgaatgccta cctgaaggag 2700 caccccgaga cacctatcat cggcatcgat cggggcgaga gaaacctgat ctatatcaca 2760 gtgatcgact ccaccggcaa gatcctggag cagcggagcc tgaacaccat ccagcagttt 2820 gattaccaga agaagctgga caacagggag aaggagaggg tggcagcaag gcaggcctgg 2880 tctgtggtgg gcacaatcaa ggatctgaag cagggctatc tgagccaggt catccacgag 2940 atcgtggacc tgatgatcca ctaccaggcc gtggtggtgc tggagaacct gaatttcggc 3000 tttaagagca agaggaccgg catcgccgag aaggccgtgt accagcagtt cgagaagatg 3060 ctgatcgata agctgaattg cctggtgctg aaggactatc cagcagagaa agtgggaggc 3120 gtgctgaacc cataccagct gacagaccag ttcacctcct ttgccaagat gggcacccag 3180 tctggcttcc tgttttacgt gcctgcccca tatacatcta agatcgatcc cctgaccggc 3240 ttcgtggacc ccttcgtgtg gaaaaccatc aagaatcacg agagccgcaa gcacttcctg 3300 gagggcttcg actttctgca ctacgacgtg aaaaccggcg acttcatcct gcactttaag 3360 atgaacagaa atctgtcctt ccagaggggc ctgcccggct ttatgcctgc atgggatatc 3420 gtgttcgaga agaacgagac acagtttgac gccaagggca cccctttcat cgccggcaag 3480 agaatcgtgc cagtgatcga gaatcacaga ttcaccggca gataccggga cctgtatcct 3540 gccaacgagc tgatcgccct gctggaggag aagggcatcg tgttcaggga tggctccaac 3600 atcctgccaa agctgctgga gaatgacgat tctcacgcca tcgacaccat ggtggccctg 3660 atccgcagcg tgctgcagat gcggaactcc aatgccgcca caggcgagga ctatatcaac 3720 agccccgtgc gcgatctgaa tggcgtgtgc ttcgactccc ggtttcagaa cccagagtgg 3780 cccatggacg ccgatgccaa tggcgcctac cacatcgccc tgaagggcca gctgctgctg 3840 aatcacctga aggagagcaa ggatctgaag ctgcagaacg gcatctccaa tcaggactgg 3900 ctggcctaca tccaggagct gcgcaacaaa aggccggcgg ccacgaaaaa ggccggccag 3960 gcaaaaaaga aaaagggatc ctacccatac gatgttccag attacgctta tccctacgac 4020 gtgcctgatt atgcataccc atatgatgtc cccgactatg cctaagaatt c 4071 <210> 1261 <211> 1307 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1261

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg

    145

    150

    155

    160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln

    865

    870

    875

    880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu 930 935 940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly 1025 1030 1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly 1115 1120 1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn 1130 1135 1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu 1205 1210 1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn 1295 1300 1305 <210> 1262 <211> 3768 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1262 ggtaccatgt actatgagtc cctgaccaag cagtaccccg tgtctaagac aatccggaat gagctgatcc ctatcggcaa gacactggat aacatccgcc agaacaatat cctggagagc gacgtgaagc ggaagcagaa ctacgagcac gtgaagggca tcctggatga gtatcacaag cagctgatca acgaggccct ggacaattgc accctgccat ccctgaagat cgccgccgag

    120

    180

    240 atctacctga agaatcagaa ggaggtgtct gacagagagg atttcaacaa gacacaggac 300 ctgctgagga aggaggtggt ggagaagctg aaggcccacg agaactttac caagatcggc 360 aagaaggaca tcctggatct gctggagaag ctgccttcca tctctgagga cgattacaat 420 gccctggaga gcttccgcaa cttttacacc tatttcacat cctacaacaa ggtgcgggag 480 aatctgtatt ctgataagga gaagagctcc acagtggcct acagactgat caacgagaat 540 ttcccaaagt ttctggacaa tgtgaagagc tataggtttg tgaaaaccgc aggcatcctg 600 gcagatggcc tgggagagga ggagcaggac tccctgttca tcgtggagac attcaacaag 660 accctgacac aggacggcat cgatacctac aattctcaag tgggcaagat caactctagc 720 atcaatctgt ataaccagaa gaatcagaag gccaatggct tcagaaagat ccccaagatg 780 aagatgctgt ataagcagat cctgtccgat agggaggagt ctttcatcga cgagtttcag 840 agcgatgagg tgctgatcga caacgtggag tcttatggca gcgtgctgat cgagtctctg 900 aagtcctcta aggtgagcgc cttctttgat gccctgagag agtctaaggg caagaacgtg 960 tacgtgaaga atgacctggc caagacagcc atgagcaaca tcgtgttcga gaattggagg 1020 acctttgacg atctgctgaa ccaggagtac gacctggcca acgagaacaa gaagaaggac 1080 gataagtatt tcgagaagcg ccagaaggag ctgaagaaga ataagagcta ctccctggag 1140 cacctgtgca acctgtccga ggattcttgt aacctgatcg agaattatat ccaccagatc 1200 tccgacgata tcgagaatat catcatcaac aatgagacat tcctgcgcat cgtgatcaat 1260 gagcacgaca ggtcccgcaa gctggccaag aaccggaagg ccgtgaaggc catcaaggac 1320 tttctggatt ctatcaaggt gctggagcgg gagctgaagc tgatcaacag ctccggccag 1380 gagctggaga aggatctgat cgtgtactct gcccacgagg agctgctggt ggagctgaag 1440 caggtggaca gcctgtataa catgaccaga aattatctga caaagaagcc tttctctacc 1500 gagaaggtga agctgaactt taatcgcagc acactgctga acggctggga tcggaataag 1560 gagacagaca acctgggcgt gctgctgctg aaggacggca agtactatct gggcatcatg 1620 aacacaagcg ccaataaggc cttcgtgaat ccccctgtgg ccaagaccga gaaggtgttt 1680 aagaaggtgg attacaagct gctgccagtg cccaaccaga tgctgccaaa ggtgttcttt 1740 gccaagagca atatcgactt ctataacccc tctagcgaga tctactccaa ttataagaag 1800 ggcacccaca agaagggcaa tatgttttcc ctggaggatt gtcacaacct gatcgacttc 1860 tttaaggagt ctatcagcaa gcacgaggac tggagcaagt tcggctttaa gttcagcgat 1920 acagcctcct acaacgacat ctccgagttc tatcgcgagg tggagaagca gggctacaag 1980 ctgacctata cagacatcga tgagacatac atcaatgatc tgatcgagcg gaacgagctg 2040 tacctgttcc agatctataa taaggacttt agcatgtact ccaagggcaa gctgaacctg 2100 cacacactgt atttcatgat gctgtttgat cagcgcaata tcgacgacgt ggtgtataag 2160 ctgaacggag aggcagaggt gttctatagg ccagcctcca tctctgagga cgagctgatc 2220 atccacaagg ccggcgagga gatcaagaac aagaatccta accgggccag aaccaaggag 2280 acaagcacct tcagctacga catcgtgaag gataagcggt atagcaagga taagtttacc 2340 ctgcacatcc ccatcacaat gaacttcggc gtggatgagg tgaagcggtt caacgacgcc 2400 gtgaacagcg ccatccggat cgatgagaat gtgaacgtga tcggcatcga ccggggcgag 2460 agaaatctgc tgtacgtggt ggtcatcgac tctaagggca acatcctgga gcagatctcc 2520 ctgaactcta tcatcaataa ggagtacgac atcgagacag attatcacgc actgctggat 2580 gagagggagg gcggcagaga taaggcccgg aaggactgga acaccgtgga gaatatcagg 2640 gacctgaagg ccggctacct gagccaggtg gtgaacgtgg tggccaagct ggtgctgaag 2700 tataatgcca tcatctgcct ggaggacctg aactttggct tcaagagggg ccgccagaag 2760 gtggagaagc aggtgtacca gaagttcgag aagatgctga tcgataagct gaattacctg 2820 gtcatcgaca agagccgcga gcagacatcc cctaaggagc tgggaggcgc cctgaacgca 2880 ctgcagctga cctctaagtt caagagcttt aaggagctgg gcaagcagtc cggcgtgatc 2940 tactatgtgc ctgcctacct gacctctaag atcgatccaa ccacaggctt cgccaatctg 3000 ttttatatga agtgtgagaa cgtggagaag tccaagagat tctttgacgg ctttgatttc 3060 atcaggttca acgccctgga gaacgtgttc gagttcggct ttgactaccg gagcttcacc 3120 cagagggcct gcggcatcaa ttccaagtgg accgtgtgca ccaacggcga gcgcatcatc 3180 aagtatcgga atccagataa gaacaatatg ttcgacgaga aggtggtggt ggtgaccgat 3240 gagatgaaga acctgtttga gcagtacaag atcccctatg aggatggcag aaatgtgaag 3300 gacatgatca tcagcaacga ggaggccgag ttctaccgga gactgtatag gctgctgcag 3360 cagaccctgc agatgagaaa cagcacctcc gacggcacaa gggattacat catctcccct 3420 gtgaagaata agagagaggc ctacttcaac agcgagctgt ccgacggctc tgtgccaaag 3480 gacgccgatg ccaacggcgc ctacaatatc gccagaaagg gcctgtgggt gctggagcag 3540 atcaggcaga agagcgaggg cgagaagatc aatctggcca tgaccaacgc cgagtggctg 3600 gagtatgccc agacacacct gctgaaaagg ccggcggcca cgaaaaaggc cggccaggca 3660 aaaaagaaaa agggatccta cccatacgat gttccagatt acgcttatcc ctacgacgtg 3720 cctgattatg catacccata tgatgtcccc gactatgcct aagaattc 3768 <210> 1263 <211> 1206 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1263

    Met Tyr Tyr Glu Ser Leu Thr Lys Gln Tyr Pro Val Ser Lys Thr Ile

    1 5 10 15

    Arg Asn Glu Leu Ile Pro Ile Gly Lys Thr Leu Asp Asn Ile Arg Gln 20 25 30

    Asn Asn Ile Leu Glu Ser Asp Val Lys Arg Lys Gln Asn Tyr Glu His 35 40 45

    Val Lys Gly Ile Leu Asp Glu Tyr His Lys Gln Leu Ile Asn Glu Ala 50 55 60

    Leu Asp Asn Cys Thr Leu Pro Ser Leu Lys Ile Ala Ala Glu Ile Tyr 65 70 75 80

    Leu Lys Asn Gln Lys Glu Val Ser Asp Arg Glu Asp Phe Asn Lys Thr 85 90 95

    Gln Asp Leu Leu Arg Lys Glu Val Val Glu Lys Leu Lys Ala His Glu 100 105 110

    Asn Phe Thr Lys Ile Gly Lys Lys Asp Ile Leu Asp Leu Leu Glu Lys 115 120 125

    Leu Pro Ser Ile Ser Glu Asp Asp Tyr Asn Ala Leu Glu Ser Phe Arg 130 135 140

    Asn Phe Tyr Thr Tyr Phe Thr Ser Tyr Asn Lys Val Arg Glu Asn Leu 145 150 155 160

    Tyr Ser Asp Lys Glu Lys Ser Ser Thr Val Ala Tyr Arg Leu Ile Asn 165 170 175

    Glu Asn Phe Pro Lys Phe Leu Asp Asn Val Lys Ser Tyr Arg Phe Val 180 185 190

    Lys Thr Ala Gly Ile Leu Ala Asp Gly Leu Gly Glu Glu Glu Gln Asp 195 200 205

    Ser Leu Phe Ile Val Glu Thr Phe Asn Lys Thr Leu Thr Gln Asp Gly

    210

    215

    220

    Ile Asp Thr Tyr Asn Ser Gln Val Gly Lys Ile Asn Ser Ser Ile Asn 225 230 235 240

    Leu Tyr Asn Gln Lys Asn Gln Lys Ala Asn Gly Phe Arg Lys Ile Pro 245 250 255

    Lys Met Lys Met Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Glu Ser 260 265 270

    Phe Ile Asp Glu Phe Gln Ser Asp Glu Val Leu Ile Asp Asn Val Glu 275 280 285

    Ser Tyr Gly Ser Val Leu Ile Glu Ser Leu Lys Ser Ser Lys Val Ser 290 295 300

    Ala Phe Phe Asp Ala Leu Arg Glu Ser Lys Gly Lys Asn Val Tyr Val 305 310 315 320

    Lys Asn Asp Leu Ala Lys Thr Ala Met Ser Asn Ile Val Phe Glu Asn 325 330 335

    Trp Arg Thr Phe Asp Asp Leu Leu Asn Gln Glu Tyr Asp Leu Ala Asn 340 345 350

    Glu Asn Lys Lys Lys Asp Asp Lys Tyr Phe Glu Lys Arg Gln Lys Glu 355 360 365

    Leu Lys Lys Asn Lys Ser Tyr Ser Leu Glu His Leu Cys Asn Leu Ser 370 375 380

    Glu Asp Ser Cys Asn Leu Ile Glu Asn Tyr Ile His Gln Ile Ser Asp 385 390 395 400

    Asp Ile Glu Asn Ile Ile Ile Asn Asn Glu Thr Phe Leu Arg Ile Val 405 410 415

    Ile Asn Glu His Asp Arg Ser Arg Lys Leu Ala Lys Asn Arg Lys Ala 420 425 430

    Val Lys Ala Ile Lys Asp Phe Leu Asp Ser Ile Lys Val Leu Glu Arg 435 440 445

    Glu Leu Lys Leu Ile Asn Ser Ser Gly Gln Glu Leu Glu Lys Asp Leu 450 455 460

    Ile Val Tyr Ser Ala His Glu Glu Leu Leu Val Glu Leu Lys Gln Val 465 470 475 480

    Asp Ser Leu Tyr Asn Met Thr Arg Asn Tyr Leu Thr Lys Lys Pro Phe 485 490 495

    Ser Thr Glu Lys Val Lys Leu Asn Phe Asn Arg Ser Thr Leu Leu Asn 500 505 510

    Gly Trp Asp Arg Asn Lys Glu Thr Asp Asn Leu Gly Val Leu Leu Leu 515 520 525

    Lys Asp Gly Lys Tyr Tyr Leu Gly Ile Met Asn Thr Ser Ala Asn Lys 530 535 540

    Ala Phe Val Asn Pro Pro Val Ala Lys Thr Glu Lys Val Phe Lys Lys 545 550 555 560

    Val Asp Tyr Lys Leu Leu Pro Val Pro Asn Gln Met Leu Pro Lys Val 565 570 575

    Phe Phe Ala Lys Ser Asn Ile Asp Phe Tyr Asn Pro Ser Ser Glu Ile 580 585 590

    Tyr Ser Asn Tyr Lys Lys Gly Thr His Lys Lys Gly Asn Met Phe Ser 595 600 605

    Leu Glu Asp Cys His Asn Leu Ile Asp Phe Phe Lys Glu Ser Ile Ser 610 615 620

    Lys His Glu Asp Trp Ser Lys Phe Gly Phe Lys Phe Ser Asp Thr Ala 625 630 635 640

    Ser Tyr Asn Asp Ile Ser Glu Phe Tyr Arg Glu Val Glu Lys Gln Gly 645 650 655

    Tyr Lys Leu Thr Tyr Thr Asp Ile Asp Glu Thr Tyr Ile Asn Asp Leu 660 665 670

    Ile Glu Arg Asn Glu Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 675 680 685

    Ser Met Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met 690 695 700

    Met Leu Phe Asp Gln Arg Asn Ile Asp Asp Val Val Tyr Lys Leu Asn 705 710 715 720

    Gly Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ser Glu Asp Glu 725 730 735

    Leu Ile Ile His Lys Ala Gly Glu Glu Ile Lys Asn Lys Asn Pro Asn 740 745 750

    Arg Ala Arg Thr Lys Glu Thr Ser Thr Phe Ser Tyr Asp Ile Val Lys 755 760 765

    Asp Lys Arg Tyr Ser Lys Asp Lys Phe Thr Leu His Ile Pro Ile Thr 770 775 780

    Met Asn Phe Gly Val Asp Glu Val Lys Arg Phe Asn Asp Ala Val Asn 785 790 795 800

    Ser Ala Ile Arg Ile Asp Glu Asn Val Asn Val Ile Gly Ile Asp Arg 805 810 815

    Gly Glu Arg Asn Leu Leu Tyr Val Val Val Ile Asp Ser Lys Gly Asn 820 825 830

    Ile Leu Glu Gln Ile Ser Leu Asn Ser Ile Ile Asn Lys Glu Tyr Asp 835 840 845

    Ile Glu Thr Asp Tyr His Ala Leu Leu Asp Glu Arg Glu Gly Gly Arg 850 855 860

    Asp Lys Ala Arg Lys Asp Trp Asn Thr Val Glu Asn Ile Arg Asp Leu 865 870 875 880

    Lys Ala Gly Tyr Leu Ser Gln Val Val Asn Val Val Ala Lys Leu Val 885 890 895

    Leu Lys Tyr Asn Ala Ile Ile Cys Leu Glu Asp Leu Asn Phe Gly Phe 900 905 910

    Lys Arg Gly Arg Gln Lys Val Glu Lys Gln Val Tyr Gln Lys Phe Glu 915 920 925

    Lys Met Leu Ile Asp Lys Leu Asn Tyr Leu Val Ile Asp Lys Ser Arg

    930

    935

    940

    Glu Gln Thr Ser Pro Lys Glu Leu Gly Gly Ala Leu Asn Ala Leu Gln 945 950 955 960

    Leu Thr Ser Lys Phe Lys Ser Phe Lys Glu Leu Gly Lys Gln Ser Gly 965 970 975

    Val Ile Tyr Tyr Val Pro Ala Tyr Leu Thr Ser Lys Ile Asp Pro Thr 980 985 990

    Thr Gly Phe Ala Asn Leu Phe Tyr Met Lys Cys Glu Asn Val Glu Lys 995 1000 1005

    Ser Lys Arg Phe Phe Asp Gly Phe Asp Phe Ile Arg Phe Asn Ala 1010 1015 1020

    Leu Glu Asn Val Phe Glu Phe Gly Phe Asp Tyr Arg Ser Phe Thr 1025 1030 1035

    Gln Arg Ala Cys Gly Ile Asn Ser Lys Trp Thr Val Cys Thr Asn 1040 1045 1050

    Gly Glu Arg Ile Ile Lys Tyr Arg Asn Pro Asp Lys Asn Asn Met 1055 1060 1065

    Phe Asp Glu Lys Val Val Val Val Thr Asp Glu Met Lys Asn Leu 1070 1075 1080

    Phe Glu Gln Tyr Lys Ile Pro Tyr Glu Asp Gly Arg Asn Val Lys 1085 1090 1095

    Asp Met Ile Ile Ser Asn Glu Glu Ala Glu Phe Tyr Arg Arg Leu 1100 1105 1110

    Tyr Arg Leu Leu Gln Gln Thr Leu Gln Met Arg Asn Ser Thr Ser 1115 1120 1125

    Asp Gly Thr Arg Asp Tyr Ile Ile Ser Pro Val Lys Asn Lys Arg 1130 1135 1140

    Glu Ala Tyr Phe Asn Ser Glu Leu Ser Asp Gly Ser Val Pro Lys 1145 1150 1155

    Asp Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu 1160 1165 1170

    Trp Val Leu Glu Gln Ile Arg Gln Lys Ser Glu Gly Glu Lys Ile 1175 1180 1185

    Asn Leu Ala Met Thr Asn Ala Glu Trp Leu Glu Tyr Ala Gln Thr 1190 1195 1200

    His Leu Leu 1205 <210> 1264 <211> 3864 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1264 ggtaccatga acaattacga cgagttcacc aagctgtatc ctatccagaa aaccatccgg tttgagctga agccacaggg cagaaccatg gagcacctgg agacattcaa cttctttgag

    120 gaggaccggg atagagccga gaagtataag atcctgaagg aggccatcga cgagtaccac 180 aagaagttta tcgatgagca cctgaccaat atgtccctgg attggaactc tctgaagcag 240 atcagcgaga agtactataa gagcagggag gagaaggaca agaaggtgtt cctgtccgag 300 cagaagagga tgcgccagga gatcgtgtct gagtttaaga aggacgatcg cttcaaggac 360 ctgttttcca agaagctgtt ctctgagctg ctgaaggagg agatctacaa gaagggcaac 420 caccaggaga tcgacgccct gaagagcttc gataagtttt ccggctattt catcggcctg 480 cacgagaata ggaagaacat gtactccgac ggcgatgaga tcaccgccat ctccaatcgc 540 atcgtgaatg agaacttccc caagtttctg gataacctgc agaagtacca ggaggccagg 600 aagaagtatc ctgagtggat catcaaggcc gagagcgccc tggtggccca caatatcaag 660 atggacgagg tgttctccct ggagtacttt aataaggtgc tgaaccagga gggcatccag 720 cggtacaacc tggccctggg cggctatgtg accaagagcg gcgagaagat gatgggcctg 780 aatgatgccc tgaacctggc ccaccagtcc gagaagagct ccaagggcag aatccacatg 840 acccccctgt tcaagcagat cctgtccgag aaggagtcct tctcttacat ccccgacgtg 900 tttacagagg attctcagct gctgcctagc atcggcggct tctttgccca gatcgagaat 960 gacaaggatg gcaacatctt cgaccgggcc ctggagctga tctctagcta cgccgagtat 1020 gataccgagc ggatctatat cagacaggcc gacatcaata gagtgtccaa cgtgatcttt 1080 ggagagtggg gcaccctggg aggcctgatg agggagtaca aggccgactc tatcaatgat 1140 atcaacctgg agcgcacatg caagaaggtg gacaagtggc tggattctaa ggagtttgcc 1200 ctgagcgatg tgctggaggc catcaagagg accggcaaca atgacgcctt caacgagtat 1260 atctccaaga tgcggacagc cagagagaag atcgatgccg cccgcaagga gatgaagttc 1320 atcagcgaga agatctccgg cgatgaggag tctatccaca tcatcaagac cctgctggac 1380 agcgtgcagc agttcctgca cttctttaat ctgtttaagg caaggcagga catcccactg 1440 gatggagcct tctacgccga gtttgacgag gtgcacagca agctgtttgc catcgtgccc 1500 ctgtataaca aggtgcggaa ctatctgacc aagaacaatc tgaacacaaa gaagatcaag 1560 ctgaatttca agaaccctac actggccaat ggctgggacc agaacaaggt gtacgattat 1620 gcctccctga tctttctgcg ggacggcaat tactatctgg gcatcatcaa tcctaagaga 1680 aagaagaaca tcaagttcga gcagggctct ggcaacggcc ccttctaccg gaagatggtg 1740 tataagcaga tccccggccc taataagaac ctgccaagag tgttcctgac ctccacaaag 1800 ggcaagaagg agtataagcc ctctaaggag atcatcgagg gctacgaggc cgacaagcac 1860 atcaggggcg ataagttcga cctggatttt tgtcacaagc tgatcgattt ctttaaggag 1920 tccatcgaga agcacaagga ctggtctaag ttcaacttct acttcagccc aaccgagagc 1980 tatggcgaca tctctgagtt ctacctggat gtggagaagc agggctatcg catgcacttt 2040 gagaatatca gcgccgagac aatcgacgag tatgtggaga agggcgatct gtttctgttc 2100 cagatctaca acaaggattt tgtgaaggcc gccaccggca agaaggacat gcacacaatc 2160 tactggaatg ccgccttcag ccccgagaac ctgcaggacg tggtggtgaa gctgaacggc 2220 gaggccgagc tgttttatag ggacaagtcc gatatcaagg agatcgtgca ccgcgagggc 2280 gagatcctgg tgaataggac ctacaacggc cgcacaccag tgcccgacaa gatccacaag 2340 aagctgaccg attatcacaa tggccggaca aaggacctgg gcgaggccaa ggagtacctg 2400 gataaggtga gatacttcaa ggcccactat gacatcacca aggatcggag atacctgaac 2460 gacaagatct atttccacgt gcctctgacc ctgaacttca aggccaacgg caagaagaat 2520 ctgaacaaga tggtcatcga gaagttcctg tccgatgaga aggcccacat catcggcatc 2580 gacaggggcg agcgcaatct gctgtactat tccatcatcg acaggtctgg caagatcatc 2640 gatcagcaga gcctgaatgt gatcgacggc tttgattatc gggagaagct gaaccagaga 2700 gagatcgaga tgaaggatgc ccgccagtct tggaacgcca tcggcaagat caaggacctg 2760 aaggagggct acctgagcaa ggccgtgcac gagatcacca agatggccat ccagtataat 2820 gccatcgtgg tcatggagga gctgaactac ggcttcaagc ggggccggtt caaggtggag 2880 aagcagatct atcagaagtt cgagaatatg ctgatcgata agatgaacta cctggtgttt 2940 aaggacgcac ctgatgagtc cccaggaggc gtgctgaatg cctaccagct gacaaaccca 3000 ctggagtctt tcgccaagct gggcaagcag accggcatcc tgttttacgt gccagccgcc 3060 tatacatcca agatcgaccc caccacaggc ttcgtgaatc tgtttaacac ctcctctaag 3120 acaaacgccc aggagcggaa ggagttcctg cagaagtttg agagcatctc ctattctgcc 3180 aaggatggcg gcatctttgc cttcgccttt gactacagaa agttcggcac cagcaagaca 3240 gatcacaaga acgtgtggac cgcctataca aacggcgaga ggatgcgcta catcaaggag 3300 aagaagcgga atgagctgtt tgacccttct aaggagatca aggaggccct gaccagctcc 3360 ggcatcaagt acgatggcgg ccagaacatc ctgccagaca tcctgaggag caacaataac 3420 ggcctgatct acacaatgta ttctagcttc atcgccgcca tccagatgcg cgtgtacgac 3480 ggcaaggagg attatatcat cagccccatc aagaactcca agggcgagtt ctttaggacc 3540 gaccccaaga ggcgcgagct gcctatcgac gccgatgcca atggcgccta caacatcgcc 3600 ctgaggggag agctgacaat gagggcaatc gcagagaagt tcgaccctga tagcgagaag 3660 atggccaagc tggagctgaa gcacaaggat tggttcgagt ttatgcagac cagaggcgac 3720 aaaaggccgg cggccacgaa aaaggccggc caggcaaaaa agaaaaaggg atcctaccca 3780 tacgatgttc cagattacgc ttatccctac gacgtgcctg attatgcata cccatatgat 3840 gtccccgact atgcctaaga attc 3864 <210> 1265 <211> 1238 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1265

    Met Asn Asn Tyr Asp Glu Phe Thr Lys Leu Tyr Pro Ile Gln Lys Thr 1 5 10 15

    Ile Arg Phe Glu Leu Lys Pro Gln Gly Arg Thr Met Glu His Leu Glu 20 25 30

    Thr Phe Asn Phe Phe Glu Glu Asp Arg Asp Arg Ala Glu Lys Tyr Lys 35 40 45

    Ile Leu Lys Glu Ala Ile Asp Glu Tyr His Lys Lys Phe Ile Asp Glu 50 55 60

    His Leu Thr Asn Met Ser Leu Asp Trp Asn Ser Leu Lys Gln Ile Ser 65 70 75 80

    Glu Lys Tyr Tyr Lys Ser Arg Glu Glu Lys Asp Lys Lys Val Phe Leu 85 90 95

    Ser Glu Gln Lys Arg Met Arg Gln Glu Ile Val Ser Glu Phe Lys Lys 100 105 110

    Asp Asp Arg Phe Lys Asp Leu Phe Ser Lys Lys Leu Phe Ser Glu Leu 115 120 125

    Leu Lys Glu Glu Ile Tyr Lys Lys Gly Asn His Gln Glu Ile Asp Ala 130 135 140

    Leu Lys Ser Phe Asp Lys Phe Ser Gly Tyr Phe Ile Gly Leu His Glu 145 150 155 160

    Asn Arg Lys Asn Met Tyr Ser Asp Gly Asp Glu Ile Thr Ala Ile Ser 165 170 175

    Asn Arg Ile Val Asn Glu Asn Phe Pro Lys Phe Leu Asp Asn Leu Gln 180 185 190

    Lys Tyr Gln Glu Ala Arg Lys Lys Tyr Pro Glu Trp Ile Ile Lys Ala 195 200 205

    Glu Ser Ala Leu Val Ala His Asn Ile Lys Met Asp Glu Val Phe Ser 210 215 220

    Leu Glu Tyr Phe Asn Lys Val Leu Asn Gln Glu Gly Ile Gln Arg Tyr 225 230 235 240

    Asn Leu Ala Leu Gly Gly Tyr Val Thr Lys Ser Gly Glu Lys Met Met 245 250 255

    Gly Leu Asn Asp Ala Leu Asn Leu Ala His Gln Ser Glu Lys Ser Ser 260 265 270

    Lys Gly Arg Ile His Met Thr Pro Leu Phe Lys Gln Ile Leu Ser Glu 275 280 285

    Lys Glu Ser Phe Ser Tyr Ile Pro Asp Val Phe Thr Glu Asp Ser Gln 290 295 300

    Leu Leu Pro Ser Ile Gly Gly Phe Phe Ala Gln Ile Glu Asn Asp Lys 305 310 315 320

    Asp Gly Asn Ile Phe Asp Arg Ala Leu Glu Leu Ile Ser Ser Tyr Ala 325 330 335

    Glu Tyr Asp Thr Glu Arg Ile Tyr Ile Arg Gln Ala Asp Ile Asn Arg 340 345 350

    Val Ser Asn Val Ile Phe Gly Glu Trp Gly Thr Leu Gly Gly Leu Met

    355

    360

    365

    Arg Glu Tyr Lys Ala Asp Ser Ile Asn Asp Ile Asn Leu Glu Arg Thr 370 375 380

    Cys Lys Lys Val Asp Lys Trp Leu Asp Ser Lys Glu Phe Ala Leu Ser 385 390 395 400

    Asp Val Leu Glu Ala Ile Lys Arg Thr Gly Asn Asn Asp Ala Phe Asn 405 410 415

    Glu Tyr Ile Ser Lys Met Arg Thr Ala Arg Glu Lys Ile Asp Ala Ala 420 425 430

    Arg Lys Glu Met Lys Phe Ile Ser Glu Lys Ile Ser Gly Asp Glu Glu 435 440 445

    Ser Ile His Ile Ile Lys Thr Leu Leu Asp Ser Val Gln Gln Phe Leu 450 455 460

    His Phe Phe Asn Leu Phe Lys Ala Arg Gln Asp Ile Pro Leu Asp Gly 465 470 475 480

    Ala Phe Tyr Ala Glu Phe Asp Glu Val His Ser Lys Leu Phe Ala Ile 485 490 495

    Val Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Lys Asn Asn Leu 500 505 510

    Asn Thr Lys Lys Ile Lys Leu Asn Phe Lys Asn Pro Thr Leu Ala Asn 515 520 525

    Gly Trp Asp Gln Asn Lys Val Tyr Asp Tyr Ala Ser Leu Ile Phe Leu 530 535 540

    Arg Asp Gly Asn Tyr Tyr Leu Gly Ile Ile Asn Pro Lys Arg Lys Lys 545 550 555 560

    Asn Ile Lys Phe Glu Gln Gly Ser Gly Asn Gly Pro Phe Tyr Arg Lys 565 570 575

    Met Val Tyr Lys Gln Ile Pro Gly Pro Asn Lys Asn Leu Pro Arg Val 580 585 590

    Phe Leu Thr Ser Thr Lys Gly Lys Lys Glu Tyr Lys Pro Ser Lys Glu 595 600 605

    Ile Ile Glu Gly Tyr Glu Ala Asp Lys His Ile Arg Gly Asp Lys Phe 610 615 620

    Asp Leu Asp Phe Cys His Lys Leu Ile Asp Phe Phe Lys Glu Ser Ile 625 630 635 640

    Glu Lys His Lys Asp Trp Ser Lys Phe Asn Phe Tyr Phe Ser Pro Thr 645 650 655

    Glu Ser Tyr Gly Asp Ile Ser Glu Phe Tyr Leu Asp Val Glu Lys Gln 660 665 670

    Gly Tyr Arg Met His Phe Glu Asn Ile Ser Ala Glu Thr Ile Asp Glu 675 680 685

    Tyr Val Glu Lys Gly Asp Leu Phe Leu Phe Gln Ile Tyr Asn Lys Asp 690 695 700

    Phe Val Lys Ala Ala Thr Gly Lys Lys Asp Met His Thr Ile Tyr Trp 705 710 715 720

    Asn Ala Ala Phe Ser Pro Glu Asn Leu Gln Asp Val Val Val Lys Leu 725 730 735

    Asn Gly Glu Ala Glu Leu Phe Tyr Arg Asp Lys Ser Asp Ile Lys Glu 740 745 750

    Ile Val His Arg Glu Gly Glu Ile Leu Val Asn Arg Thr Tyr Asn Gly 755 760 765

    Arg Thr Pro Val Pro Asp Lys Ile His Lys Lys Leu Thr Asp Tyr His 770 775 780

    Asn Gly Arg Thr Lys Asp Leu Gly Glu Ala Lys Glu Tyr Leu Asp Lys 785 790 795 800

    Val Arg Tyr Phe Lys Ala His Tyr Asp Ile Thr Lys Asp Arg Arg Tyr 805 810 815

    Leu Asn Asp Lys Ile Tyr Phe His Val Pro Leu Thr Leu Asn Phe Lys 820 825 830

    Ala Asn Gly Lys Lys Asn Leu Asn Lys Met Val Ile Glu Lys Phe Leu 835 840 845

    Ser Asp Glu Lys Ala His Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn 850 855 860

    Leu Leu Tyr Tyr Ser Ile Ile Asp Arg Ser Gly Lys Ile Ile Asp Gln 865 870 875 880

    Gln Ser Leu Asn Val Ile Asp Gly Phe Asp Tyr Arg Glu Lys Leu Asn 885 890 895

    Gln Arg Glu Ile Glu Met Lys Asp Ala Arg Gln Ser Trp Asn Ala Ile 900 905 910

    Gly Lys Ile Lys Asp Leu Lys Glu Gly Tyr Leu Ser Lys Ala Val His 915 920 925

    Glu Ile Thr Lys Met Ala Ile Gln Tyr Asn Ala Ile Val Val Met Glu 930 935 940

    Glu Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln 945 950 955 960

    Ile Tyr Gln Lys Phe Glu Asn Met Leu Ile Asp Lys Met Asn Tyr Leu 965 970 975

    Val Phe Lys Asp Ala Pro Asp Glu Ser Pro Gly Gly Val Leu Asn Ala 980 985 990

    Tyr Gln Leu Thr Asn Pro Leu Glu Ser Phe Ala Lys Leu Gly Lys Gln 995 1000 1005

    Thr Gly Ile Leu Phe Tyr Val Pro Ala Ala Tyr Thr Ser Lys Ile 1010 1015 1020

    Asp Pro Thr Thr Gly Phe Val Asn Leu Phe Asn Thr Ser Ser Lys 1025 1030 1035

    Thr Asn Ala Gln Glu Arg Lys Glu Phe Leu Gln Lys Phe Glu Ser 1040 1045 1050

    Ile Ser Tyr Ser Ala Lys Asp Gly Gly Ile Phe Ala Phe Ala Phe 1055 1060 1065

    Asp Tyr Arg Lys Phe Gly Thr Ser Lys Thr Asp His Lys Asn Val

    1070

    1075

    1080

    Trp Thr Ala Tyr Thr Asn Gly Glu Arg Met Arg Tyr Ile Lys Glu 1085 1090 1095

    Lys Lys Arg Asn Glu Leu Phe Asp Pro Ser Lys Glu Ile Lys Glu 1100 1105 1110

    Ala Leu Thr Ser Ser Gly Ile Lys Tyr Asp Gly Gly Gln Asn Ile 1115 1120 1125

    Leu Pro Asp Ile Leu Arg Ser Asn Asn Asn Gly Leu Ile Tyr Thr 1130 1135 1140

    Met Tyr Ser Ser Phe Ile Ala Ala Ile Gln Met Arg Val Tyr Asp 1145 1150 1155

    Gly Lys Glu Asp Tyr Ile Ile Ser Pro Ile Lys Asn Ser Lys Gly 1160 1165 1170

    Glu Phe Phe Arg Thr Asp Pro Lys Arg Arg Glu Leu Pro Ile Asp 1175 1180 1185

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Leu Arg Gly Glu Leu 1190 1195 1200

    Thr Met Arg Ala Ile Ala Glu Lys Phe Asp Pro Asp Ser Glu Lys 1205 1210 1215

    Met Ala Lys Leu Glu Leu Lys His Lys Asp Trp Phe Glu Phe Met 1220 1225 1230

    Gln Thr Arg Gly Asp 1235 <210> 1266 <211> 3996 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1266 ggtaccatga acggcaatag gtccatcgtg taccgcgagt tcgtgggcgt gatccccgtg 60 gccaagaccc tgaggaatga gctgcgccct gtgggccaca cacaggagca catcatccag 120 aacggcctga tccaggagga cgagctgcgg caggagaaga gcaccgagct gaagaacatc 180 atggacgatt actatagaga gtacatcgat aagtctctga gcggcgtgac cgacctggac 240 ttcaccctgc tgttcgagct gatgaacctg gtgcagagct ccccctccaa ggacaataag 300 aaggccctgg agaaggagca gtctaagatg agggagcaga tctgcaccca cctgcagtcc 360 gactctaact acaagaatat ctttaacgcc aagctgctga aggagatcct gcctgatttc 420 atcaagaact acaatcagta tgacgtgaag gataaggccg gcaagctgga gacactggcc 480 ctgtttaatg gcttcagcac atactttacc gacttctttg agaagaggaa gaacgtgttc 540 accaaggagg ccgtgagcac atccatcgcc taccgcatcg tgcacgagaa ctccctgatc 600 ttcctggcca atatgacctc ttataagaag atcagcgaga aggccctgga tgagatcgaa 660 gtgatcgaga agaacaatca ggacaagatg ggcgattggg agctgaatca gatctttaac 720 cctgacttct acaatatggt gctgatccag tccggcatcg acttctacaa cgagatctgc 780 ggcgtggtga atgcccacat gaacctgtac tgtcagcaga ccaagaacaa ttataacctg 840 ttcaagatgc ggaagctgca caagcagatc ctggcctaca ccagcaccag cttcgaggtg 900 cccaagatgt tcgaggacga tatgagcgtg tataacgccg tgaacgcctt catcgacgag 960 acagagaagg gcaacatcat cggcaagctg aaggatatcg tgaataagta cgacgagctg 1020 gatgagaaga gaatctatat cagcaaggac ttttacgaga cactgagctg cttcatgtcc 1080 ggcaactgga atctgatcac aggctgcgtg gagaacttct acgatgagaa catccacgcc 1140 aagggcaagt ccaaggagga gaaggtgaag aaggccgtga aggaggacaa gtacaagtct 1200 atcaatgacg tgaacgatct ggtggagaag tatatcgatg agaaggagag gaatgagttc 1260 aagaacagca atgccaagca gtacatccgc gagatctcca acatcatcac cgacacagag 1320 acagcccacc tggagtatga cgatcacatc tctctgatcg agagcgagga gaaggccgac 1380 gagatgaaga agcggctgga tatgtatatg aacatgtacc actgggccaa ggcctttatc 1440 gtggacgagg tgctggacag agatgagatg ttctacagcg atatcgacga tatctataat 1500 atcctggaga acatcgtgcc actgtataat cgggtgagaa actacgtgac ccagaagccc 1560 tacaactcta agaagatcaa gctgaatttc cagagcccta cactggccaa tggctggtcc 1620 cagtctaagg agttcgacaa caatgccatc atcctgatca gagataacaa gtactatctg 1680 gccatcttca atgccaagaa caagccagac aagaagatca tccagggcaa ctccgataag 1740 aagaacgaca acgattacaa gaagatggtg tataacctgc tgccaggcgc caacaagatg 1800 ctgcccaagg tgtttctgtc taagaagggc atcgagacat tcaagccctc cgactatatc 1860 atctctggct acaacgccca caagcacatc aagacaagcg agaattttga tatctccttc 1920 tgtcgggacc tgatcgatta cttcaagaac agcatcgaga agcacgccga gtggagaaag 1980 tatgagttca agttttccgc caccgacagc tactccgata tctctgagtt ctatcgggag 2040 gtggagatgc agggctacag aatcgactgg acatatatca gcgaggccga catcaacaag 2100 ctggatgagg agggcaagat ctatctgttt cagatctaca ataaggattt cgccgagaac 2160 agcaccggca aggagaatct gcacacaatg tactttaaga acatcttctc cgaggagaat 2220 ctgaaggaca tcatcatcaa gctgaacggc caggccgagc tgttttatcg gagagcctct 2280 gtgaagaatc ccgtgaagca caagaaggat agcgtgctgg tgaacaagac ctacaagaat 2340 cagctggaca acggcgacgt ggtgagaatc cccatccctg acgatatcta taacgagatc 2400 tacaagatgt ataatggcta catcaaggag tccgacctgt ctgaggccgc caaggagtac 2460 ctggataagg tggaggtgag gaccgcccag aaggacatcg tgaaggatta ccgctataca 2520 gtggacaagt acttcatcca cacacctatc accatcaact ataaggtgac cgcccgcaac 2580 aatgtgaatg atatggtggt gaagtacatc gcccagaacg acgatatcca cgtgatcggc 2640 atcgaccggg gcgagagaaa cctgatctac atctccgtga tcgattctca cggcaacatc 2700 gtgaagcaga aatcctacaa catcctgaac aactacgact acaagaagaa gctggtggag 2760 aaggagaaaa cccgggagta cgccagaaag aactggaaga gcatcggcaa tatcaaggag 2820 ctgaaggagg gctatatctc cggcgtggtg cacgagatcg ccatgctgat cgtggagtac 2880 aacgccatca tcgccatgga ggacctgaat tatggcttta agaggggccg cttcaaggtg 2940 gagcggcagg tgtaccagaa gtttgagagc atgctgatca ataagctgaa ctatttcgcc 3000 agcaaggaga agtccgtgga cgagccagga ggcctgctga agggctatca gctgacctac 3060 gtgcccgata atatcaagaa cctgggcaag cagtgcggcg tgatctttta cgtgcctgcc 3120 gccttcacca gcaagatcga cccatccaca ggctttatct ctgccttcaa ctttaagtct 3180 atcagcacaa atgcctctcg gaagcagttc tttatgcagt ttgacgagat cagatactgt 3240 gccgagaagg atatgttcag ctttggcttc gactacaaca acttcgatac ctacaacatc 3300 acaatgggca agacacagtg gaccgtgtat acaaacggcg agagactgca gtctgagttc 3360 aacaatgcca ggcgcaccgg caagacaaag agcatcaatc tgacagagac aatcaagctg 3420 ctgctggagg acaatgagat caactacgcc gacggccacg atatcaggat cgatatggag 3480 aagatggacg aggataagaa gagcgagttc tttgcccagc tgctgagcct gtataagctg 3540 accgtgcaga tgcgcaattc ctatacagag gccgaggagc aggagaacgg catctcttac 3600 gacaagatca tcagccctgt gatcaatgat gagggcgagt tctttgactc cgataactat 3660 aaggagtctg acgataagga gtgcaagatg ccaaaggacg ccgatgccaa cggcgcctac 3720 tgtatcgccc tgaagggcct gtatgaggtg ctgaagatca agagcgagtg gaccgaggac 3780 ggctttgata ggaattgcct gaagctgcca cacgcagagt ggctggactt catccagaac 3840 aagcggtacg agaaaaggcc ggcggccacg aaaaaggccg gccaggcaaa aaagaaaaag 3900 ggatcctacc catacgatgt tccagattac gcttatccct acgacgtgcc tgattatgca 3960 tacccatatg atgtccccga ctatgcctaa gaattc 3996 <210> 1267 <211> 1282 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1267

    Met Asn Gly Asn Arg Ser Ile Val Tyr Arg Glu Phe Val Gly Val Ile 1 5 10 15

    Pro Val Ala Lys Thr Leu Arg Asn Glu Leu Arg Pro Val Gly His Thr 20 25 30

    Gln Glu His Ile Ile Gln Asn Gly Leu Ile Gln Glu Asp Glu Leu Arg 35 40 45

    Gln Glu Lys Ser Thr Glu Leu Lys Asn Ile Met Asp Asp Tyr Tyr Arg 50 55 60

    Glu Tyr Ile Asp Lys Ser Leu Ser Gly Val Thr Asp Leu Asp Phe Thr 65 70 75 80

    Leu Leu Phe Glu Leu Met Asn Leu Val Gln Ser Ser Pro Ser Lys Asp 85 90 95

    Asn Lys Lys Ala Leu Glu Lys Glu Gln Ser Lys Met Arg Glu Gln Ile 100 105 110

    Cys Thr His Leu Gln Ser Asp Ser Asn Tyr Lys Asn Ile Phe Asn Ala 115 120 125

    Lys Leu Leu Lys Glu Ile Leu Pro Asp Phe Ile Lys Asn Tyr Asn Gln 130 135 140

    Tyr Asp Val Lys Asp Lys Ala Gly Lys Leu Glu Thr Leu Ala Leu Phe 145 150 155 160

    Asn Gly Phe Ser Thr Tyr Phe Thr Asp Phe Phe Glu Lys Arg Lys Asn 165 170 175

    Val Phe Thr Lys Glu Ala Val Ser Thr Ser Ile Ala Tyr Arg Ile Val 180 185 190

    His Glu Asn Ser Leu Ile Phe Leu Ala Asn Met Thr Ser Tyr Lys Lys 195 200 205

    Ile Ser Glu Lys Ala Leu Asp Glu Ile Glu Val Ile Glu Lys Asn Asn 210 215 220

    Gln Asp Lys Met Gly Asp Trp Glu Leu Asn Gln Ile Phe Asn Pro Asp 225 230 235 240

    Phe Tyr Asn Met Val Leu Ile Gln Ser Gly Ile Asp Phe Tyr Asn Glu 245 250 255

    Ile Cys Gly Val Val Asn Ala His Met Asn Leu Tyr Cys Gln Gln Thr 260 265 270

    Lys Asn Asn Tyr Asn Leu Phe Lys Met Arg Lys Leu His Lys Gln Ile 275 280 285

    Leu Ala Tyr Thr Ser Thr Ser Phe Glu Val Pro Lys Met Phe Glu Asp 290 295 300

    Asp Met Ser Val Tyr Asn Ala Val Asn Ala Phe Ile Asp Glu Thr Glu 305 310 315 320

    Lys Gly Asn Ile Ile Gly Lys Leu Lys Asp Ile Val Asn Lys Tyr Asp 325 330 335

    Glu Leu Asp Glu Lys Arg Ile Tyr Ile Ser Lys Asp Phe Tyr Glu Thr 340 345 350

    Leu Ser Cys Phe Met Ser Gly Asn Trp Asn Leu Ile Thr Gly Cys Val 355 360 365

    Glu Asn Phe Tyr Asp Glu Asn Ile His Ala Lys Gly Lys Ser Lys Glu 370 375 380

    Glu Lys Val Lys Lys Ala Val Lys Glu Asp Lys Tyr Lys Ser Ile Asn 385 390 395 400

    Asp Val Asn Asp Leu Val Glu Lys Tyr Ile Asp Glu Lys Glu Arg Asn 405 410 415

    Glu Phe Lys Asn Ser Asn Ala Lys Gln Tyr Ile Arg Glu Ile Ser Asn 420 425 430

    Ile Ile Thr Asp Thr Glu Thr Ala His Leu Glu Tyr Asp Asp His Ile 435 440 445

    Ser Leu Ile Glu Ser Glu Glu Lys Ala Asp Glu Met Lys Lys Arg Leu

    450

    455

    460

    Asp Met Tyr Met Asn Met Tyr His Trp Ala Lys Ala Phe Ile Val Asp 465 470 475 480

    Glu Val Leu Asp Arg Asp Glu Met Phe Tyr Ser Asp Ile Asp Asp Ile 485 490 495

    Tyr Asn Ile Leu Glu Asn Ile Val Pro Leu Tyr Asn Arg Val Arg Asn 500 505 510

    Tyr Val Thr Gln Lys Pro Tyr Asn Ser Lys Lys Ile Lys Leu Asn Phe 515 520 525

    Gln Ser Pro Thr Leu Ala Asn Gly Trp Ser Gln Ser Lys Glu Phe Asp 530 535 540

    Asn Asn Ala Ile Ile Leu Ile Arg Asp Asn Lys Tyr Tyr Leu Ala Ile 545 550 555 560

    Phe Asn Ala Lys Asn Lys Pro Asp Lys Lys Ile Ile Gln Gly Asn Ser 565 570 575

    Asp Lys Lys Asn Asp Asn Asp Tyr Lys Lys Met Val Tyr Asn Leu Leu 580 585 590

    Pro Gly Ala Asn Lys Met Leu Pro Lys Val Phe Leu Ser Lys Lys Gly 595 600 605

    Ile Glu Thr Phe Lys Pro Ser Asp Tyr Ile Ile Ser Gly Tyr Asn Ala 610 615 620

    His Lys His Ile Lys Thr Ser Glu Asn Phe Asp Ile Ser Phe Cys Arg 625 630 635 640

    Asp Leu Ile Asp Tyr Phe Lys Asn Ser Ile Glu Lys His Ala Glu Trp 645 650 655

    Arg Lys Tyr Glu Phe Lys Phe Ser Ala Thr Asp Ser Tyr Ser Asp Ile 660 665 670

    Ser Glu Phe Tyr Arg Glu Val Glu Met Gln Gly Tyr Arg Ile Asp Trp 675 680 685

    Thr Tyr Ile Ser Glu Ala Asp Ile Asn Lys Leu Asp Glu Glu Gly Lys 690 695 700

    Ile Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Glu Asn Ser Thr 705 710 715 720

    Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn Ile Phe Ser Glu 725 730 735

    Glu Asn Leu Lys Asp Ile Ile Ile Lys Leu Asn Gly Gln Ala Glu Leu 740 745 750

    Phe Tyr Arg Arg Ala Ser Val Lys Asn Pro Val Lys His Lys Lys Asp 755 760 765

    Ser Val Leu Val Asn Lys Thr Tyr Lys Asn Gln Leu Asp Asn Gly Asp 770 775 780

    Val Val Arg Ile Pro Ile Pro Asp Asp Ile Tyr Asn Glu Ile Tyr Lys 785 790 795 800

    Met Tyr Asn Gly Tyr Ile Lys Glu Ser Asp Leu Ser Glu Ala Ala Lys 805 810 815

    Glu Tyr Leu Asp Lys Val Glu Val Arg Thr Ala Gln Lys Asp Ile Val 820 825 830

    Lys Asp Tyr Arg Tyr Thr Val Asp Lys Tyr Phe Ile His Thr Pro Ile 835 840 845

    Thr Ile Asn Tyr Lys Val Thr Ala Arg Asn Asn Val Asn Asp Met Val 850 855 860

    Val Lys Tyr Ile Ala Gln Asn Asp Asp Ile His Val Ile Gly Ile Asp 865 870 875 880

    Arg Gly Glu Arg Asn Leu Ile Tyr Ile Ser Val Ile Asp Ser His Gly 885 890 895

    Asn Ile Val Lys Gln Lys Ser Tyr Asn Ile Leu Asn Asn Tyr Asp Tyr 900 905 910

    Lys Lys Lys Leu Val Glu Lys Glu Lys Thr Arg Glu Tyr Ala Arg Lys 915 920 925

    Asn Trp Lys Ser Ile Gly Asn Ile Lys Glu Leu Lys Glu Gly Tyr Ile 930 935 940

    Ser Gly Val Val His Glu Ile Ala Met Leu Ile Val Glu Tyr Asn Ala 945 950 955 960

    Ile Ile Ala Met Glu Asp Leu Asn Tyr Gly Phe Lys Arg Gly Arg Phe 965 970 975

    Lys Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Ser Met Leu Ile Asn 980 985 990

    Lys Leu Asn Tyr Phe Ala Ser Lys Glu Lys Ser Val Asp Glu Pro Gly 995 1000 1005

    Gly Leu Leu Lys Gly Tyr Gln Leu Thr Tyr Val Pro Asp Asn Ile 1010 1015 1020

    Lys Asn Leu Gly Lys Gln Cys Gly Val Ile Phe Tyr Val Pro Ala 1025 1030 1035

    Ala Phe Thr Ser Lys Ile Asp Pro Ser Thr Gly Phe Ile Ser Ala 1040 1045 1050

    Phe Asn Phe Lys Ser Ile Ser Thr Asn Ala Ser Arg Lys Gln Phe 1055 1060 1065

    Phe Met Gln Phe Asp Glu Ile Arg Tyr Cys Ala Glu Lys Asp Met 1070 1075 1080

    Phe Ser Phe Gly Phe Asp Tyr Asn Asn Phe Asp Thr Tyr Asn Ile 1085 1090 1095

    Thr Met Gly Lys Thr Gln Trp Thr Val Tyr Thr Asn Gly Glu Arg 1100 1105 1110

    Leu Gln Ser Glu Phe Asn Asn Ala Arg Arg Thr Gly Lys Thr Lys 1115 1120 1125

    Ser Ile Asn Leu Thr Glu Thr Ile Lys Leu Leu Leu Glu Asp Asn 1130 1135 1140

    Glu Ile Asn Tyr Ala Asp Gly His Asp Ile Arg Ile Asp Met Glu 1145 1150 1155

    Lys Met Asp Glu Asp Lys Lys Ser Glu Phe Phe Ala Gln Leu Leu

    1160

    1165

    1170

    Ser Leu Tyr Lys Leu Thr Val Gln Met Arg Asn Ser Tyr Thr Glu 1175 1180 1185

    Ala Glu Glu Gln Glu Asn Gly Ile Ser Tyr Asp Lys Ile Ile Ser 1190 1195 1200

    Pro Val Ile Asn Asp Glu Gly Glu Phe Phe Asp Ser Asp Asn Tyr 1205 1210 1215

    Lys Glu Ser Asp Asp Lys Glu Cys Lys Met Pro Lys Asp Ala Asp 1220 1225 1230

    Ala Asn Gly Ala Tyr Cys Ile Ala Leu Lys Gly Leu Tyr Glu Val 1235 1240 1245

    Leu Lys Ile Lys Ser Glu Trp Thr Glu Asp Gly Phe Asp Arg Asn 1250 1255 1260

    Cys Leu Lys Leu Pro His Ala Glu Trp Leu Asp Phe Ile Gln Asn 1265 1270 1275

    Lys Arg Tyr Glu 1280 <210> 1268 <211> 4269 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1268 ggtaccatgc tgttccagga ctttacccac ctgtatccac tgtccaagac agtgagattt 60 gagctgaagc ccatcgatag gaccctggag cacatccacg ccaagaactt cctgtctcag 120 gacgagacaa tggccgatat gcaccagaag gtgaaagtga tcctggacga ttaccaccgc 180 gacttcatcg ccgatatgat gggcgaggtg aagctgacca agctggccga gttctatgac 240 gtgtacctga agtttcggaa gaacccaaag gacgatgagc tgcagaagca gctgaaggat 300 ctgcaggccg tgctgagaaa ggagatcgtg aagcccatcg gcaatggcgg caagtataag 360 gccggctacg acaggctgtt cggcgccaag ctgtttaagg acggcaagga gctgggcgat 420 ctggccaagt tcgtgatcgc acaggaggga gagagctccc caaagctggc ccacctggcc 480 cacttcgaga agttttccac ctatttcaca ggctttcacg ataaccggaa gaatatgtat 540 tctgacgagg ataagcacac cgccatcgcc taccgcctga tccacgagaa cctgccccgg 600 tttatcgaca atctgcagat cctgaccaca atcaagcaga agcactctgc cctgtacgat 660 cagatcatca acgagctgac cgccagcggc ctggacgtgt ctctggccag ccacctggat 720 ggctatcaca agctgctgac acaggagggc atcaccgcct acaatacact gctgggagga 780 atctccggag aggcaggctc tcctaagatc cagggcatca acgagctgat caattctcac 840 cacaaccagc actgccacaa gagcgagaga atcgccaagc tgaggccact gcacaagcag 900 atcctgtccg acggcatgag cgtgtccttc ctgccctcta agtttgccga cgatagcgag 960 atgtgccagg ccgtgaacga gttctatcgc cactacgccg acgtgttcgc caaggtgcag 1020 agcctgttcg acggctttga cgatcaccag aaggatggca tctacgtgga gcacaagaac 1080 ctgaatgagc tgtccaagca ggccttcggc gactttgcac tgctgggacg cgtgctggac 1140 ggatactatg tggatgtggt gaatccagag ttcaacgagc ggtttgccaa ggccaagacc 1200 gacaatgcca aggccaagct gacaaaggag aaggataagt tcatcaaggg cgtgcactcc 1260 ctggcctctc tggagcaggc catcgagcac tataccgcaa ggcacgacga tgagagcgtg 1320 caggcaggca agctgggaca gtacttcaag cacggcctgg ccggagtgga caaccccatc 1380 cagaagatcc acaacaatca cagcaccatc aagggctttc tggagaggga gcgccctgca 1440 ggagagagag ccctgccaaa gatcaagtcc ggcaagaatc ctgagatgac acagctgagg 1500 cagctgaagg agctgctgga taacgccctg aatgtggccc acttcgccaa gctgctgacc 1560 acaaagacca cactggacaa tcaggatggc aacttctatg gcgagtttgg cgtgctgtac 1620 gacgagctgg ccaagatccc caccctgtat aacaaggtga gagattacct gagccagaag 1680 cctttctcca ccgagaagta caagctgaac tttggcaatc caacactgct gaatggctgg 1740 gacctgaaca aggagaagga taatttcggc gtgatcctgc agaaggacgg ctgctactat 1800 ctggccctgc tggacaaggc ccacaagaag gtgtttgata acgcccctaa tacaggcaag 1860 agcatctatc agaagatgat ctataagtac ctggaggtga ggaagcagtt ccccaaggtg 1920 ttcttttcca aggaggccat cgccatcaac taccaccctt ctaaggagct ggtggagatc 1980 aaggacaagg gccggcagag atccgacgat gagcgcctga agctgtatcg gtttatcctg 2040 gagtgtctga agatccaccc taagtacgat aagaagttcg agggcgccat cggcgacatc 2100 cagctgttta agaaggataa gaagggcaga gaggtgccaa tcagcgagaa ggacctgttc 2160 gataagatca acggcatctt ttctagcaag cctaagctgg agatggagga cttctttatc 2220 ggcgagttca agaggtataa cccaagccag gacctggtgg atcagtataa tatctacaag 2280 aagatcgact ccaacgataa tcgcaagaag gagaatttct acaacaatca ccccaagttt 2340 aagaaggatc tggtgcggta ctattacgag tctatgtgca agcacgagga gtgggaggag 2400 agcttcgagt tttccaagaa gctgcaggac atcggctgtt acgtggatgt gaacgagctg 2460 tttaccgaga tcgagacacg gagactgaat tataagatct ccttctgcaa catcaatgcc 2520 gactacatcg atgagctggt ggagcagggc cagctgtatc tgttccagat ctacaacaag 2580 gacttttccc caaaggccca cggcaagccc aatctgcaca ccctgtactt caaggccctg 2640 ttttctgagg acaacctggc cgatcctatc tataagctga atggcgaggc ccagatcttc 2700 tacagaaagg cctccctgga catgaacgag acaacaatcc acagggccgg cgaggtgctg 2760 gagaacaaga atcccgataa tcctaagaag agacagttcg tgtacgacat catcaaggat 2820 aagaggtaca cacaggacaa gttcatgctg cacgtgccaa tcaccatgaa ctttggcgtg 2880 cagggcatga caatcaagga gttcaataag aaggtgaacc agtctatcca gcagtatgac 2940 gaggtgaacg tgatcggcat cgatcggggc gagagacacc tgctgtacct gaccgtgatc 3000 aatagcaagg gcgagatcct ggagcagtgt tccctgaacg acatcaccac agcctctgcc 3060 aatggcacac agatgaccac accttaccac aagatcctgg ataagaggga gatcgagcgc 3120 ctgaacgccc gggtgggatg gggcgagatc gagacaatca aggagctgaa gtctggctat 3180 ctgagccacg tggtgcacca gatcagccag ctgatgctga agtacaacgc catcgtggtg 3240 ctggaggacc tgaatttcgg ctttaagagg ggccgcttta aggtggagaa gcagatctat 3300 cagaacttcg agaatgccct gatcaagaag ctgaaccacc tggtgctgaa ggacaaggcc 3360 gacgatgaga tcggctctta caagaatgcc ctgcagctga ccaacaattt cacagatctg 3420 aagagcatcg gcaagcagac cggcttcctg ttttatgtgc ccgcctggaa cacctctaag 3480 atcgaccctg agacaggctt tgtggatctg ctgaagccaa gatacgagaa catcgcccag 3540 agccaggcct tctttggcaa gttcgacaag atctgctata atgccgacaa ggattacttc 3600 gagtttcaca tcgactacgc caagtttacc gataaggcca agaatagccg ccagatctgg 3660 acaatctgtt cccacggcga caagcggtac gtgtacgata agacagccaa ccagaataag 3720 ggcgccgcca agggcatcaa cgtgaatgat gagctgaagt ccctgttcgc ccgccaccac 3780 atcaacgaga agcagcccaa cctggtcatg gacatctgcc agaacaatga taaggagttt 3840 cacaagtctc tgatgtacct gctgaaaacc ctgctggccc tgcggtacag caacgcctcc 3900 tctgacgagg atttcatcct gtcccccgtg gcaaacgacg agggcgtgtt ctttaatagc 3960 gccctggccg acgatacaca gcctcagaat gccgatgcca acggcgccta ccacatcgcc 4020 ctgaagggcc tgtggctgct gaatgagctg aagaactccg acgatctgaa caaggtgaag 4080 ctggccatcg acaatcagac ctggctgaat ttcgcccaga acaggaaaag gccggcggcc 4140 acgaaaaagg ccggccaggc aaaaaagaaa aagggatcct acccatacga tgttccagat 4200 tacgcttatc cctacgacgt gcctgattat gcatacccat atgatgtccc cgactatgcc 4260 taagaattc 4269 <210> 1269 <211> 1373 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1269

    Met Leu Phe Gln Asp Phe Thr His Leu Tyr Pro Leu Ser Lys Thr Val 1 5 10 15

    Arg Phe Glu Leu Lys Pro Ile Asp Arg Thr Leu Glu His Ile His Ala 20 25 30

    Lys Asn Phe Leu Ser Gln Asp Glu Thr Met Ala Asp Met His Gln Lys 35 40 45

    Val Lys Val Ile Leu Asp Asp Tyr His Arg Asp Phe Ile Ala Asp Met 50 55 60

    Met Gly Glu Val Lys Leu Thr Lys Leu Ala Glu Phe Tyr Asp Val Tyr 65 70 75 80

    Leu Lys Phe Arg Lys Asn Pro Lys Asp Asp Glu Leu Gln Lys Gln Leu 85 90 95

    Lys Asp Leu Gln Ala Val Leu Arg Lys Glu Ile Val Lys Pro Ile Gly

    100

    105

    110

    Asn Gly Gly Lys Tyr Lys Ala Gly Tyr Asp Arg Leu Phe Gly Ala Lys 115 120 125

    Leu Phe Lys Asp Gly Lys Glu Leu Gly Asp Leu Ala Lys Phe Val Ile 130 135 140

    Ala Gln Glu Gly Glu Ser Ser Pro Lys Leu Ala His Leu Ala His Phe 145 150 155 160

    Glu Lys Phe Ser Thr Tyr Phe Thr Gly Phe His Asp Asn Arg Lys Asn 165 170 175

    Met Tyr Ser Asp Glu Asp Lys His Thr Ala Ile Ala Tyr Arg Leu Ile 180 185 190

    His Glu Asn Leu Pro Arg Phe Ile Asp Asn Leu Gln Ile Leu Thr Thr 195 200 205

    Ile Lys Gln Lys His Ser Ala Leu Tyr Asp Gln Ile Ile Asn Glu Leu 210 215 220

    Thr Ala Ser Gly Leu Asp Val Ser Leu Ala Ser His Leu Asp Gly Tyr 225 230 235 240

    His Lys Leu Leu Thr Gln Glu Gly Ile Thr Ala Tyr Asn Thr Leu Leu 245 250 255

    Gly Gly Ile Ser Gly Glu Ala Gly Ser Pro Lys Ile Gln Gly Ile Asn 260 265 270

    Glu Leu Ile Asn Ser His His Asn Gln His Cys His Lys Ser Glu Arg 275 280 285

    Ile Ala Lys Leu Arg Pro Leu His Lys Gln Ile Leu Ser Asp Gly Met 290 295 300

    Ser Val Ser Phe Leu Pro Ser Lys Phe Ala Asp Asp Ser Glu Met Cys 305 310 315 320

    Gln Ala Val Asn Glu Phe Tyr Arg His Tyr Ala Asp Val Phe Ala Lys 325 330 335

    Val Gln Ser Leu Phe Asp Gly Phe Asp Asp His Gln Lys Asp Gly Ile 340 345 350

    Tyr Val Glu His Lys Asn Leu Asn Glu Leu Ser Lys Gln Ala Phe Gly 355 360 365

    Asp Phe Ala Leu Leu Gly Arg Val Leu Asp Gly Tyr Tyr Val Asp Val 370 375 380

    Val Asn Pro Glu Phe Asn Glu Arg Phe Ala Lys Ala Lys Thr Asp Asn 385 390 395 400

    Ala Lys Ala Lys Leu Thr Lys Glu Lys Asp Lys Phe Ile Lys Gly Val 405 410 415

    His Ser Leu Ala Ser Leu Glu Gln Ala Ile Glu His Tyr Thr Ala Arg 420 425 430

    His Asp Asp Glu Ser Val Gln Ala Gly Lys Leu Gly Gln Tyr Phe Lys 435 440 445

    His Gly Leu Ala Gly Val Asp Asn Pro Ile Gln Lys Ile His Asn Asn 450 455 460

    His Ser Thr Ile Lys Gly Phe Leu Glu Arg Glu Arg Pro Ala Gly Glu 465 470 475 480

    Arg Ala Leu Pro Lys Ile Lys Ser Gly Lys Asn Pro Glu Met Thr Gln 485 490 495

    Leu Arg Gln Leu Lys Glu Leu Leu Asp Asn Ala Leu Asn Val Ala His 500 505 510

    Phe Ala Lys Leu Leu Thr Thr Lys Thr Thr Leu Asp Asn Gln Asp Gly 515 520 525

    Asn Phe Tyr Gly Glu Phe Gly Val Leu Tyr Asp Glu Leu Ala Lys Ile 530 535 540

    Pro Thr Leu Tyr Asn Lys Val Arg Asp Tyr Leu Ser Gln Lys Pro Phe 545 550 555 560

    Ser Thr Glu Lys Tyr Lys Leu Asn Phe Gly Asn Pro Thr Leu Leu Asn 565 570 575

    Gly Trp Asp Leu Asn Lys Glu Lys Asp Asn Phe Gly Val Ile Leu Gln 580 585 590

    Lys Asp Gly Cys Tyr Tyr Leu Ala Leu Leu Asp Lys Ala His Lys Lys 595 600 605

    Val Phe Asp Asn Ala Pro Asn Thr Gly Lys Ser Ile Tyr Gln Lys Met 610 615 620

    Ile Tyr Lys Tyr Leu Glu Val Arg Lys Gln Phe Pro Lys Val Phe Phe 625 630 635 640

    Ser Lys Glu Ala Ile Ala Ile Asn Tyr His Pro Ser Lys Glu Leu Val 645 650 655

    Glu Ile Lys Asp Lys Gly Arg Gln Arg Ser Asp Asp Glu Arg Leu Lys 660 665 670

    Leu Tyr Arg Phe Ile Leu Glu Cys Leu Lys Ile His Pro Lys Tyr Asp 675 680 685

    Lys Lys Phe Glu Gly Ala Ile Gly Asp Ile Gln Leu Phe Lys Lys Asp 690 695 700

    Lys Lys Gly Arg Glu Val Pro Ile Ser Glu Lys Asp Leu Phe Asp Lys 705 710 715 720

    Ile Asn Gly Ile Phe Ser Ser Lys Pro Lys Leu Glu Met Glu Asp Phe 725 730 735

    Phe Ile Gly Glu Phe Lys Arg Tyr Asn Pro Ser Gln Asp Leu Val Asp 740 745 750

    Gln Tyr Asn Ile Tyr Lys Lys Ile Asp Ser Asn Asp Asn Arg Lys Lys 755 760 765

    Glu Asn Phe Tyr Asn Asn His Pro Lys Phe Lys Lys Asp Leu Val Arg 770 775 780

    Tyr Tyr Tyr Glu Ser Met Cys Lys His Glu Glu Trp Glu Glu Ser Phe 785 790 795 800

    Glu Phe Ser Lys Lys Leu Gln Asp Ile Gly Cys Tyr Val Asp Val Asn 805 810 815

    Glu Leu Phe Thr Glu Ile Glu Thr Arg Arg Leu Asn Tyr Lys Ile Ser

    820

    825

    830

    Phe Cys Asn Ile Asn Ala Asp Tyr Ile Asp Glu Leu Val Glu Gln Gly 835 840 845

    Gln Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Pro Lys Ala 850 855 860

    His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala Leu Phe Ser 865 870 875 880

    Glu Asp Asn Leu Ala Asp Pro Ile Tyr Lys Leu Asn Gly Glu Ala Gln 885 890 895

    Ile Phe Tyr Arg Lys Ala Ser Leu Asp Met Asn Glu Thr Thr Ile His 900 905 910

    Arg Ala Gly Glu Val Leu Glu Asn Lys Asn Pro Asp Asn Pro Lys Lys 915 920 925

    Arg Gln Phe Val Tyr Asp Ile Ile Lys Asp Lys Arg Tyr Thr Gln Asp 930 935 940

    Lys Phe Met Leu His Val Pro Ile Thr Met Asn Phe Gly Val Gln Gly 945 950 955 960

    Met Thr Ile Lys Glu Phe Asn Lys Lys Val Asn Gln Ser Ile Gln Gln 965 970 975

    Tyr Asp Glu Val Asn Val Ile Gly Ile Asp Arg Gly Glu Arg His Leu 980 985 990

    Leu Tyr Leu Thr Val Ile Asn Ser Lys Gly Glu Ile Leu Glu Gln Cys 995 1000 1005

    Ser Leu Asn Asp Ile Thr Thr Ala Ser Ala Asn Gly Thr Gln Met 1010 1015 1020

    Thr Thr Pro Tyr His Lys Ile Leu Asp Lys Arg Glu Ile Glu Arg 1025 1030 1035

    Leu Asn Ala Arg Val Gly Trp Gly Glu Ile Glu Thr Ile Lys Glu 1040 1045 1050

    Leu Lys Ser Gly Tyr Leu Ser His Val Val His Gln Ile Ser Gln 1055 1060 1065

    Leu Met Leu Lys Tyr Asn Ala Ile Val Val Leu Glu Asp Leu Asn 1070 1075 1080

    Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Ile Tyr 1085 1090 1095

    Gln Asn Phe Glu Asn Ala Leu Ile Lys Lys Leu Asn His Leu Val 1100 1105 1110

    Leu Lys Asp Lys Ala Asp Asp Glu Ile Gly Ser Tyr Lys Asn Ala 1115 1120 1125

    Leu Gln Leu Thr Asn Asn Phe Thr Asp Leu Lys Ser Ile Gly Lys 1130 1135 1140

    Gln Thr Gly Phe Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys 1145 1150 1155

    Ile Asp Pro Glu Thr Gly Phe Val Asp Leu Leu Lys Pro Arg Tyr 1160 1165 1170

    Glu Asn Ile Ala Gln Ser Gln Ala Phe Phe Gly Lys Phe Asp Lys 1175 1180 1185

    Ile Cys Tyr Asn Ala Asp Lys Asp Tyr Phe Glu Phe His Ile Asp 1190 1195 1200

    Tyr Ala Lys Phe Thr Asp Lys Ala Lys Asn Ser Arg Gln Ile Trp 1205 1210 1215

    Thr Ile Cys Ser His Gly Asp Lys Arg Tyr Val Tyr Asp Lys Thr 1220 1225 1230

    Ala Asn Gln Asn Lys Gly Ala Ala Lys Gly Ile Asn Val Asn Asp 1235 1240 1245

    Glu Leu Lys Ser Leu Phe Ala Arg His His Ile Asn Glu Lys Gln 1250 1255 1260

    Pro Asn Leu Val Met Asp Ile Cys Gln Asn Asn Asp Lys Glu Phe 1265 1270 1275

    His Lys Ser Leu Met Tyr Leu Leu Lys Thr Leu Leu Ala Leu Arg 1280 1285 1290

    Tyr Ser Asn Ala Ser Ser Asp Glu Asp Phe Ile Leu Ser Pro Val 1295 1300 1305

    Ala Asn Asp Glu Gly Val Phe Phe Asn Ser Ala Leu Ala Asp Asp 1310 1315 1320

    Thr Gln Pro Gln Asn Ala Asp Ala Asn Gly Ala Tyr His Ile Ala 1325 1330 1335

    Leu Lys Gly Leu Trp Leu Leu

    1340

    1345

    Asn Glu Leu Lys Asn Ser Asp Asp 1350

    Leu Asn Lys Val Lys Leu Ala

    1355

    1360

    Ile Asp Asn Gln Thr Trp Leu Asn 1365

    Phe Ala Gln Asn Arg 1370 <210> 1270 <211> 3939 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1270 ggtaccatgg aggactattc cggctttgtg aacatctact ctatccagaa aaccctgagg 60 ttcgagctga agccagtggg caagacactg gagcacatcg agaagaaggg cttcctgaag 120 aaggacaaga tccgggccga ggattacaag gccgtgaaga agatcatcga taagtaccac 180 agagcctata tcgaggaggt gtttgattcc gtgctgcacc agaagaagaa gaaggacaag 240 acccgctttt ctacacagtt catcaaggag atcaaggagt tcagcgagct gtactataag 300 accgagaaga acatccccga caaggagagg ctggaggccc tgagcgagaa gctgcgcaag 360 atgctggtgg gcgcctttaa gggcgagttc tccgaggagg tggccgagaa gtataagaac 420 ctgttttcta aggagctgat caggaatgag atcgagaagt tctgcgagac agacgaggag 480 cgcaagcagg tgtctaactt caagagcttc accacatact ttaccggctt ccactccaac 540 aggcagaata tctattccga cgagaagaag tctacagcca tcggctaccg catcatccac 600 cagaacctgc ctaagttcct ggataatctg aagatcatcg agtccatcca gcggcggttc 660 aaggacttcc catggtctga tctgaagaag aacctgaaga agatcgataa gaatatcaag 720 ctgaccgagt acttcagcat cgacggcttc gtgaacgtgc tgaatcagaa gggcatcgat 780 gcctacaaca caatcctggg cggcaagtcc gaggagtctg gcgagaagat ccagggcctg 840 aacgagtaca tcaatctgta tcggcagaag aacaatatcg acagaaagaa cctgcccaat 900 gtgaagatcc tgtttaagca gatcctgggc gatagggaga caaagagctt tatccctgag 960 gccttcccag acgatcagtc cgtgctgaac tctatcacag agttcgccaa gtacctgaag 1020 ctggataaga agaagaagag catcatcgcc gagctgaaga agtttctgag ctccttcaat 1080 cgctacgagc tggacggcat ctatctggcc aacgataata gcctggcctc tatcagcacc 1140 ttcctgtttg acgattggtc ctttatcaag aagtccgtgt ctttcaagta tgacgagtcc 1200 gtgggcgacc ccaagaagaa gatcaagtct cccctgaagt acgagaagga gaaggagaag 1260 tggctgaagc agaagtacta tacaatctct ttcctgaacg atgccatcga gagctattcc 1320 aagtctcagg acgagaagag ggtgaagatc cgcctggagg cctactttgc cgagttcaag 1380 agcaaggacg atgccaagaa gcagttcgac ctgctggaga ggatcgagga ggcctatgcc 1440 atcgtggagc ctctgctggg agcagagtac ccaagggacc gcaacctgaa ggccgataag 1500 aaggaagtgg gcaagatcaa ggacttcctg gatagcatca agtccctgca gttctttctg 1560 aagcctctgc tgtccgccga gatctttgac gagaaggatc tgggcttcta caatcagctg 1620 gagggctact atgaggagat cgattctatc ggccacctgt ataacaaggt gcggaattat 1680 ctgaccggca agatctacag caaggagaag tttaagctga acttcgagaa cagcaccctg 1740 ctgaagggct gggacgagaa ccgggaggtg gccaatctgt gcgtgatctt cagagaggac 1800 cagaagtact atctgggcgt gatggataag gagaacaata ccatcctgtc cgacatcccc 1860 aaggtgaagc ctaacgagct gttttacgag aagatggtgt ataagctgat ccccacacct 1920 cacatgcagc tgccccggat catcttctct agcgacaacc tgtctatcta taatcctagc 1980 aagtccatcc tgaagatcag agaggccaag agctttaagg agggcaagaa cttcaagctg 2040 aaggactgtc acaagtttat cgatttctac aaggagtcta tcagcaagaa tgaggactgg 2100 agcagattcg acttcaagtt cagcaagacc agcagctacg agaacatcag cgagttttac 2160 cgggaggtgg agagacaggg ctataacctg gacttcaaga aggtgtctaa gttctacatc 2220 gacagcctgg tggaggatgg caagctgtac ctgttccaga tctataacaa ggacttttct 2280 atcttcagca agggcaagcc caatctgcac accatctatt ttcggtccct gttctctaag 2340 gagaacctga aggacgtgtg cctgaagctg aatggcgagg ccgagatgtt ctttcggaag 2400 aagtccatca actacgatga gaagaagaag cgggagggcc accaccccga gctgtttgag 2460 aagctgaagt atcctatcct gaaggacaag agatacagcg aggataagtt tcagttccac 2520 ctgcccatca gcctgaactt caagtccaag gagcggctga actttaatct gaaagtgaat 2580 gagttcctga agagaaacaa ggacatcaat atcatcggca tcgatcgggg cgagagaaac 2640 ctgctgtacc tggtcatgat caatcagaag ggcgagatcc tgaagcagac cctgctggac 2700 agcatgcagt ccggcaaggg ccggcctgag atcaactaca aggagaagct gcaggagaag 2760 gagatcgaga gggataaggc ccgcaagagc tggggcacag tggagaatat caaggagctg 2820 aaggagggct atctgtctat cgtgatccac cagatcagca agctgatggt ggagaacaat 2880 gccatcgtgg tgctggagga cctgaacatc ggctttaagc ggggcagaca gaaggtggag 2940 cggcaggtgt accagaagtt cgagaagatg ctgatcgata agctgaactt tctggtgttc 3000 aaggagaata agccaaccga gccaggaggc gtgctgaagg cctatcagct gacagacgag 3060 tttcagtctt tcgagaagct gagcaagcag accggctttc tgttctacgt gccaagctgg 3120 aacacctcca agatcgaccc cagaacaggc tttatcgatt tcctgcaccc tgcctacgag 3180 aatatcgaga aggccaagca gtggatcaac aagtttgatt ccatcaggtt caattctaag 3240 atggactggt ttgagttcac cgccgataca cgcaagtttt ccgagaacct gatgctgggc 3300 aagaatcggg tgtgggtcat ctgcaccaca aatgtggagc ggtacttcac cagcaagacc 3360 gccaacagct ccatccagta caatagcatc cagatcaccg agaagctgaa ggagctgttt 3420 gtggacatcc ctttcagcaa cggccaggat ctgaagccag agatcctgag gaagaatgac 3480 gccgtgttct ttaagagcct gctgttttac atcaagacca cactgtccct gcgccagaac 3540 aatggcaaga agggcgagga ggagaaggac ttcatcctga gcccagtggt ggattccaag 3600 ggccggttct ttaactctct ggaggccagc gacgatgagc ccaaggacgc cgatgccaat 3660 ggcgcctacc acatcgccct gaagggcctg atgaacctgc tggtgctgaa tgagacaaag 3720 gaggagaacc tgagcagacc aaagtggaag atcaagaata aggactggct ggagttcgtg 3780 tgggagagga accgcaaaag gccggcggcc acgaaaaagg ccggccaggc aaaaaagaaa 3840 aagggatcct acccatacga tgttccagat tacgcttatc cctacgacgt gcctgattat 3900 gcatacccat atgatgtccc cgactatgcc taagaattc 3939 <210> 1271 <211> 1263 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1271

    Met Glu Asp Tyr Ser Gly Phe Val Asn Ile Tyr Ser Ile Gln Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu His Ile Glu 20 25 30

    Lys Lys Gly Phe Leu Lys Lys Asp Lys Ile Arg Ala Glu Asp Tyr Lys 35 40 45

    Ala Val Lys Lys Ile Ile Asp Lys Tyr His Arg Ala Tyr Ile Glu Glu 50 55 60

    Val Phe Asp Ser Val Leu His Gln Lys Lys Lys Lys Asp Lys Thr Arg 65 70 75 80

    Phe Ser Thr Gln Phe Ile Lys Glu Ile Lys Glu Phe Ser Glu Leu Tyr 85 90 95

    Tyr Lys Thr Glu Lys Asn Ile Pro Asp Lys Glu Arg Leu Glu Ala Leu 100 105 110

    Ser Glu Lys Leu Arg Lys Met Leu Val Gly Ala Phe Lys Gly Glu Phe 115 120 125

    Ser Glu Glu Val Ala Glu Lys Tyr Lys Asn Leu Phe Ser Lys Glu Leu 130 135 140

    Ile Arg Asn Glu Ile Glu Lys Phe Cys Glu Thr Asp Glu Glu Arg Lys 145 150 155 160

    Gln Val Ser Asn Phe Lys Ser Phe Thr Thr Tyr Phe Thr Gly Phe His 165 170 175

    Ser Asn Arg Gln Asn Ile Tyr Ser Asp Glu Lys Lys Ser Thr Ala Ile 180 185 190

    Gly Tyr Arg Ile Ile His Gln Asn Leu Pro Lys Phe Leu Asp Asn Leu 195 200 205

    Lys Ile Ile Glu Ser Ile Gln Arg Arg Phe Lys Asp Phe Pro Trp Ser 210 215 220

    Asp Leu Lys Lys Asn Leu Lys Lys Ile Asp Lys Asn Ile Lys Leu Thr 225 230 235 240

    Glu Tyr Phe Ser Ile Asp Gly Phe Val Asn Val Leu Asn Gln Lys Gly 245 250 255

    Ile Asp Ala Tyr Asn Thr Ile Leu Gly Gly Lys Ser Glu Glu Ser Gly 260 265 270

    Glu Lys Ile Gln Gly Leu Asn Glu Tyr Ile Asn Leu Tyr Arg Gln Lys 275 280 285

    Asn Asn Ile Asp Arg Lys Asn Leu Pro Asn Val Lys Ile Leu Phe Lys 290 295 300

    Gln Ile Leu Gly Asp Arg Glu Thr Lys Ser Phe Ile Pro Glu Ala Phe 305 310 315 320

    Pro Asp Asp Gln Ser Val Leu Asn Ser Ile Thr Glu Phe Ala Lys Tyr 325 330 335

    Leu Lys Leu Asp Lys Lys Lys Lys Ser Ile Ile Ala Glu Leu Lys Lys 340 345 350

    Phe Leu Ser Ser Phe Asn Arg Tyr Glu Leu Asp Gly Ile Tyr Leu Ala 355 360 365

    Asn Asp Asn Ser Leu Ala Ser Ile Ser Thr Phe Leu Phe Asp Asp Trp 370 375 380

    Ser Phe Ile Lys Lys Ser Val Ser Phe Lys Tyr Asp Glu Ser Val Gly 385 390 395 400

    Asp Pro Lys Lys Lys Ile Lys Ser Pro Leu Lys Tyr Glu Lys Glu Lys 405 410 415

    Glu Lys Trp Leu Lys Gln Lys Tyr Tyr Thr Ile Ser Phe Leu Asn Asp

    420

    425

    430

    Ala Ile Glu Ser Tyr Ser Lys Ser Gln Asp Glu Lys Arg Val Lys Ile 435 440 445

    Arg Leu Glu Ala Tyr Phe Ala Glu Phe Lys Ser Lys Asp Asp Ala Lys 450 455 460

    Lys Gln Phe Asp Leu Leu Glu Arg Ile Glu Glu Ala Tyr Ala Ile Val 465 470 475 480

    Glu Pro Leu Leu Gly Ala Glu Tyr Pro Arg Asp Arg Asn Leu Lys Ala 485 490 495

    Asp Lys Lys Glu Val Gly Lys Ile Lys Asp Phe Leu Asp Ser Ile Lys 500 505 510

    Ser Leu Gln Phe Phe Leu Lys Pro Leu Leu Ser Ala Glu Ile Phe Asp 515 520 525

    Glu Lys Asp Leu Gly Phe Tyr Asn Gln Leu Glu Gly Tyr Tyr Glu Glu 530 535 540

    Ile Asp Ser Ile Gly His Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr 545 550 555 560

    Gly Lys Ile Tyr Ser Lys Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser 565 570 575

    Thr Leu Leu Lys Gly Trp Asp Glu Asn Arg Glu Val Ala Asn Leu Cys 580 585 590

    Val Ile Phe Arg Glu Asp Gln Lys Tyr Tyr Leu Gly Val Met Asp Lys 595 600 605

    Glu Asn Asn Thr Ile Leu Ser Asp Ile Pro Lys Val Lys Pro Asn Glu 610 615 620

    Leu Phe Tyr Glu Lys Met Val Tyr Lys Leu Ile Pro Thr Pro His Met 625 630 635 640

    Gln Leu Pro Arg Ile Ile Phe Ser Ser Asp Asn Leu Ser Ile Tyr Asn 645 650 655

    Pro Ser Lys Ser Ile Leu Lys Ile Arg Glu Ala Lys Ser Phe Lys Glu 660 665 670

    Gly Lys Asn Phe Lys Leu Lys Asp Cys His Lys Phe Ile Asp Phe Tyr 675 680 685

    Lys Glu Ser Ile Ser Lys Asn Glu Asp Trp Ser Arg Phe Asp Phe Lys 690 695 700

    Phe Ser Lys Thr Ser Ser Tyr Glu Asn Ile Ser Glu Phe Tyr Arg Glu 705 710 715 720

    Val Glu Arg Gln Gly Tyr Asn Leu Asp Phe Lys Lys Val Ser Lys Phe 725 730 735

    Tyr Ile Asp Ser Leu Val Glu Asp Gly Lys Leu Tyr Leu Phe Gln Ile 740 745 750

    Tyr Asn Lys Asp Phe Ser Ile Phe Ser Lys Gly Lys Pro Asn Leu His 755 760 765

    Thr Ile Tyr Phe Arg Ser Leu Phe Ser Lys Glu Asn Leu Lys Asp Val 770 775 780

    Cys Leu Lys Leu Asn Gly Glu Ala Glu Met Phe Phe Arg Lys Lys Ser 785 790 795 800

    Ile Asn Tyr Asp Glu Lys Lys Lys Arg Glu Gly His His Pro Glu Leu 805 810 815

    Phe Glu Lys Leu Lys Tyr Pro Ile Leu Lys Asp Lys Arg Tyr Ser Glu 820 825 830

    Asp Lys Phe Gln Phe His Leu Pro Ile Ser Leu Asn Phe Lys Ser Lys 835 840 845

    Glu Arg Leu Asn Phe Asn Leu Lys Val Asn Glu Phe Leu Lys Arg Asn 850 855 860

    Lys Asp Ile Asn Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu 865 870 875 880

    Tyr Leu Val Met Ile Asn Gln Lys Gly Glu Ile Leu Lys Gln Thr Leu 885 890 895

    Leu Asp Ser Met Gln Ser Gly Lys Gly Arg Pro Glu Ile Asn Tyr Lys 900 905 910

    Glu Lys Leu Gln Glu Lys Glu Ile Glu Arg Asp Lys Ala Arg Lys Ser 915 920 925

    Trp Gly Thr Val Glu Asn Ile Lys Glu Leu Lys Glu Gly Tyr Leu Ser 930 935 940

    Ile Val Ile His Gln Ile Ser Lys Leu Met Val Glu Asn Asn Ala Ile 945 950 955 960

    Val Val Leu Glu Asp Leu Asn Ile Gly Phe Lys Arg Gly Arg Gln Lys 965 970 975

    Val Glu Arg Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys 980 985 990

    Leu Asn Phe Leu Val Phe Lys Glu Asn Lys Pro Thr Glu Pro Gly Gly 995 1000 1005

    Val Leu Lys Ala Tyr Gln Leu Thr Asp Glu Phe Gln Ser Phe Glu 1010 1015 1020

    Lys Leu Ser Lys Gln Thr Gly Phe Leu Phe Tyr Val Pro Ser Trp 1025 1030 1035

    Asn Thr Ser Lys Ile Asp Pro Arg Thr Gly Phe Ile Asp Phe Leu 1040 1045 1050

    His Pro Ala Tyr Glu Asn Ile Glu Lys Ala Lys Gln Trp Ile Asn 1055 1060 1065

    Lys Phe Asp Ser Ile Arg Phe Asn Ser Lys Met Asp Trp Phe Glu 1070 1075 1080

    Phe Thr Ala Asp Thr Arg Lys Phe Ser Glu Asn Leu Met Leu Gly 1085 1090 1095

    Lys Asn Arg Val Trp Val Ile Cys Thr Thr Asn Val Glu Arg Tyr 1100 1105 1110

    Phe Thr Ser Lys Thr Ala Asn Ser Ser Ile Gln Tyr Asn Ser Ile 1115 1120 1125

    Gln Ile Thr Glu Lys Leu Lys Glu Leu Phe Val Asp Ile Pro Phe

    1130 1135 1140

    Ser Asn Gly Gln Asp Leu Lys Pro Glu Ile Leu Arg Lys Asn Asp 1145 1150 1155

    Ala Val Phe Phe Lys Ser Leu Leu Phe Tyr Ile Lys Thr Thr Leu 1160 1165 1170

    Ser Leu Arg Gln Asn Asn Gly Lys Lys Gly Glu Glu Glu Lys Asp 1175 1180 1185

    Phe Ile Leu Ser Pro Val Val Asp Ser Lys Gly Arg Phe Phe Asn 1190 1195 1200

    Ser Leu Glu Ala Ser Asp Asp Glu Pro Lys Asp Ala Asp Ala Asn 1205 1210 1215

    Gly Ala Tyr His Ile Ala Leu Lys Gly Leu Met Asn Leu Leu Val 1220 1225 1230

    Leu Asn Glu Thr Lys Glu Glu Asn Leu Ser Arg Pro Lys Trp Lys 1235 1240 1245

    Ile Lys Asn Lys Asp Trp Leu Glu Phe Val Trp Glu Arg Asn Arg 1250 1255 1260 <210> 1272 <211> 3834 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1272 ggtaccatga gcaagctgga gaagtttaca aactgctact ccctgtctaa gaccctgagg 60 ttcaaggcca tccctgtggg caagacccag gagaacatcg acaataagcg gctgctggtg 120 gaggacgaga agagagccga ggattataag ggcgtgaaga agctgctgga tcgctactat 180 ctgtctttta tcaacgacgt gctgcacagc atcaagctga agaatctgaa caattacatc 240 agcctgttcc ggaagaaaac cagaaccgag aaggagaata aggagctgga gaacctggag 300 atcaatctgc ggaaggagat cgccaaggcc ttcaagggca acgagggcta caagtccctg 360 tttaagaagg atatcatcga gacaatcctg ccagagttcc tggacgataa ggacgagatc 420 gccctggtga acagcttcaa tggctttacc acagccttca ccggcttctt tgataacaga 480 gagaatatgt tttccgagga ggccaagagc acatccatcg ccttcaggtg tatcaacgag 540 aatctgaccc gctacatctc taatatggac atcttcgaga aggtggacgc catctttgat 600 aagcacgagg tgcaggagat caaggagaag atcctgaaca gcgactatga tgtggaggat 660 ttctttgagg gcgagttctt taactttgtg ctgacacagg agggcatcga cgtgtataac 720 gccatcatcg gcggcttcgt gaccgagagc ggcgagaaga tcaagggcct gaacgagtac 780 atcaacctgt ataatcagaa aaccaagcag aagctgccta agtttaagcc actgtataag 840 caggtgctga gcgatcggga gtctctgagc ttctacggcg agggctatac atccgatgag 900 gaggtgctgg aggtgtttag aaacaccctg aacaagaaca gcgagatctt cagctccatc 960 aagaagctgg agaagctgtt caagaatttt gacgagtact ctagcgccgg catctttgtg 1020 aagaacggcc ccgccatcag cacaatctcc aaggatatct tcggcgagtg gaacgtgatc 1080 cgggacaagt ggaatgccga gtatgacgat atccacctga agaagaaggc cgtggtgacc 1140 gagaagtacg aggacgatcg gagaaagtcc ttcaagaaga tcggctcctt ttctctggag 1200 cagctgcagg agtacgccga cgccgatctg tctgtggtgg agaagctgaa ggagatcatc 1260 atccagaagg tggatgagat ctacaaggtg tatggctcct ctgagaagct gttcgacgcc 1320 gattttgtgc tggagaagag cctgaagaag aacgacgccg tggtggccat catgaaggac 1380 ctgctggatt ctgtgaagag cttcgagaat tacatcaagg ccttctttgg cgagggcaag 1440 gagacaaaca gggacgagtc cttctatggc gattttgtgc tggcctacga catcctgctg 1500 aaggtggacc acatctacga tgccatccgc aattatgtga cccagaagcc ctactctaag 1560 gataagttca agctgtattt tcagaaccct cagttcatgg gcggctggga caaggataag 1620 gagacagact atcgggccac catcctgaga tacggctcca agtactatct ggccatcatg 1680 gataagaagt acgccaagtg cctgcagaag atcgacaagg acgatgtgaa cggcaattac 1740 gagaagatca actataagct gctgcccggc cctaataaga tgctgccaaa ggtgttcttt 1800 tctaagaagt ggatggccta ctataacccc agcgaggaca tccagaagat ctacaagaat 1860 ggcacattca agaagggcga tatgtttaac ctgaatgact gtcacaagct gatcgacttc 1920 tttaaggata gcatctcccg gtatccaaag tggtccaatg cctacgattt caacttttct 1980 gagacagaga agtataagga catcgccggc ttttacagag aggtggagga gcagggctat 2040 aaggtgagct tcgagtctgc cagcaagaag gaggtggata agctggtgga ggagggcaag 2100 ctgtatatgt tccagatcta taacaaggac ttttccgata agtctcacgg cacacccaat 2160 ctgcacacca tgtacttcaa gctgctgttt gacgagaaca atcacggaca gatcaggctg 2220 agcggaggag cagagctgtt catgaggcgc gcctccctga agaaggagga gctggtggtg 2280 cacccagcca actcccctat cgccaacaag aatccagata atcccaagaa aaccacaacc 2340 ctgtcctacg acgtgtataa ggataagagg ttttctgagg accagtacga gctgcacatc 2400 ccaatcgcca tcaataagtg ccccaagaac atcttcaaga tcaatacaga ggtgcgcgtg 2460 ctgctgaagc acgacgataa cccctatgtg atcggcatcg ataggggcga gcgcaatctg 2520 ctgtatatcg tggtggtgga cggcaagggc aacatcgtgg agcagtattc cctgaacgag 2580 atcatcaaca acttcaacgg catcaggatc aagacagatt accactctct gctggacaag 2640 aaggagaagg agaggttcga ggcccgccag aactggacct ccatcgagaa tatcaaggag 2700 ctgaaggccg gctatatctc tcaggtggtg cacaagatct gcgagctggt ggagaagtac 2760 gatgccgtga tcgccctgga ggacctgaac tctggcttta agaatagccg cgtgaaggtg 2820 gagaagcagg tgtatcagaa gttcgagaag atgctgatcg ataagctgaa ctacatggtg 2880 gacaagaagt ctaatccttg tgcaacaggc ggcgccctga agggctatca gatcaccaat 2940 aagttcgaga gctttaagtc catgtctacc cagaacggct tcatctttta catccctgcc 3000 tggctgacat ccaagatcga tccatctacc ggctttgtga acctgctgaa aaccaagtat 3060 accagcatcg ccgattccaa gaagttcatc agctcctttg acaggatcat gtacgtgccc 3120 gaggaggatc tgttcgagtt tgccctggac tataagaact tctctcgcac agacgccgat 3180 tacatcaaga agtggaagct gtactcctac ggcaaccgga tcagaatctt ccggaatcct 3240 aagaagaaca acgtgttcga ctgggaggag gtgtgcctga ccagcgccta taaggagctg 3300 ttcaacaagt acggcatcaa ttatcagcag ggcgatatca gagccctgct gtgcgagcag 3360 tccgacaagg ccttctactc tagctttatg gccctgatga gcctgatgct gcagatgcgg 3420 aacagcatca caggccgcac cgacgtggat tttctgatca gccctgtgaa gaactccgac 3480 ggcatcttct acgatagccg gaactatgag gcccaggaga atgccatcct gccaaagaac 3540 gccgacgcca atggcgccta taacatcgcc agaaaggtgc tgtgggccat cggccagttc 3600 aagaaggccg aggacgagaa gctggataag gtgaagatcg ccatctctaa caaggagtgg 3660 ctggagtacg cccagaccag cgtgaagcac aaaaggccgg cggccacgaa aaaggccggc 3720 caggcaaaaa agaaaaaggg atcctaccca tacgatgttc cagattacgc ttatccctac 3780 gacgtgcctg attatgcata cccatatgat gtccccgact atgcctaaga attc 3834 <210> 1273 <211> 1228 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1273

    Met Ser Lys Leu Glu Lys Phe Thr Asn Cys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Lys Ala Ile Pro Val Gly Lys Thr Gln Glu Asn Ile Asp 20 25 30

    Asn Lys Arg Leu Leu Val Glu Asp Glu Lys Arg Ala Glu Asp Tyr Lys 35 40 45

    Gly Val Lys Lys Leu Leu Asp Arg Tyr Tyr Leu Ser Phe Ile Asn Asp 50 55 60

    Val Leu His Ser Ile Lys Leu Lys Asn Leu Asn Asn Tyr Ile Ser Leu 65 70 75 80

    Phe Arg Lys Lys Thr Arg Thr Glu Lys Glu Asn Lys Glu Leu Glu Asn 85 90 95

    Leu Glu Ile Asn Leu Arg Lys Glu Ile Ala Lys Ala Phe Lys Gly Asn 100 105 110

    Glu Gly Tyr Lys Ser Leu Phe Lys Lys Asp Ile Ile Glu Thr Ile Leu 115 120 125

    Pro Glu Phe Leu Asp Asp Lys Asp Glu Ile Ala Leu Val Asn Ser Phe 130 135 140

    Asn Gly Phe Thr Thr Ala Phe Thr Gly Phe Phe Asp Asn Arg Glu Asn 145 150 155 160

    Met Phe Ser Glu Glu Ala Lys Ser Thr Ser Ile Ala Phe Arg Cys Ile

    165

    170

    175

    Asn Glu Asn Leu Thr Arg Tyr Ile Ser Asn Met Asp Ile Phe Glu Lys 180 185 190

    Val Asp Ala Ile Phe Asp Lys His Glu Val Gln Glu Ile Lys Glu Lys 195 200 205

    Ile Leu Asn Ser Asp Tyr Asp Val Glu Asp Phe Phe Glu Gly Glu Phe 210 215 220

    Phe Asn Phe Val Leu Thr Gln Glu Gly Ile Asp Val Tyr Asn Ala Ile 225 230 235 240

    Ile Gly Gly Phe Val Thr Glu Ser Gly Glu Lys Ile Lys Gly Leu Asn 245 250 255

    Glu Tyr Ile Asn Leu Tyr Asn Gln Lys Thr Lys Gln Lys Leu Pro Lys 260 265 270

    Phe Lys Pro Leu Tyr Lys Gln Val Leu Ser Asp Arg Glu Ser Leu Ser 275 280 285

    Phe Tyr Gly Glu Gly Tyr Thr Ser Asp Glu Glu Val Leu Glu Val Phe 290 295 300

    Arg Asn Thr Leu Asn Lys Asn Ser Glu Ile Phe Ser Ser Ile Lys Lys 305 310 315 320

    Leu Glu Lys Leu Phe Lys Asn Phe Asp Glu Tyr Ser Ser Ala Gly Ile 325 330 335

    Phe Val Lys Asn Gly Pro Ala Ile Ser Thr Ile Ser Lys Asp Ile Phe 340 345 350

    Gly Glu Trp Asn Val Ile Arg Asp Lys Trp Asn Ala Glu Tyr Asp Asp 355 360 365

    Ile His Leu Lys Lys Lys Ala Val Val Thr Glu Lys Tyr Glu Asp Asp 370 375 380

    Arg Arg Lys Ser Phe Lys Lys Ile Gly Ser Phe Ser Leu Glu Gln Leu 385 390 395 400

    Gln Glu Tyr Ala Asp Ala Asp Leu Ser Val Val Glu Lys Leu Lys Glu 405 410 415

    Ile Ile Ile Gln Lys Val Asp Glu Ile Tyr Lys Val Tyr Gly Ser Ser 420 425 430

    Glu Lys Leu Phe Asp Ala Asp Phe Val Leu Glu Lys Ser Leu Lys Lys 435 440 445

    Asn Asp Ala Val Val Ala Ile Met Lys Asp Leu Leu Asp Ser Val Lys 450 455 460

    Ser Phe Glu Asn Tyr Ile Lys Ala Phe Phe Gly Glu Gly Lys Glu Thr 465 470 475 480

    Asn Arg Asp Glu Ser Phe Tyr Gly Asp Phe Val Leu Ala Tyr Asp Ile 485 490 495

    Leu Leu Lys Val Asp His Ile Tyr Asp Ala Ile Arg Asn Tyr Val Thr 500 505 510

    Gln Lys Pro Tyr Ser Lys Asp Lys Phe Lys Leu Tyr Phe Gln Asn Pro 515 520 525

    Gln Phe Met Gly Gly Trp Asp Lys Asp Lys Glu Thr Asp Tyr Arg Ala 530 535 540

    Thr Ile Leu Arg Tyr Gly Ser Lys Tyr Tyr Leu Ala Ile Met Asp Lys 545 550 555 560

    Lys Tyr Ala Lys Cys Leu Gln Lys Ile Asp Lys Asp Asp Val Asn Gly 565 570 575

    Asn Tyr Glu Lys Ile Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met 580 585 590

    Leu Pro Lys Val Phe Phe Ser Lys Lys Trp Met Ala Tyr Tyr Asn Pro 595 600 605

    Ser Glu Asp Ile Gln Lys Ile Tyr Lys Asn Gly Thr Phe Lys Lys Gly 610 615 620

    Asp Met Phe Asn Leu Asn Asp Cys His Lys Leu Ile Asp Phe Phe Lys 625 630 635 640

    Asp Ser Ile Ser Arg Tyr Pro Lys Trp Ser Asn Ala Tyr Asp Phe Asn 645 650 655

    Phe Ser Glu Thr Glu Lys Tyr Lys Asp Ile Ala Gly Phe Tyr Arg Glu 660 665 670

    Val Glu Glu Gln Gly Tyr Lys Val Ser Phe Glu Ser Ala Ser Lys Lys 675 680 685

    Glu Val Asp Lys Leu Val Glu Glu Gly Lys Leu Tyr Met Phe Gln Ile 690 695 700

    Tyr Asn Lys Asp Phe Ser Asp Lys Ser His Gly Thr Pro Asn Leu His 705 710 715 720

    Thr Met Tyr Phe Lys Leu Leu Phe Asp Glu Asn Asn His Gly Gln Ile 725 730 735

    Arg Leu Ser Gly Gly Ala Glu Leu Phe Met Arg Arg Ala Ser Leu Lys 740 745 750

    Lys Glu Glu Leu Val Val His Pro Ala Asn Ser Pro Ile Ala Asn Lys 755 760 765

    Asn Pro Asp Asn Pro Lys Lys Thr Thr Thr Leu Ser Tyr Asp Val Tyr 770 775 780

    Lys Asp Lys Arg Phe Ser Glu Asp Gln Tyr Glu Leu His Ile Pro Ile 785 790 795 800

    Ala Ile Asn Lys Cys Pro Lys Asn Ile Phe Lys Ile Asn Thr Glu Val 805 810 815

    Arg Val Leu Leu Lys His Asp Asp Asn Pro Tyr Val Ile Gly Ile Asp 820 825 830

    Arg Gly Glu Arg Asn Leu Leu Tyr Ile Val Val Val Asp Gly Lys Gly 835 840 845

    Asn Ile Val Glu Gln Tyr Ser Leu Asn Glu Ile Ile Asn Asn Phe Asn 850 855 860

    Gly Ile Arg Ile Lys Thr Asp Tyr His Ser Leu Leu Asp Lys Lys Glu 865 870 875 880

    Lys Glu Arg Phe Glu Ala Arg Gln Asn Trp Thr Ser Ile Glu Asn Ile

    885

    890

    895

    Lys Glu Leu Lys Ala Gly Tyr Ile Ser Gln Val Val His Lys Ile Cys 900 905 910

    Glu Leu Val Glu Lys Tyr Asp Ala Val Ile Ala Leu Glu Asp Leu Asn 915 920 925

    Ser Gly Phe Lys Asn Ser Arg Val Lys Val Glu Lys Gln Val Tyr Gln 930 935 940

    Lys Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Tyr Met Val Asp Lys 945 950 955 960

    Lys Ser Asn Pro Cys Ala Thr Gly Gly Ala Leu Lys Gly Tyr Gln Ile 965 970 975

    Thr Asn Lys Phe Glu Ser Phe Lys Ser Met Ser Thr Gln Asn Gly Phe 980 985 990

    Ile Phe Tyr Ile Pro Ala Trp Leu Thr Ser Lys Ile Asp Pro Ser Thr 995 1000 1005

    Gly Phe Val Asn Leu Leu Lys Thr Lys Tyr Thr Ser Ile Ala Asp 1010 1015 1020

    Ser Lys Lys Phe Ile Ser Ser Phe Asp Arg Ile Met Tyr Val Pro 1025 1030 1035

    Glu Glu Asp Leu Phe Glu Phe Ala Leu Asp Tyr Lys Asn Phe Ser 1040 1045 1050

    Arg Thr Asp Ala Asp Tyr Ile Lys Lys Trp Lys Leu Tyr Ser Tyr 1055 1060 1065

    Gly Asn Arg Ile Arg Ile Phe Arg Asn Pro Lys Lys Asn Asn Val 1070 1075 1080

    Phe Asp Trp Glu Glu Val Cys Leu Thr Ser Ala Tyr Lys Glu Leu 1085 1090 1095

    Phe Asn Lys Tyr Gly Ile Asn Tyr Gln Gln Gly Asp Ile Arg Ala 1100 1105 1110

    Leu Leu Cys Glu Gln Ser Asp Lys Ala Phe Tyr Ser Ser Phe Met 1115 1120 1125

    Ala Leu Met Ser Leu Met Leu Gln Met Arg Asn Ser Ile Thr Gly 1130 1135 1140

    Arg Thr Asp Val Asp Phe Leu Ile Ser Pro Val Lys Asn Ser Asp 1145 1150 1155

    Gly Ile Phe Tyr Asp Ser Arg Asn Tyr Glu Ala Gln Glu Asn Ala 1160 1165 1170

    Ile Leu Pro Lys Asn Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala 1175 1180 1185

    Arg Lys Val Leu Trp Ala Ile Gly Gln Phe Lys Lys Ala Glu Asp 1190 1195 1200

    Leu Glu Tyr Ala Gln Thr Ser Val Lys His 1220 1225

    Glu Lys Leu Asp Lys Val Lys Ile Ala Ile Ser Asn Lys Glu Trp

    1205 1210 1215 <210> 1274 <211>3930 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1274 ggtaccatgg acagcctgaa ggatttcacc aacctgtacc ccgtgtccaa gacactgcgg 60 tttgagctga agcctgtggg caagaccctg gagaatatcg agaaggccgg catcctgaag 120 gaggatgagc acagagccga gagctaccgg agagtgaaga agatcatcga tacatatcac 180 aaggtgttca tcgacagctc cctggagaac atggccaaga tgggcatcga gaatgagatc 240 aaggccatgc tgcagtcctt ttgcgagctg tataagaagg accacaggac cgagggagag 300 gacaaggccc tggataagat cagggccgtg ctgaggggcc tgatcgtggg agccttcacc 360 ggcgtgtgcg gccggcggga gaacacagtg cagaatgaga agtatgagag cctgtttaag 420 gagaagctga tcaaggagat cctgccagat ttcgtgctgt ctacagaggc cgagtccctg 480 cccttttctg tggaggaggc caccagaagc ctgaaggagt tcgactcctt tacatcttac 540 ttcgccggct tttatgagaa ccggaagaat atctactcta ccaagcccca gagcacagcc 600 atcgcctata gactgatcca cgagaacctg cctaagttca tcgataatat cctggtgttt 660 cagaagatca aggagccaat cgccaaggag ctggagcaca tcagggcaga cttcagcgcc 720 ggcggctaca tcaagaagga tgagcgcctg gaggacatct tttccctgaa ctactatatc 780 cacgtgctgt ctcaggccgg catcgagaag tacaatgccc tgatcggcaa gatcgtgacc 840 gagggcgatg gcgagatgaa gggcctgaac gagcacatca acctgtataa tcagcagagg 900 ggccgcgagg accggctgcc actgttcaga cccctgtata agcagatcct gtctgatagg 960 gagcagctgt cctatctgcc agagtctttc gagaaggacg aggagctgct gagggccctg 1020

    aaggagtttt acgatcacat cgcagaggac atcctgggaa ggacccagca gctgatgaca 1080 agcatctccg agtacgatct gtcccggatc tatgtgagaa acgatagcca gctgaccgac 1140 atctccaaga agatgctggg cgattggaat gccatctaca tggcccggga gagagcctat 1200

    gaccacgagc aggcccccaa gcgcatcaca gccaagtacg agagggaccg catcaaggcc 1260

    ctgaagggcg aggagtctat cagcctggcc aacctgaaca gctgcatcgc cttcctggac 1320 aacgtgaggg attgtcgcgt ggacacctat ctgtctacac tgggacagaa ggagggacct 1380 cacggcctga gcaacctggt ggagaacgtg ttcgcctcct accacgaggc cgagcagctg 1440

    ctgtcttttc cctatcctga ggagaacaat ctgatccagg acaaggataa cgtggtgctg 1500

    atcaagaacc tgctggataa tatcagcgac ctgcagaggt tcctgaagcc actgtggggc 1560 atgggcgatg agcccgacaa ggatgagagg ttttacggcg agtacaatta tatcaggggc 1620 gccctggacc aggtcatccc tctgtataac aaggtgcgga attatctgac ccgcaagcca 1680 tactccacac gcaaggtgaa gctgaacttc ggcaatagcc agctgctgtc cggctgggat 1740 aggaacaagg agaaggacaa ttcttgcgtg atcctgcgca agggccagaa cttctacctg 1800 gccatcatga acaatcggca caagcggagc ttcgagaata agatgctgcc cgagtataag 1860 gagggcgagc cttacttcga gaagatggat tataagtttc tgccagaccc caacaagatg 1920 ctgcccaagg tgttcctgtc taagaagggc atcgagatct acaagcctag cccaaagctg 1980 ctggagcagt atggccacgg cacccacaag aagggcgata ccttcagcat ggacgatctg 2040 cacgagctga tcgacttctt taagcactcc atcgaggccc acgaggattg gaagcagttc 2100 ggctttaagt tcagcgacac cgccacatac gagaacgtga gcagcttcta ccgggaggtg 2160

    gaggaccagg gctacaagct gtcttttaga aaggtgtccg agtcttacgt gtatagcctg 2220 atcgatcagg gcaagctgta cctgttccag atctataaca aggactttag cccttgttcc 2280 aagggcaccc caaatctgca cacactgtac tggcggatgc tgttcgatga gagaaacctg 2340 gccgacgtga tctataagct ggatggcaag gccgagatct tctttcggga gaagtccctg 2400 aagaatgacc acccaaccca ccctgcaggc aagcccatca agaagaagag ccggcagaag 2460 aagggcgagg agagcctgtt cgagtacgat ctggtgaagg accggagata taccatggat 2520 aagtttcagt tccacgtgcc aatcacaatg aactttaagt gctctgccgg cagcaaggtg 2580 aacgacatgg tgaatgccca catcagggag gccaaggaca tgcacgtgat cggcatcgat 2640 aggggcgagc gcaatctgct gtatatctgc gtgatcgaca gccgcggcac catcctggat 2700 cagatctccc tgaacacaat caatgacatc gattatcacg atctgctgga gtccagggac 2760 aaggatcgcc agcaggagca caggaactgg cagaccatcg agggcatcaa ggagctgaag 2820 cagggctacc tgtctcaggc cgtgcaccgc atcgccgagc tgatggtggc ctataaggcc 2880 gtggtggccc tggaggacct gaacatgggc ttcaagcggg gcagacagaa ggtggagagc 2940 agcgtgtacc agcagtttga gaagcagctg atcgacaagc tgaattatct ggtggataag 3000 aagaagcggc ccgaggacat cggaggcctg ctgagagcct accagttcac cgcccctttc 3060 aagagcttta aggagatggg caagcagaac ggctttctgt tctatatccc tgcctggaac 3120 acatccaata tcgacccaac cacaggcttc gtgaacctgt ttcacgtgca gtacgagaat 3180 gtggataagg ccaagagctt ctttcagaag ttcgacagca tctcctacaa ccctaagaag 3240 gattggtttg agttcgcctt tgactataag aacttcacca agaaggccga gggctctagg 3300 agcatgtgga ttctgtgcac ccacggctcc cggatcaaga acttcagaaa ttctcagaag 3360 aatggccagt gggatagcga ggagtttgcc ctgaccgagg ccttcaagtc cctgtttgtg 3420 cggtacgaga tcgattatac cgccgacctg aaaaccgcca tcgtggacga gaagcagaag 3480 gatttctttg tggacctgct gaagctgttc aagctgaccg tgcagatgag aaactcctgg 3540 aaggagaagg acctggatta cctgatctct ccagtggccg gcgccgatgg caggttcttt 3600 gacacacgcg agggcaataa gagcctgccc aaggacgcag atgcaaacgg agcctataat 3660 atcgccctga agggcctgtg ggcactgagg cagatcagac agacctccga gggcggcaag 3720

    3840 ctgaagctgg ccatctctaa caaggagtgg ctgcagtttg tgcaggagag atcctacgag 3780 aaggacaaaa ggccggcggc cacgaaaaag gccggccagg caaaaaagaa aaagggatcc tacccatacg atgttccaga ttacgcttat ccctacgacg tgcctgatta tgcataccca 3900 tatgatgtcc ccgactatgc ctaagaattc 3930 <210> 1275 <211> 1260 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1275

    Met Asp Ser Leu Lys Asp Phe Thr Asn Leu Tyr Pro Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Val Gly Lys Thr Leu Glu Asn Ile Glu 20 25 30

    Lys Ala Gly Ile Leu Lys Glu Asp Glu His Arg Ala Glu Ser Tyr Arg 35 40 45

    Arg Val Lys Lys Ile Ile Asp Thr Tyr His Lys Val Phe Ile Asp Ser 50 55 60

    Ser Leu Glu Asn Met Ala Lys Met Gly Ile Glu Asn Glu Ile Lys Ala 65 70 75 80

    Met Leu Gln Ser Phe Cys Glu Leu Tyr Lys Lys Asp His Arg Thr Glu 85 90 95

    Gly Glu Asp Lys Ala Leu Asp Lys Ile Arg Ala Val Leu Arg Gly Leu 100 105 110

    Ile Val Gly Ala Phe Thr Gly Val Cys Gly Arg Arg Glu Asn Thr Val 115 120 125

    Gln Asn Glu Lys Tyr Glu Ser Leu Phe Lys Glu Lys Leu Ile Lys Glu 130 135 140

    Ile Leu Pro Asp Phe Val Leu Ser Thr Glu Ala Glu Ser Leu Pro Phe 145 150 155 160

    Ser Val Glu Glu Ala Thr Arg Ser Leu Lys Glu Phe Asp Ser Phe Thr 165 170 175

    Ser Tyr Phe Ala Gly Phe Tyr Glu Asn Arg Lys Asn Ile Tyr Ser Thr 180 185 190

    Lys Pro Gln Ser Thr Ala Ile Ala Tyr Arg Leu Ile His Glu Asn Leu 195 200 205

    Pro Lys Phe Ile Asp Asn Ile Leu Val Phe Gln Lys Ile Lys Glu Pro 210 215 220

    Ile Ala Lys Glu Leu Glu His Ile Arg Ala Asp Phe Ser Ala Gly Gly 225 230 235 240

    Tyr Ile Lys Lys Asp Glu Arg Leu Glu Asp Ile Phe Ser Leu Asn Tyr 245 250 255

    Tyr Ile His Val Leu Ser Gln Ala Gly Ile Glu Lys Tyr Asn Ala Leu 260 265 270

    Ile Gly Lys Ile Val Thr Glu Gly Asp Gly Glu Met Lys Gly Leu Asn 275 280 285

    Glu His Ile Asn Leu Tyr Asn Gln Gln Arg Gly Arg Glu Asp Arg Leu 290 295 300

    Pro Leu Phe Arg Pro Leu Tyr Lys Gln Ile Leu Ser Asp Arg Glu Gln 305 310 315 320

    Leu Ser Tyr Leu Pro Glu Ser Phe Glu Lys Asp Glu Glu Leu Leu Arg 325 330 335

    Ala Leu Lys Glu Phe Tyr Asp His Ile Ala Glu Asp Ile Leu Gly Arg 340 345 350

    Thr Gln Gln Leu Met Thr Ser Ile Ser Glu Tyr Asp Leu Ser Arg Ile 355 360 365

    Tyr Val Arg Asn Asp Ser Gln Leu Thr Asp Ile Ser Lys Lys Met Leu 370 375 380

    Gly Asp Trp Asn Ala Ile Tyr Met Ala Arg Glu Arg Ala Tyr Asp His 385 390 395 400

    Glu Gln Ala Pro Lys Arg Ile Thr Ala Lys Tyr Glu Arg Asp Arg Ile 405 410 415

    Lys Ala Leu Lys Gly Glu Glu Ser Ile Ser Leu Ala Asn Leu Asn Ser 420 425 430

    Cys Ile Ala Phe Leu Asp Asn Val Arg Asp Cys Arg Val Asp Thr Tyr 435 440 445

    Leu Ser Thr Leu Gly Gln Lys Glu Gly Pro His Gly Leu Ser Asn Leu 450 455 460

    Val Glu Asn Val Phe Ala Ser Tyr His Glu Ala Glu Gln Leu Leu Ser 465 470 475 480

    Phe Pro Tyr Pro Glu Glu Asn Asn Leu Ile Gln Asp Lys Asp Asn Val 485 490 495

    Val Leu Ile Lys Asn Leu Leu Asp Asn Ile Ser Asp Leu Gln Arg Phe 500 505 510

    Leu Lys Pro Leu Trp Gly Met Gly Asp Glu Pro Asp Lys Asp Glu Arg 515 520 525

    Phe Tyr Gly Glu Tyr Asn Tyr Ile Arg Gly Ala Leu Asp Gln Val Ile 530 535 540

    Pro Leu Tyr Asn Lys Val Arg Asn Tyr Leu Thr Arg Lys Pro Tyr Ser 545 550 555 560

    Thr Arg Lys Val Lys Leu Asn Phe Gly Asn Ser Gln Leu Leu Ser Gly 565 570 575

    Trp Asp Arg Asn Lys Glu Lys Asp Asn Ser Cys Val Ile Leu Arg Lys 580 585 590

    Gly Gln Asn Phe Tyr Leu Ala Ile Met Asn Asn Arg His Lys Arg Ser 595 600 605

    Phe Glu Asn Lys Met Leu Pro Glu Tyr Lys Glu Gly Glu Pro Tyr Phe 610 615 620

    Glu Lys Met Asp Tyr Lys Phe Leu Pro Asp Pro Asn Lys Met Leu Pro 625 630 635 640

    Lys Val Phe Leu Ser Lys Lys Gly Ile Glu Ile Tyr Lys Pro Ser Pro

    645

    650

    655

    Lys Leu Leu Glu Gln Tyr Gly His Gly Thr His Lys Lys Gly Asp Thr 660 665 670

    Phe Ser Met Asp Asp Leu His Glu Leu Ile Asp Phe Phe Lys His Ser 675 680 685

    Ile Glu Ala His Glu Asp Trp Lys Gln Phe Gly Phe Lys Phe Ser Asp 690 695 700

    Thr Ala Thr Tyr Glu Asn Val Ser Ser Phe Tyr Arg Glu Val Glu Asp 705 710 715 720

    Gln Gly Tyr Lys Leu Ser Phe Arg Lys Val Ser Glu Ser Tyr Val Tyr 725 730 735

    Ser Leu Ile Asp Gln Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys 740 745 750

    Asp Phe Ser Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr 755 760 765

    Trp Arg Met Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys 770 775 780

    Leu Asp Gly Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys Asn 785 790 795 800

    Asp His Pro Thr His Pro Ala Gly Lys Pro Ile Lys Lys Lys Ser Arg 805 810 815

    Gln Lys Lys Gly Glu Glu Ser Leu Phe Glu Tyr Asp Leu Val Lys Asp 820 825 830

    Arg Arg Tyr Thr Met Asp Lys Phe Gln Phe His Val Pro Ile Thr Met 835 840 845

    Asn Phe Lys Cys Ser Ala Gly Ser Lys Val Asn Asp Met Val Asn Ala 850 855 860

    His Ile Arg Glu Ala Lys Asp Met His Val Ile Gly Ile Asp Arg Gly 865 870 875 880

    Glu Arg Asn Leu Leu Tyr Ile Cys Val Ile Asp Ser Arg Gly Thr Ile 885 890 895

    Leu Asp Gln Ile Ser Leu Asn Thr Ile Asn Asp Ile Asp Tyr His Asp 900 905 910

    Leu Leu Glu Ser Arg Asp Lys Asp Arg Gln Gln Glu His Arg Asn Trp 915 920 925

    Gln Thr Ile Glu Gly Ile Lys Glu Leu Lys Gln Gly Tyr Leu Ser Gln 930 935 940

    Ala Val His Arg Ile Ala Glu Leu Met Val Ala Tyr Lys Ala Val Val 945 950 955 960

    Ala Leu Glu Asp Leu Asn Met Gly Phe Lys Arg Gly Arg Gln Lys Val 965 970 975

    Glu Ser Ser Val Tyr Gln Gln Phe Glu Lys Gln Leu Ile Asp Lys Leu 980 985 990

    Asn Tyr Leu Val Asp Lys Lys Lys Arg Pro Glu Asp Ile Gly Gly Leu 995 1000 1005

    Leu Arg Ala Tyr Gln Phe Thr Ala Pro Phe Lys Ser Phe Lys Glu 1010 1015 1020

    Met Gly Lys Gln Asn Gly Phe Leu Phe Tyr Ile Pro Ala Trp Asn 1025 1030 1035

    Thr Ser Asn Ile Asp Pro Thr Thr Gly Phe Val Asn Leu Phe His 1040 1045 1050 Val Gln Tyr Glu Asn Val Asp Lys Ala Lys Ser Phe Phe Gln Lys 1055 1060 1065 Phe Asp Ser Ile Ser Tyr Asn Pro Lys Lys Asp Trp Phe Glu Phe 1070 1075 1080

    Ala Phe Asp Tyr Lys Asn Phe Thr Lys Lys Ala Glu Gly Ser Arg 1085 1090 1095

    Ser Met Trp Ile Leu Cys Thr His Gly Ser Arg Ile Lys Asn Phe 1100 1105 1110

    Arg Asn Ser Gln Lys Asn Gly Gln Trp Asp Ser Glu Glu Phe Ala 1115 1120 1125

    Leu Thr Glu Ala Phe Lys Ser Leu Phe Val Arg Tyr Glu Ile Asp 1130 1135 1140

    Tyr Thr Ala Asp Leu Lys Thr Ala Ile Val Asp Glu Lys Gln Lys 1145 1150 1155

    Asp Phe Phe Val Asp Leu Leu Lys Leu Phe Lys Leu Thr Val Gln 1160 1165 1170

    Met Arg Asn Ser Trp Lys Glu Lys Asp Leu Asp Tyr Leu Ile Ser 1175 1180 1185

    Pro Val Ala Gly Ala Asp Gly Arg Phe Phe Asp Thr Arg Glu Gly 1190 1195 1200

    Asn Lys Ser Leu Pro Lys Asp Ala Asp Ala Asn Gly Ala Tyr Asn 1205 1210 1215

    Ile Ala Leu Lys Gly Leu Trp Ala Leu Arg Gln Ile Arg Gln Thr 1220 1225 1230

    Ser Glu Gly Gly Lys Leu Lys Leu Ala Ile Ser Asn Lys Glu Trp 1235 1240 1245

    Leu Gln Phe Val Gln Glu Arg Ser Tyr Glu Lys Asp 1250 1255 1260 <210> 1276 <211> 4119 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1276 ggtaccatgg agaactatca ggagttcacc aacctgtttc agctgaataa gacactgaga ttcgagctga agcccatcgg caagacctgc gagctgctgg aggagggcaa gatcttcgcc agcggctcct ttctggagaa ggacaaggtg agggccgata acgtgagcta cgtgaagaag gagatcgaca agaagcacaa gatctttatc gaggagacac tgagctcctt ctctatcagc aacgatctgc tgaagcagta ctttgactgc tataatgagc tgaaggcctt caagaaggac tgtaagagcg atgaggagga ggtgaagaaa accgccctgc gcaacaagtg tacctccatc

    120

    180

    240

    300

    360 cagagggcca tgcgcgaggc catctctcag gcctttctga agagccccca gaagaagctg 420 ctggccatca agaacctgat cgagaacgtg ttcaaggccg acgagaatgt gcagcacttc 480 tccgagttta ccagctattt ctccggcttt gagacaaaca gagagaattt ctactctgac 540 gaggagaagt ccacatctat cgcctatagg ctggtgcacg ataacctgcc tatcttcatc 600 aagaacatct acatcttcga gaagctgaag gagcagttcg acgccaagac cctgagcgag 660 atcttcgaga actacaagct gtatgtggcc ggctctagcc tggatgaggt gttctccctg 720 gagtacttta acaataccct gacacagaag ggcatcgaca actataatgc cgtgatcggc 780 aagatcgtga aggaggataa gcaggagatc cagggcctga acgagcacat caacctgtat 840 aatcagaagc acaaggaccg gagactgccc ttctttatct ccctgaagaa gcagatcctg 900 tccgatcggg aggccctgtc ttggctgcct gacatgttca agaatgattc tgaagtgatc 960 aaggccctga agggcttcta catcgaggac ggctttgaga acaatgtgct gacacctctg 1020 gccaccctgc tgtcctctct ggataagtac aacctgaatg gcatctttat ccgcaacaat 1080 gaggccctga gctccctgtc ccagaacgtg tatcggaatt tttctatcga cgaggccatc 1140 gatgccaacg ccgagctgca gaccttcaac aattacgagc tgatcgccaa tgccctgcgc 1200 gccaagatca agaaggagac aaagcagggc cggaagtctt tcgagaagta cgaggagtat 1260 atcgataaga aggtgaaggc catcgacagc ctgtccatcc aggagatcaa cgagctggtg 1320 gagaattacg tgagcgagtt taactctaat agcggcaaca tgccaagaaa ggtggaggac 1380 tacttcagcc tgatgaggaa gggcgacttc ggctccaacg atctgatcga aaatatcaag 1440 accaagctga gcgccgcaga gaagctgctg ggcacaaagt accaggagac agccaaggac 1500 atcttcaaga aggatgagaa ctccaagctg atcaaggagc tgctggacgc caccaagcag 1560 ttccagcact ttatcaagcc actgctgggc acaggcgagg aggcagatcg ggacctggtg 1620 ttctacggcg attttctgcc cctgtatgag aagtttgagg agctgaccct gctgtataac 1680 aaggtgcgga atagactgac acagaagccc tattccaagg acaagatccg cctgtgcttc 1740 aacaagccta agctgatgac aggctgggtg gattccaaga ccgagaagtc tgacaacggc 1800

    acacagtacg gcggctatct gtttcggaag aagaatgaga tcggcgagta cgattatttt 1860 ctgggcatct ctagcaaggc ccagctgttc agaaagaacg aggccgtgat cggcgactac 1920 gagaggctgg attactatca gccaaaggcc aataccatct acggctctgc ctatgagggc 1980

    gagaacagct acaaggagga caagaagcgg ctgaacaaag tgatcatcgc ctatatcgag 2040

    cagatcaagc agacaaacat caagaagtct atcatcgagt ccatctctaa gtatcctaat 2100 atcagcgacg atgacaaggt gaccccatcc tctctgctgg agaagatcaa gaaggtgtct 2160 atcgacagct acaacggcat cctgtccttc aagtcttttc agagcgtgaa caaggaagtg 2220 atcgataacc tgctgaaaac catcagcccc ctgaagaaca aggccgagtt tctggacctg 2280 atcaataagg attatcagat cttcaccgag gtgcaggccg tgatcgacga gatctgcaag 2340 cagaaaacct tcatctactt tccaatctcc aacgtggagc tggagaagga gatgggcgat 2400 aaggacaagc ccctgtgcct gttccagatc agcaataagg atctgtcctt cgccaagacc 2460 tttagcgcca acctgcggaa gaagagaggc gccgagaatc tgcacacaat gctgtttaag 2520 gccctgatgg agggcaacca ggataatctg gacctgggct ctggcgccat cttctacaga 2580

    gccaagagcc tggacggcaa caagcccaca caccctgcca atgaggccat caagtgtagg 2640

    aacgtggcca ataaggataa ggtgtccctg ttcacctacg acatctataa gaacaggcgc 2700 tacatggaga ataagttcct gtttcacctg agcatcgtgc agaactataa ggccgccaat 2760 gactccgccc agctgaacag ctccgccacc gagtatatca gaaaggccga tgacctgcac 2820 atcatcggca tcgatagggg cgagcgcaat ctgctgtact attccgtgat cgatatgaag 2880 ggcaacatcg tggagcagga ctctctgaat atcatcagga acaatgacct ggagacagat 2940

    taccacgacc tgctggataa gagggagaag gagcgcaagg ccaaccggca gaattgggag 3000 gccgtggagg gcatcaagga cctgaagaag ggctacctga gccaggccgt gcaccagatc 3060 gcccagctga tgctgaagta taacgccatc atcgccctgg aggatctggg ccagatgttt 3120 gtgacccgcg gccagaagat cgagaaggcc gtgtaccagc agttcgagaa gagcctggtg 3180 gataagctgt cctacctggt ggacaagaag cggccttata atgagctggg cggcatcctg 3240 aaggcctacc agctggcctc tagcatcacc aagaacaatt ctgacaagca gaacggcttc 3300 ctgttttatg tgccagcctg gaatacaagc aagatcgatc ccgtgaccgg ctttacagac 3360 ctgctgcggc ccaaggccat gaccatcaag gaggcccagg acttctttgg cgccttcgat 3420 aacatctctt acaatgacaa gggctatttc gagtttgaga caaactacga caagtttaag 3480 atcagaatga agagcgccca gaccaggtgg acaatctgca ccttcggcaa tcggatcaag 3540 agaaagaagg ataagaacta ctggaattat gaggaggtgg agctgaccga ggagttcaag 3600 aagctgttta aggacagcaa catcgattac gagaactgta atctgaagga ggagatccag 3660 aacaaggaca atcgcaagtt ctttgatgac ctgatcaagc tgctgcagct gacactgcag 3720 atgcggaact ccgatgacaa gggcaatgat tatatcatct ctcctgtggc caacgccgag 3780 ggccagttct ttgactcccg caatggcgat aagaagctgc cactggatgc agacgcaaac 3840 ggagcctaca atatcgcccg caagggcctg tggaacatcc ggcagatcaa gcagaccaag 3900 aacgacaaga agctgaatct gagcatctcc tctacagagt ggctggattt cgtgcgggag 3960 aagccttacc tgaagaaaag gccggcggcc acgaaaaagg ccggccaggc aaaaaagaaa 4020 aagggatcct acccatacga tgttccagat tacgcttatc cctacgacgt gcctgattat 4080 gcatacccat atgatgtccc cgactatgcc taagaattc 4119 <210> 1277 <211> 1323 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1277

    Met Glu Asn Tyr Gln Glu Phe Thr Asn Leu Phe Gln Leu Asn Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Cys Glu Leu Leu Glu 20 25 30

    Glu Gly Lys Ile Phe Ala Ser Gly Ser Phe Leu Glu Lys Asp Lys Val 35 40 45

    Arg Ala Asp Asn Val Ser Tyr Val Lys Lys Glu Ile Asp Lys Lys His 50 55 60

    Lys Ile Phe Ile Glu Glu Thr Leu Ser Ser Phe Ser Ile Ser Asn Asp 65 70 75 80

    Leu Leu Lys Gln Tyr Phe Asp Cys Tyr Asn Glu Leu Lys Ala Phe Lys 85 90 95

    Lys Asp Cys Lys Ser Asp Glu Glu Glu Val Lys Lys Thr Ala Leu Arg 100 105 110

    Asn Lys Cys Thr Ser Ile Gln Arg Ala Met Arg Glu Ala Ile Ser Gln 115 120 125

    Ala Phe Leu Lys Ser Pro Gln Lys Lys Leu Leu Ala Ile Lys Asn Leu 130 135 140

    Ile Glu Asn Val Phe Lys Ala Asp Glu Asn Val Gln His Phe Ser Glu 145 150 155 160

    Phe Thr Ser Tyr Phe Ser Gly Phe Glu Thr Asn Arg Glu Asn Phe Tyr 165 170 175

    Ser Asp Glu Glu Lys Ser Thr Ser Ile Ala Tyr Arg Leu Val His Asp 180 185 190

    Asn Leu Pro Ile Phe Ile Lys Asn Ile Tyr Ile Phe Glu Lys Leu Lys 195 200 205

    Glu Gln Phe Asp Ala Lys Thr Leu Ser Glu Ile Phe Glu Asn Tyr Lys 210 215 220

    Leu Tyr Val Ala Gly Ser Ser Leu Asp Glu Val Phe Ser Leu Glu Tyr 225 230 235 240

    Phe Asn Asn Thr Leu Thr Gln Lys Gly Ile Asp Asn Tyr Asn Ala Val 245 250 255

    Ile Gly Lys Ile Val Lys Glu Asp Lys Gln Glu Ile Gln Gly Leu Asn 260 265 270

    Glu His Ile Asn Leu Tyr Asn Gln Lys His Lys Asp Arg Arg Leu Pro 275 280 285

    Phe Phe Ile Ser Leu Lys Lys Gln Ile Leu Ser Asp Arg Glu Ala Leu 290 295 300

    Ser Trp Leu Pro Asp Met Phe Lys Asn Asp Ser Glu Val Ile Lys Ala 305 310 315 320

    Leu Lys Gly Phe Tyr Ile Glu Asp Gly Phe Glu Asn Asn Val Leu Thr 325 330 335

    Pro Leu Ala Thr Leu Leu Ser Ser Leu Asp Lys Tyr Asn Leu Asn Gly 340 345 350

    Ile Phe Ile Arg Asn Asn Glu Ala Leu Ser Ser Leu Ser Gln Asn Val 355 360 365

    Tyr Arg Asn Phe Ser Ile Asp Glu Ala Ile Asp Ala Asn Ala Glu Leu 370 375 380

    Gln Thr Phe Asn Asn Tyr Glu Leu Ile Ala Asn Ala Leu Arg Ala Lys 385 390 395 400

    Ile Lys Lys Glu Thr Lys Gln Gly Arg Lys Ser Phe Glu Lys Tyr Glu 405 410 415

    Glu Tyr Ile Asp Lys Lys Val Lys Ala Ile Asp Ser Leu Ser Ile Gln 420 425 430

    Glu Ile Asn Glu Leu Val Glu Asn Tyr Val Ser Glu Phe Asn Ser Asn 435 440 445

    Ser Gly Asn Met Pro Arg Lys Val Glu Asp Tyr Phe Ser Leu Met Arg 450 455 460

    Lys Gly Asp Phe Gly Ser Asn Asp Leu Ile Glu Asn Ile Lys Thr Lys 465 470 475 480

    Leu Ser Ala Ala Glu Lys Leu Leu Gly Thr Lys Tyr Gln Glu Thr Ala 485 490 495

    Lys Asp Ile Phe Lys Lys Asp Glu Asn Ser Lys Leu Ile Lys Glu Leu 500 505 510

    Leu Asp Ala Thr Lys Gln Phe Gln His Phe Ile Lys Pro Leu Leu Gly 515 520 525

    Thr Gly Glu Glu Ala Asp Arg Asp Leu Val Phe Tyr Gly Asp Phe Leu 530 535 540

    Pro Leu Tyr Glu Lys Phe Glu Glu Leu Thr Leu Leu Tyr Asn Lys Val 545 550 555 560

    Arg Asn Arg Leu Thr Gln Lys Pro Tyr Ser Lys Asp Lys Ile Arg Leu 565 570 575

    Cys Phe Asn Lys Pro Lys Leu Met Thr Gly Trp Val Asp Ser Lys Thr 580 585 590

    Glu Lys Ser Asp Asn Gly Thr Gln Tyr Gly Gly Tyr Leu Phe Arg Lys 595 600 605

    Lys Asn Glu Ile Gly Glu Tyr Asp Tyr Phe Leu Gly Ile Ser Ser Lys 610 615 620

    Ala Gln Leu Phe Arg Lys Asn Glu Ala Val Ile Gly Asp Tyr Glu Arg 625 630 635 640

    Leu Asp Tyr Tyr Gln Pro Lys Ala Asn Thr Ile Tyr Gly Ser Ala Tyr 645 650 655

    Glu Gly Glu Asn Ser Tyr Lys Glu Asp Lys Lys Arg Leu Asn Lys Val 660 665 670

    Ile Ile Ala Tyr Ile Glu Gln Ile Lys Gln Thr Asn Ile Lys Lys Ser 675 680 685

    Ile Ile Glu Ser Ile Ser Lys Tyr Pro Asn Ile Ser Asp Asp Asp Lys 690 695 700

    Val Thr Pro Ser Ser Leu Leu Glu Lys Ile Lys Lys Val Ser Ile Asp

    705

    710

    715

    720

    Ser Tyr Asn Gly Ile Leu Ser Phe Lys Ser Phe Gln Ser Val Asn Lys 725 730 735

    Glu Val Ile Asp Asn Leu Leu Lys Thr Ile Ser Pro Leu Lys Asn Lys 740 745 750

    Ala Glu Phe Leu Asp Leu Ile Asn Lys Asp Tyr Gln Ile Phe Thr Glu 755 760 765

    Val Gln Ala Val Ile Asp Glu Ile Cys Lys Gln Lys Thr Phe Ile Tyr 770 775 780

    Phe Pro Ile Ser Asn Val Glu Leu Glu Lys Glu Met Gly Asp Lys Asp 785 790 795 800

    Lys Pro Leu Cys Leu Phe Gln Ile Ser Asn Lys Asp Leu Ser Phe Ala 805 810 815

    Lys Thr Phe Ser Ala Asn Leu Arg Lys Lys Arg Gly Ala Glu Asn Leu 820 825 830

    His Thr Met Leu Phe Lys Ala Leu Met Glu Gly Asn Gln Asp Asn Leu 835 840 845

    Asp Leu Gly Ser Gly Ala Ile Phe Tyr Arg Ala Lys Ser Leu Asp Gly 850 855 860

    Asn Lys Pro Thr His Pro Ala Asn Glu Ala Ile Lys Cys Arg Asn Val 865 870 875 880

    Ala Asn Lys Asp Lys Val Ser Leu Phe Thr Tyr Asp Ile Tyr Lys Asn 885 890 895

    Arg Arg Tyr Met Glu Asn Lys Phe Leu Phe His Leu Ser Ile Val Gln 900 905 910

    Asn Tyr Lys Ala Ala Asn Asp Ser Ala Gln Leu Asn Ser Ser Ala Thr 915 920 925

    Glu Tyr Ile Arg Lys Ala Asp Asp Leu His Ile Ile Gly Ile Asp Arg 930 935 940

    Gly Glu Arg Asn Leu Leu Tyr Tyr Ser Val Ile Asp Met Lys Gly Asn 945 950 955 960

    Ile Val Glu Gln Asp Ser Leu Asn Ile Ile Arg Asn Asn Asp Leu Glu 965 970 975

    Thr Asp Tyr His Asp Leu Leu Asp Lys Arg Glu Lys Glu Arg Lys Ala 980 985 990

    Asn Arg Gln Asn Trp Glu Ala Val Glu Gly Ile Lys Asp Leu Lys Lys 995 1000 1005

    Gly Tyr Leu Ser Gln Ala Val His Gln Ile Ala Gln Leu Met Leu 1010 1015 1020

    Lys Tyr Asn Ala Ile Ile Ala Leu Glu Asp Leu Gly Gln Met Phe 1025 1030 1035

    Val Thr Arg Gly Gln Lys Ile Glu Lys Ala Val Tyr Gln Gln Phe 1040 1045 1050

    Glu Lys Ser Leu Val Asp Lys Leu Ser Tyr Leu Val Asp Lys Lys 1055 1060 1065

    Arg Pro Tyr Asn Glu Leu Gly Gly Ile Leu Lys Ala Tyr Gln Leu 1070 1075 1080

    Ala Ser Ser Ile Thr Lys Asn Asn Ser Asp Lys Gln Asn Gly Phe 1085 1090 1095

    Leu Phe Tyr Val Pro Ala Trp Asn Thr Ser Lys Ile Asp Pro Val 1100 1105 1110

    Thr Gly Phe Thr Asp Leu Leu Arg Pro Lys Ala Met Thr Ile Lys 1115 1120 1125

    Glu Ala Gln Asp Phe Phe Gly Ala Phe Asp Asn Ile Ser Tyr Asn 1130 1135 1140

    Asp Lys Gly Tyr Phe Glu Phe Glu Thr Asn Tyr Asp Lys Phe Lys 1145 1150 1155

    Ile Arg Met Lys Ser Ala Gln Thr Arg Trp Thr Ile Cys Thr Phe 1160 1165 1170

    Gly Asn Arg Ile Lys Arg Lys Lys Asp Lys Asn Tyr Trp Asn Tyr 1175 1180 1185

    Glu Glu Val Glu Leu Thr Glu Glu Phe Lys Lys Leu Phe Lys Asp 1190 1195 1200

    Ser Asn Ile Asp Tyr Glu Asn Cys Asn Leu Lys Glu Glu Ile Gln 1205 1210 1215

    Asn Lys Asp Asn Arg Lys Phe Phe Asp Asp Leu Ile Lys Leu Leu 1220 1225 1230

    Gln Leu Thr Leu Gln Met Arg Asn Ser Asp Asp Lys Gly Asn Asp 1235 1240 1245

    Tyr Ile Ile Ser Pro Val Ala Asn Ala Glu Gly Gln Phe Phe Asp 1250 1255 1260

    Ser Arg Asn Gly Asp Lys Lys Leu Pro Leu Asp Ala Asp Ala Asn 1265 1270 1275

    Gly Ala Tyr Asn Ile Ala Arg Lys Gly Leu Trp Asn Ile Arg Gln 1280 1285 1290

    Ile Lys Gln Thr Lys Asn Asp Lys Lys Leu Asn Leu Ser Ile Ser 1295 1300 1305

    Ser Thr Glu Trp Leu Asp Phe Val Arg Glu Lys Pro Tyr Leu Lys 1310 1315 1320 <210> 1278 <211> 3888 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1278 ggtaccatga aaacccagca cttctttgag gacttcacaa gcctgtactc tctgagcaag 60 accatccggt ttgagctgaa gccaatcggc aagaccctgg agaacatcaa gaagaatggc 120 ctgatccgga gagatgagca gagactggac gattacgaga agctgaagaa agtgatcgac 180 gagtatcacg aggatttcat cgccaacatc ctgagctcct tttccttctc tgaggagatc 240 ctgcagtcct acatccagaa tctgagcgag tccgaggcca gggccaagat cgagaaaacc 300 atgcgcgaca cactggccaa ggccttctct gaggatgaga ggtacaagag catctttaag 360 aaggagctgg tgaagaagga catccccgtg tggtgccctg cctataagag cctgtgcaag 420 aagttcgata actttaccac atctctggtg cccttccacg agaacaggaa gaacctgtat 480 accagcaatg agatcacagc ctctatccct tatcgcatcg tgcacgtgaa cctgccaaag 540 tttatccaga atatcgaggc cctgtgcgag ctgcagaaga agatgggcgc cgacctgtac 600 ctggagatga tggagaacct gcgcaacgtg tggcccagct tcgtgaaaac cccagacgac 660 ctgtgcaacc tgaaaaccta taatcacctg atggtgcagt ctagcatcag cgagtacaac 720 aggtttgtgg gcggctattc caccgaggac ggcacaaagc accagggcat caacgagtgg 780 atcaatatct acagacagag gaataaggag atgcgcctgc ctggcctggt gttcctgcac 840 aagcagatcc tggccaaggt ggactcctct agcttcatca gcgatacact ggagaacgac 900 gatcaggtgt tttgcgtgct gagacagttc aggaagctgt tttggaatac cgtgtcctct 960 aaggaggacg atgccgcctc cctgaaggac ctgttctgtg gcctgtctgg ctatgaccct 1020 gaggccatct acgtgagcga tgcccacctg gccacaatct ccaagaacat ctttgacaga 1080 tggaattaca tctccgatgc catcaggcgc aagaccgagg tgctgatgcc acggaagaag 1140 gagagcgtgg agagatatgc cgagaagatc tccaagcaga tcaagaagag acagtcttac 1200 agcctggccg agctggacga tctgctggcc cactatagcg aggagtccct gcccgcaggc 1260 ttctctctgc tgagctactt tacatctctg ggcggccaga agtatctggt gagcgacggc 1320 gaagtgatcc tgtacgagga gggcagcaac atctgggacg aggtgctgat cgccttcagg 1380 gatctgcagg tcatcctgga caaggacttc accgagaaga agctgggcaa ggatgaggag 1440 gccgtgtctg tgatcaagaa ggccctggac agcgccctgc gcctgcggaa gttctttgat 1500 ctgctgtccg gcacaggcgc agagatcagg agagacagct ccttctatgc cctgtatacc 1560 gaccggatgg ataagctgaa gggcctgctg aagatgtatg ataaggtgag aaactacctg 1620 accaagaagc cttattccat cgagaagttc aagctgcact ttgacaaccc atccctgctg 1680 tctggctggg ataagaataa ggagctgaac aatctgtctg tgatcttccg gcagaacggc 1740 tactattacc tgggcatcat gacacccaag ggcaagaatc tgttcaagac cctgcctaag 1800 ctgggcgccg aggagatgtt ttatgagaag atggagtaca agcagatcgc cgagcctatg 1860 ctgatgctgc caaaggtgtt ctttcccaag aaaaccaagc cagccttcgc cccagaccag 1920 agcgtggtgg atatctacaa caagaaaacc ttcaagacag gccagaaggg ctttaataag 1980 aaggacctgt accggctgat cgacttctac aaggaggccc tgacagtgca cgagtggaag 2040 ctgtttaact tctccttttc tccaaccgag cagtatcgga atatcggcga gttctttgac 2100 gaggtgagag agcaggccta caaggtgtcc atggtgaacg tgcccgcctc ttatatcgac 2160 gaggccgtgg agaacggcaa gctgtatctg ttccagatct acaataagga cttcagcccc 2220 tactccaagg gcatccctaa cctgcacaca ctgtattgga aggccctgtt cagcgagcag 2280 aatcagagcc gggtgtataa gctgtgcgga ggaggagagc tgttttatag aaaggccagc 2340 ctgcacatgc aggacaccac agtgcacccc aagggcatct ctatccacaa gaagaacctg 2400 aataagaagg gcgagacaag cctgttcaac tacgacctgg tgaaggataa gaggtttacc 2460 gaggacaagt tctttttcca cgtgcctatc tctatcaact acaagaataa gaagatcacc 2520 aacgtgaatc agatggtgcg cgattatatc gcccagaacg acgatctgca gatcatcggc 2580 atcgaccgcg gcgagcggaa tctgctgtat atcagccgga tcgatacaag gggcaacctg 2640 ctggagcagt tcagcctgaa tgtgatcgag tccgacaagg gcgatctgag aaccgactat 2700 cagaagatcc tgggcgatcg cgagcaggag cggctgaggc gccggcagga gtggaagtct 2760 atcgagagca tcaaggacct gaaggatggc tacatgagcc aggtggtgca caagatctgt 2820 aacatggtgg tggagcacaa ggccatcgtg gtgctggaga acctgaatct gagcttcatg 2880 aagggcagga agaaggtgga gaagtccgtg tacgagaagt ttgagcgcat gctggtggac 2940 aagctgaact atctggtggt ggataagaag aacctgtcca atgagccagg aggcctgtat 3000 gcagcatacc agctgaccaa tccactgttc tcttttgagg agctgcacag atacccccag 3060 agcggcatcc tgtttttcgt ggacccatgg aacacctctc tgacagatcc cagcacaggc 3120 ttcgtgaatc tgctgggcag aatcaactac accaatgtgg gcgacgcccg caagtttttc 3180 gatcggttta acgccatcag atatgacggc aagggcaata tcctgttcga cctggatctg 3240 tccagatttg atgtgagggt ggagacacag aggaagctgt ggacactgac cacattcggc 3300 tctcgcatcg ccaaatccaa gaagtctggc aagtggatgg tggagcggat cgagaacctg 3360 agcctgtgct ttctggagct gttcgagcag tttaatatcg gctacagagt ggagaaggac 3420 ctgaagaagg ccatcctgag ccaggatagg aaggagttct atgtgcgcct gatctacctg 3480 tttaacctga tgatgcagat ccggaacagc gacggcgagg aggattatat cctgtctccc 3540 gccctgaacg agaagaatct gcagttcgac agcaggctga tcgaggccaa ggatctgcct 3600 gtggacgcag atgcaaacgg agcatacaat gtggcccgca agggcctgat ggtggtgcag 3660 agaatcaaga ggggcgacca cgagtccatc cacaggatcg gaagggcaca gtggctgaga 3720 tatgtgcagg agggcatcgt ggagaaaagg ccggcggcca cgaaaaaggc cggccaggca 3780 aaaaagaaaa agggatccta cccatacgat gttccagatt acgcttatcc ctacgacgtg 3840 cctgattatg catacccata tgatgtcccc gactatgcct aagaattc 3888 <210> 1279 <211> 1246 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1279

    Met Lys Thr Gln His Phe Phe Glu Asp Phe Thr Ser Leu Tyr Ser Leu

    1 5 10 15

    Ser Lys Thr Ile Arg Phe Glu Leu Lys Pro Ile Gly Lys Thr Leu Glu

    Asn Ile Lys Lys Asn Gly Leu Ile Arg Arg Asp Glu Gln Arg Leu Asp 35 40 45

    Asp Tyr Glu Lys Leu Lys Lys Val Ile Asp Glu Tyr His Glu Asp Phe 50 55 60

    Ile Ala Asn Ile Leu Ser Ser Phe Ser Phe Ser Glu Glu Ile Leu Gln 65 70 75 80

    Ser Tyr Ile Gln Asn Leu Ser Glu Ser Glu Ala Arg Ala Lys Ile Glu 85 90 95

    Lys Thr Met Arg Asp Thr Leu Ala Lys Ala Phe Ser Glu Asp Glu Arg 100 105 110

    Tyr Lys Ser Ile Phe Lys Lys Glu Leu Val Lys Lys Asp Ile Pro Val 115 120 125

    Trp Cys Pro Ala Tyr Lys Ser Leu Cys Lys Lys Phe Asp Asn Phe Thr 130 135 140

    Thr Ser Leu Val Pro Phe His Glu Asn Arg Lys Asn Leu Tyr Thr Ser 145 150 155 160

    Asn Glu Ile Thr Ala Ser Ile Pro Tyr Arg Ile Val His Val Asn Leu 165 170 175

    Pro Lys Phe Ile Gln Asn Ile Glu Ala Leu Cys Glu Leu Gln Lys Lys 180 185 190

    Met Gly Ala Asp Leu Tyr Leu Glu Met Met Glu Asn Leu Arg Asn Val 195 200 205

    Trp Pro Ser Phe Val Lys Thr Pro Asp Asp Leu Cys Asn Leu Lys Thr 210 215 220

    Tyr Asn His Leu Met Val Gln Ser Ser Ile Ser Glu Tyr Asn Arg Phe 225 230 235 240

    Val Gly Gly Tyr Ser Thr Glu Asp Gly Thr Lys His Gln Gly Ile Asn 245 250 255

    Glu Trp Ile Asn Ile Tyr Arg Gln Arg Asn Lys Glu Met Arg Leu Pro 260 265 270

    Gly Leu Val Phe Leu His Lys Gln Ile Leu Ala Lys Val Asp Ser Ser 275 280 285

    Ser Phe Ile Ser Asp Thr Leu Glu Asn Asp Asp Gln Val Phe Cys Val 290 295 300

    Leu Arg Gln Phe Arg Lys Leu Phe Trp Asn Thr Val Ser Ser Lys Glu 305 310 315 320

    Asp Asp Ala Ala Ser Leu Lys Asp Leu Phe Cys Gly Leu Ser Gly Tyr 325 330 335

    Asp Pro Glu Ala Ile Tyr Val Ser Asp Ala His Leu Ala Thr Ile Ser 340 345 350

    Lys Asn Ile Phe Asp Arg Trp Asn Tyr Ile Ser Asp Ala Ile Arg Arg 355 360 365

    Lys Thr Glu Val Leu Met Pro Arg Lys Lys Glu Ser Val Glu Arg Tyr 370 375 380

    Ala Glu Lys Ile Ser Lys Gln Ile Lys Lys Arg Gln Ser Tyr Ser Leu 385 390 395 400

    Ala Glu Leu Asp Asp Leu Leu Ala His Tyr Ser Glu Glu Ser Leu Pro 405 410 415

    Ala Gly Phe Ser Leu Leu Ser Tyr Phe Thr Ser Leu Gly Gly Gln Lys 420 425 430

    Tyr Leu Val Ser Asp Gly Glu Val Ile Leu Tyr Glu Glu Gly Ser Asn 435 440 445

    Ile Trp Asp Glu Val Leu Ile Ala Phe Arg Asp Leu Gln Val Ile Leu 450 455 460

    Asp Lys Asp Phe Thr Glu Lys Lys Leu Gly Lys Asp Glu Glu Ala Val 465 470 475 480

    Ser Val Ile Lys Lys Ala Leu Asp Ser Ala Leu Arg Leu Arg Lys Phe 485 490 495

    Phe Asp Leu Leu Ser Gly Thr Gly Ala Glu Ile Arg Arg Asp Ser Ser 500 505 510

    Phe Tyr Ala Leu Tyr Thr Asp Arg Met Asp Lys Leu Lys Gly Leu Leu 515 520 525

    Lys Met Tyr Asp Lys Val Arg Asn Tyr Leu Thr Lys Lys Pro Tyr Ser 530 535 540

    Ile Glu Lys Phe Lys Leu His Phe Asp Asn Pro Ser Leu Leu Ser Gly 545 550 555 560

    Trp Asp Lys Asn Lys Glu Leu Asn Asn Leu Ser Val Ile Phe Arg Gln 565 570 575

    Asn Gly Tyr Tyr Tyr Leu Gly Ile Met Thr Pro Lys Gly Lys Asn Leu 580 585 590

    Phe Lys Thr Leu Pro Lys Leu Gly Ala Glu Glu Met Phe Tyr Glu Lys 595 600 605

    Met Glu Tyr Lys Gln Ile Ala Glu Pro Met Leu Met Leu Pro Lys Val 610 615 620

    Phe Phe Pro Lys Lys Thr Lys Pro Ala Phe Ala Pro Asp Gln Ser Val 625 630 635 640

    Val Asp Ile Tyr Asn Lys Lys Thr Phe Lys Thr Gly Gln Lys Gly Phe 645 650 655

    Asn Lys Lys Asp Leu Tyr Arg Leu Ile Asp Phe Tyr Lys Glu Ala Leu 660 665 670

    Thr Val His Glu Trp Lys Leu Phe Asn Phe Ser Phe Ser Pro Thr Glu 675 680 685

    Gln Tyr Arg Asn Ile Gly Glu Phe Phe Asp Glu Val Arg Glu Gln Ala 690 695 700

    Tyr Lys Val Ser Met Val Asn Val Pro Ala Ser Tyr Ile Asp Glu Ala 705 710 715 720

    Val Glu Asn Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe 725 730 735

    Ser Pro Tyr Ser Lys Gly Ile Pro Asn Leu His Thr Leu Tyr Trp Lys

    740

    745

    750

    Ala Leu Phe Ser Glu Gln Asn Gln Ser Arg Val Tyr Lys Leu Cys Gly 755 760 765

    Gly Gly Glu Leu Phe Tyr Arg Lys Ala Ser Leu His Met Gln Asp Thr 770 775 780

    Thr Val His Pro Lys Gly Ile Ser Ile His Lys Lys Asn Leu Asn Lys 785 790 795 800

    Lys Gly Glu Thr Ser Leu Phe Asn Tyr Asp Leu Val Lys Asp Lys Arg 805 810 815

    Phe Thr Glu Asp Lys Phe Phe Phe His Val Pro Ile Ser Ile Asn Tyr 820 825 830

    Lys Asn Lys Lys Ile Thr Asn Val Asn Gln Met Val Arg Asp Tyr Ile 835 840 845

    Ala Gln Asn Asp Asp Leu Gln Ile Ile Gly Ile Asp Arg Gly Glu Arg 850 855 860

    Asn Leu Leu Tyr Ile Ser Arg Ile Asp Thr Arg Gly Asn Leu Leu Glu 865 870 875 880

    Gln Phe Ser Leu Asn Val Ile Glu Ser Asp Lys Gly Asp Leu Arg Thr 885 890 895

    Asp Tyr Gln Lys Ile Leu Gly Asp Arg Glu Gln Glu Arg Leu Arg Arg 900 905 910

    Arg Gln Glu Trp Lys Ser Ile Glu Ser Ile Lys Asp Leu Lys Asp Gly 915 920 925

    Tyr Met Ser Gln Val Val His Lys Ile Cys Asn Met Val Val Glu His 930 935 940

    Lys Ala Ile Val Val Leu Glu Asn Leu Asn Leu Ser Phe Met Lys Gly 945 950 955 960

    Arg Lys Lys Val Glu Lys Ser Val Tyr Glu Lys Phe Glu Arg Met Leu 965 970 975

    Val Asp Lys Leu Asn Tyr Leu Val Val Asp Lys Lys Asn Leu Ser Asn 980 985 990

    Glu Pro Gly Gly Leu Tyr Ala Ala Tyr Gln Leu Thr Asn Pro Leu Phe 995 1000 1005

    Ser Phe Glu Glu Leu His Arg Tyr Pro Gln Ser Gly Ile Leu Phe 1010 1015 1020

    Phe Val Asp Pro Trp Asn Thr Ser Leu Thr Asp Pro Ser Thr Gly 1025 1030 1035

    Phe Val Asn Leu Leu Gly Arg Ile Asn Tyr Thr Asn Val Gly Asp 1040 1045 1050

    Ala Arg Lys Phe Phe Asp Arg Phe Asn Ala Ile Arg Tyr Asp Gly 1055 1060 1065

    Lys Gly Asn Ile Leu Phe Asp Leu Asp Leu Ser Arg Phe Asp Val 1070 1075 1080

    Arg Val Glu Thr Gln Arg Lys Leu Trp Thr Leu Thr Thr Phe Gly 1085 1090 1095

    Ser Arg Ile Ala Lys Ser Lys Lys Ser Gly Lys Trp Met Val Glu 1100 1105 1110

    Arg Ile Glu Asn Leu Ser Leu Cys Phe Leu Glu Leu Phe Glu Gln 1115 1120 1125 Phe Asn Ile Gly Tyr Arg Val Glu Lys Asp Leu Lys Lys Ala Ile 1130 1135 1140 Leu Ser Gln Asp Arg Lys Glu Phe Tyr Val Arg Leu Ile Tyr Leu 1145 1150 1155 Phe Asn Leu Met Met Gln Ile Arg Asn Ser Asp Gly Glu Glu Asp 1160 1165 1170

    Tyr Ile Leu Ser Pro Ala Leu Asn Glu Lys Asn Leu Gln Phe Asp 1175 1180 1185

    Ser Arg Leu Ile Glu Ala Lys Asp Leu Pro Val Asp Ala Asp Ala 1190 1195 1200

    Asn Gly Ala Tyr Asn Val Ala Arg Lys Gly Leu Met Val Val Gln 1205 1210 1215

    Arg Ile Lys Arg Gly Asp His Glu Ser Ile His Arg Ile Gly Arg 1220 1225 1230

    Ala Gln Trp Leu Arg Tyr Val Gln Glu Gly Ile Val Glu 1235 1240 1245 <210> 1280 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1280 gucuaagaac uuuaaauaau uucuacuguu guagau <210> 1281 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1281 gucuaagaac uuuaaauaau uucuacuguu guagau <210> 1282 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1282 gcuauaaugc cuauauaauu ucuacuauug uagau <400> 1283 <210> 1283 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide gcuauaaugc cuauauaauu ucuacuauug uagau <210> 1284 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1284 gccuauaagg cuuuaguaau uucuacuauu guagau <210> 1285 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1285 guuuuggagu accuuagaaa ugcaugguuc ucaugc <210> 1286 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1286 gucaauaaga cucauuuaau uucuacuucg guagau <210> 1287 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1287 guuuuagaac cuuaaaaauu accuaguaau uaggu <210> 1288 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1288 gucuagguac ucucuuuaau uucuacuauu guagau <210> 1289 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1289 guuuaaaagu ccuauuggau uucuacuuuu guagau <210> 1290 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1290 guuucaaaga uuaaauaauu ucuacuaagu guagau <210> 1291 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1291 gccaaauacc ucuauaaaau uucuacuuuu guagau <210> 1292 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1292 cucuaaagag aggaaagaau uucuacuuuu guagau <210> 1293 <211> 32 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1293 guuucaaucc acgcgcccac gcggggcgcg ac 32 <210> 1294 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1294 gucuaacgac cuuuuaaauu ucuacuguuu guagau <210> 1295 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1295 gucaaaagac cuuuuuaauu ucuacucuug uagau <210> 1296 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1296 guuugaauaa ccuuaaauaa uuucuacuuu guagau <210> 1297 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1297 gcuuagaaca uuuaaagaau uucuacuauu guagau <210> 1298 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1298 cucaaaacuc auucgaaucu cuacucuuug uagau <210> 1299 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1299 cucaaaacuc auucgaaucu cuacucuuug uagau <210> 1300 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1300 gcuuagaaca uuuaaagaau uucuacuauu guagau <210> 1301 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1301 guuugaauaa ccuuaaauaa uuucuacuuu guagau <210> 1302 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1302 gucaaaagac cuuuuuaauu ucuacucuug uagau <210> 1303 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1303 gucuaacgac cuuuuaaauu ucuacuguuu guagau <220>

    <223> Description of Artificial Sequence: Synthetic <210> 1304 <211> 32 <212> RNA <213> Artificial Sequence oligonucleotide <400> 1304 guuucaaucc acgcgcccac gcggggcgcg ac 32 <210> 1305 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1305 cucuaaagag aggaaagaau uucuacuuuu guagau <210> 1306 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1306 gccaaauacc ucuauaaaau uucuacuuuu guagau <210> 1307 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1307 guuucaaaga uuaaauaauu ucuacuaagu guagau <210> 1308 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1308 guuuaaaagu ccuauuggau uucuacuuuu guagau <210> 1309 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1309 gucuagguac ucucuuuaau uucuacuauu guagau <210> 1310 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1310 guuuuagaac cuuaaaaauu accuaguaau uaggu <210> 1311 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1311 gucaauaaga cucauuuaau uucuacuucg guagau <210> 1312 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1312 guuuuggagu accuuagaaa ugcaugguuc ucaugc <210> 1313 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1313 gccuauaagg cuuuaguaau uucuacuauu guagau <210> 1314 <211> 77 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1314 gggacuuuaa auaauuucua cuguuguaga uaggccccag uggcugcucu gggggccucc 60 gucuaagaac uuuaaau <210> 1315 <211> 77 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1315 gggacuuuaa auaauuucua cuguuguaga uucaucugug ccccucccuc ccuggcccag gucuaagaac uuuaaau 77 <210> 1316 <211> 77 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1316 gggacuuuaa auaauuucua cuguuguaga ugugguugcc cacccuaguc auuggaggug gucuaagaac uuuaaau 77 <210> 1317 <211> 77 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1317 gggacuuuaa auaauuucua cuguuguaga uggggcccca ggccgggguc cccucugacc gucuaagaac uuuaaau <210> 1318 <211> 639 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1318 ccatcccctt ctgtgaatgt tagacccatg ggagcagctg gtcagagggg accccggcct 60 ggggccccta accctatgta gcctcagtct tcccatcagg ctctcagctc agcctgagtg 120 ttgaggcccc agtggctgct ctgggggcct cctgagtttc tcatctgtgc ccctccctcc 180 ctggcccagg tgaaggtgtg gttccagaac cggaggacaa agtacaaacg gcagaagctg 240 gaggaggaag ggcctgagtc cgagcagaag aagaagggct cccatcacat caaccggtgg 300 cgcattgcca cgaagcaggc caatggggag gacatcgatg tcacctccaa tgactagggt 360 gggcaaccac aaacccacga gggcagagtg ctgcttgctg ctggccaggc ccctgcgtgg 420 gcccaagctg gactctggcc actccctggc caggctttgg ggaggcctgg agtcatggcc 480 ccacagggct tgaagcccgg ggccgccatt gacagaggga caagcaatgg gctggctgag 540 gcctgggacc acttggcctt ctcctcggag agcctgcctg cctgggcggg cccgcccgcc 600 accgcagcct cccagctgct ctccgtgtct ccaatctcc 639 <210> 1319 <211> 106 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1319 ggggucuaag aacuuuaaau aauuucuacu guuguagaug agaagucauu uaauaaggcc acuguuaaaa gucuaagaac uuuaaauaau uucuacuguu guagau 106 <210> 1320 <211> 100 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1320 ggggaacuuu aaauaauuuc uacuguugua gaugagaagu cauuuaauaa ggccacuguu aaaagucuaa gaacuuuaaa uaauuucuac uguuguagau 100 <210> 1321 <211> 94 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1321 ggguaaauaa uuucuacugu uguagaugag aagucauuua auaaggccac uguuaaaagu cuaagaacuu uaaauaauuu cuacuguugu agau 94 <210> 1322 <211> 88 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1322 gggauuucua cuguuguaga ugagaaguca uuuaauaagg ccacuguuaa aagucuaaga acuuuaaaua auuucuacug uuguagau 88 <210> 1323 <211> 82 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1323 gggacuguug uagaugagaa gucauuuaau aaggccacug uuaaaagucu aagaacuuua aauaauuucu acuguuguag au 82 <210> 1324 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1324 gucuaagaac uuuaaauaau uucuacuguu guagau 36 <210> 1325 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1325 gggactttaa ataatttcta ctgttgtaga ttagaagtca tttaataagg ccactgttaa 60 aagtctaaga actttaaat <210> 1326 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1326 gggactttaa ataatttcta ctgttgtaga tgaggagtca tttaataagg ccactgttaa aagtctaaga actttaaat 79 <210> 1327 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1327 gggactttaa ataatttcta ctgttgtaga tgagaagcca tttaataagg ccactgttaa aagtctaaga actttaaat 79 <210> 1328 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1328 gggactttaa ataatttcta ctgttgtaga tgagaagtca attaataagg ccactgttaa aagtctaaga actttaaat <210> 1329 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1329 gggactttaa ataatttcta ctgttgtaga tgagaagtca ttttataagg ccactgttaa aagtctaaga actttaaat 79 <210> 1330 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1330 gggactttaa ataatttcta ctgttgtaga tgagaagtca tttaatgagg ccactgttaa aagtctaaga actttaaat 79 <210> 1331 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1331 gggactttaa ataatttcta ctgttgtaga tgagaagtca tttaataagc ccactgttaa aagtctaaga actttaaat <210> 1332 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1332 gggactttaa ataatttcta ctgttgtaga tgagaagtca tttaataagg cctctgttaa aagtctaaga actttaaat 79 <210> 1333 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1333 gggactttaa ataatttcta ctgttgtaga tgagaagtca tttaataagg ccactattaa aagtctaaga actttaaat 79 <210> 1334 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1334 gggactttaa ataatttcta ctgttgtaga tgagaagtca tttaataagg ccactgttta aagtctaaga actttaaat <210> 1335 <211> 79 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1335 gggactttaa ataatttcta ctgttgtaga tgagaagtca tttaataagg ccactgttaa 60 aggtctaaga actttaaat 79 <210> 1336 <211> 76 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1336 acuuuaaaua auuucuacug uuguagauga gaagucauuu aauaaggcca cuguuaaaag ucuaagaacu uuaaau 76 <210> 1337 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1337 gucuaagaac uuuaaauaau uucuacuguu guagau <210> 1338 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1338 gcuauaaugc cuauauaauu ucuacuauug uagau 35 <210> 1339 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (20)..(43) <223> a, c, u, g, unknown or other <220>

    <221> misc_feature <222> (40)..(43) <223> May or may not be present <400> 1339 aauuucuacu guuguagaun nnnnnnnnnn nnnnnnnnnn nnn <210> 1340 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (20)..(43) <223> a, c, u, g, unknown or other <400> 1340 aauuucuacu guuguagaun nnnnnnnnnn nnnnnnnnnn nnn <210> 1341 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (20)..(43) <223> a, c, u, g, unknown or other <220>

    <221> misc_feature <222> (40)..(43) <223> May or may not be present <400> 1341 aauuucuacu auuguagaun nnnnnnnnnn nnnnnnnnnn nnn <210> 1342 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (20)..(43) <223> a, c, u, g, unknown or other <400> 1342 aauuucuacu auuguagaun nnnnnnnnnn nnnnnnnnnn nnn <210> 1343 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1343 ttaataaggc cactgttaaa a 21 <210> 1344 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (14)..(14) <223> a, c, t, g, unknown or other <400> 1344 ttaataaggc cacn 14 <210> 1345 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1345 gccactgtta aaa 13 <210> 1346 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1346 aauuucuacu uguguagaug agaagucauu uaauaaggcc acu <210> 1347 <211> 22 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1347 gagaagucau uuaauaaggc ca 22 <210> 1348 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1348 gagaagucau uuaauaaggc 20 <210> 1349 <211> 18 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1349 gagaagucau uuaauaag 18 <210> 1350 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1350 gagaagucau uuaauaa 17 <210> 1351 <211> 16 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1351 gagaagucau uuaaua 16 <210> 1352 <211> 15 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1352 gagaagucau uuaau 15 <210> 1353 <211> 68 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1353 gaattatctg aaggcacagg aatagtagca tctacaacag tagaaattat ttaaagttct tagacttt 68 <210> 1354 <211> 36 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1354 atctacaaca gtagaaatta tttaaagttc ttagac 36 <210> 1355 <211> 42 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1355 tctgaaggca caggaatagt agcatctaca acagtagaaa tt <210> 1356 <211> 42 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1356 tctgaaggca caggaatagt agcatctaca acagtagaaa tt <210> 1357 <211> 42 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1357 tctgaaggca caggaatagt agcatctaca acagtagaaa tt <210> 1358 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1358 atctacaaca gta <210> 1359 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1359 atctacaaca gta 13 <210> 1360 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1360 atctacaaca gta 13 <210> 1361 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1361 atctacaaca gta 13 <210> 1362 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1362 atctacaaca gta 13 <210> 1363 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1363 atctacaaca gta 13 <210> 1364 <211> 77 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1364 agacttttaa cagtggcctt attaaatgac ttctcatcta caacagtaga aattatttaa agttcttaga cccgttt 77 <210> 1365 <211> 36 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1365 atctacaaca gtagaaatta tttaaagttc ttagac <210> 1366 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1366 agacttttaa cagt 14 <210> 1367 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1367 aatgacttct catctaca 18 <210> 1368 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1368 atttaaagtt cttagaccc 19 <210> 1369 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1369 agacttttaa cagt 14 <210> 1370 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1370 aatgacttct catctacaac agta <210> 1371 <211> 17 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1371 agttcttaga cccgttt 17 <210> 1372 <211> 26 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1372 gacttttaac agtggcctta ttaaat 26 <210> 1373 <211> 40 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1373 ctacaacagt agaaattatt taaagttctt agacccgttt <210> 1374 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1374 agacttttaa cagtggcct 19 <210> 1375 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1375 cttctcatct acaacagt <210> 1376 <211> 17 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1376 agttcttaga cccgttt 17 <210> 1377 <211> 16 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1377 cttattaaat gacttc 16 <210> 1378 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1378 gtagaaatta tttaaagttc ttagacccgt tt <210> 1379 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1379 agacttttaa cagtggcctt attaaatgac ttctc <210> 1380 <211> 31 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1380 tagaaattat ttaaagttct tagacccgtt t <210> 1381 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1381 agacttttaa cag 13 <210> 1382 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1382 aaatgacttc tgatctacaa cagt <210> 1383 <211> 16 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1383 gttcttagac ccgttt 16 <210> 1384 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1384 agacttttaa cagtggcctt a 21 <210> 1385 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1385 tctcatctac aacagtag 18 <210> 1386 <211> 16 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1386 gttcttagac ccgttt 16 <210> 1387 <211> 10 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1387 agacttttaa 10 <210> 1388 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1388 attaaatgac ttctcatcta caac <210> 1389 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1389 ttaaagttct tagacccgtt t <210> 1390 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1390 agacttttaa cagt 14 <210> 1391 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1391 aatgacttct catctacaac agtag <210> 1392 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1392 tcttagaccc gttt 14 <210> 1393 <211> 40 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1393 agacttttaa cagtggcctt attaaatgac ttctcatcta <210> 1394 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1394 aattatttaa agttcttaga cccgttt 27 <210> 1395 <211> 16 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1395 agacttttaa cagtgg 16 <210> 1396 <211> 18 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1396 tgacttctca tctacaac <210> 1397 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1397 ttaaagttct tagacccgtt t 21 <210> 1398 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1398 agacttttaa cag 13 <210> 1399 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1399 aaatgacttc tcatctacaa cagt 24 <210> 1400 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1400 tcttagaccc gttt 14 <210> 1401 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1401 atctacaaca gtagaaatta tttaaagttc tt 32 <210> 1402 <211> 65 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1402 ggtacccggg gatcctttag agaagtcatt taataaggcc actgttaaaa agcttggcgt aatca 65 <210> 1403 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1403 aauuucuacu guuguagaug agaagucauu uaauaaggcc acu <210> 1404 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1404 ttaataaggc cactgttaaa a 21 <210> 1405 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1405 ngccactgtt aaaa 14 <210> 1406 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <220>

    <221> modified_base <222> (14)..(14) <223> a, c, t, g, unknown or other <400> 1406 ttaataaggc cacn 14 <210> 1407 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1407 aauuucuacu guuguagaug agaagucauu uaauaaggcc acu <210> 1408 <211> 22 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1408 gagaagucau uuaauaaggc ca 22 <210> 1409 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1409 gagaagucau uuaauaaggc 20 <210> 1410 <211> 18 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1410 gagaagucau uuaauaag 18 <210> 1411 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1411 gagaagucau uuaauaa 17 <210> 1412 <211> 16 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1412 gagaagucau uuaaua <210> 1413 <211> 15 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1413 gagaagucau uuaau 15 <210> 1414 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1414 aauuucuacu guuguagaug agaagucauu uaauaaggcc acu <210> 1415 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1415 gataagucau uuaauaaggc cacu 24 <210> 1416 <211> 24 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1416 gagaaggcau uuaauaaggc cacu <210> 1417 <211> 24 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1417 gagaagucau guaauaaggc cacu <210> 1418 <211> 24 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1418 gagaagucau uuaagaaggc cacu <210> 1419 <211> 24 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1419 gagaagucau uuaauaagtc cacu 24 <210> 1420 <211> 24 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1420 gagaagucau uuaauaaggc caau 24 <210> 1421 <211> 43 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1421 aauuucuacu guuguagaug agaagucauu uaauaaggcc acu <210> 1422 <211> 19 <212> RNA <213> Artificial Sequence <400> 1422 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide aauuucugcu guugcagau <210> 1423 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1423 aauuuccacu guuguggau <210> 1424 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1424 aauuccuacu guuguaggu <210> 1425 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1425 aauuuauacu guuguagau <210> 1426 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1426 aauuucgacu guuguagau <210> 1427 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1427 aauuucuagu guuguagau <210> 1428 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1428 aauuucaucu auuguagau <210> 1429 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1429 aauuucaucu gcuguagau 19 <210> 1430 <211> 18 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1430 aauuucaucu uuguagau 18 <210> 1431 <211> 17 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1431 aauuucaucu uguagau 17 <210> 1432 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1432 aauuucuacu uuuguagaa 19 <210> 1433 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1433 aauuucuacu uuuguagac 19 <210> 1434 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1434 gucuaagaac uuuaaauaau uucuacuguu guagau <210> 1435 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1435 guuuuggagu accuuagaaa ugcaugguuc ucaugc <210> 1436 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1436 guuuuagaac cuuaaaaauu accuaguaau uaggu <210> 1437 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1437 guuuaaaagu ccuauuggau uucuacuuuu guagau <210> 1438 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1438 gccaaauacc ucuauaaaau uucuacuuuu guagau <210> 1439 <211> 32 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1439 guuucaaucc acgcgcccac gcggggcgcg ac 32 <210> 1440 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1440 gucaaaagac cuuuuuaauu ucuacucuug uagau <210> 1441 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1441 gcuuagaaca uuuaaagaau uucuacuauu guagau <210> 1442 <211> 35 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1442 cucaaaacuc auucgaaucu cuacucuuug uagau <220>

    <223> Description of Artificial Sequence: Synthetic <210> 1443 <211> 36 <212> RNA <213> Artificial Sequence oligonucleotide <400> 1443 guuugaauaa ccuuaaauaa uuucuacuuu guagau <210> 1444 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1444 gucuaacgac cuuuuaaauu ucuacuguuu guagau <210> 1445 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1445 cucuaaagag aggaaagaau uucuacuuuu guagau <210> 1446 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1446 guuucaaaga uuaaauaauu ucuacuaagu guagau <210> 1447 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1447 gucuagguac ucucuuuaau uucuacuauu guagau <210> 1448 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1448 gucaauaaga cucauuuaau uucuacuucg guagau <210> 1449 <211> 36 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1449 gccuauaagg cuuuaguaau uucuacuauu guagau <210> 1450 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1450 uaauuucuac uguuguagau <210> 1451 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1451 gaaaugcaug guucucaugc <210> 1452 <211> 20 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1452 aaauuaccua guaauuaggu <210> 1453 <211> 32 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1453 guuucaaucc acgcgcccac gcggggcgcg ac <210> 1454 <211> 36 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1454 aatgtttcct gatggtccat gtctgttact cgcctg <210> 1455 <211> 23 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1455 cugauggucc augucuguua cuc <210> 1456 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1456 aatgtttcct gactcgcctg 20 <210> 1457 <211> 12 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1457 aatgtttcct ga 12 <210> 1458 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1458 aatgtttcct gatggtccat gtctgtcgcc tg <210> 1459 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1459 aatgtttcct gatggtccat gtctgtcgcc tg <210> 1460 <211> 30 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1460 aatgtttcct gatggtccat gttgtgcctg <210> 1461 <211> 31 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1461 aatgtttcct gatggtccat gtactcgcct g <210> 1462 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1462 aatgtttcct gatggtccat gtctgtcgcc tg <210> 1463 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1463 aatgtttcct gatggtccat gttactcgcc tg <210> 1464 <211> 33 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1464 aatgtttcct gatggtccat gtctgttcgc ctg 33 <210> 1465 <211> 34 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1465 aatgtttcct gatggtccat gtcttactcg cctg 34 <210> 1466 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1466 tttccctcac tcctgctcgg tgaattt 27 <210> 1467 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1467 tttgaggagt gttcagtctc cgtgaac <210> 1468 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1468 tttcctgatg gtccatgtct gttactc 27 <210> 1469 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1469 tttatttccc ttcagctaaa ataaagg 27 <210> 1470 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1470 tcactcctgc tcggtgaatt tgg 23 <210> 1471 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1471 aaccctctgg ggaccgtttg agg 23 <210> 1472 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1472 agtacgttaa tgtttcctga tgg 23 <210> 1473 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1473 tttcccttca gctaaaataa agg 23 <210> 1474 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1474 tttggagaag tcatttaata aggccactgt taaaa <210> 1475 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1475 tttagagaag tcatttaata aggccactgt taaaa <210> 1476 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1476 ngccactgtt aaaa 14 <210> 1477 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1477 ngccactgtt aaaa 14 <210> 1478 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1478 tttggagaag tcatttaata aggccacn <210> 1479 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1479 tttagagaag tcatttaata aggccacn <210> 1480 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1480 tttcgagaag tcatttaata aggccactgt taaaa <210> 1481 <211> 14 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1481 ngccactgtt aaaa 14 <210> 1482 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1482 tttcgagaag tcatttaata aggccacn <210> 1483 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1483 tttggctact attcctgtgc cttcagataa ttcaa <210> 1484 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1484 ttttgctact attcctgtgc cttcagataa ttcaa <210> 1485 <211> 15 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1485 nttcagataa ttcaa 15 <210> 1486 <211> 15 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1486 nttcagataa ttcaa 15 <210> 1487 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1487 tttggctact attcctgtgc cttcagan <210> 1488 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1488 ttttgctact attcctgtgc cttcaga 27 <210> 1489 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1489 tttcgtctag agccttttgt attagtagcc gagct <210> 1490 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1490 tttggtctag agccttttgt attagtagcc gagct <210> 1491 <211> 15 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1491 nttagtagcc gagct 15 <210> 1492 <211> 15 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1492 nttagtagcc gagct 15 <210> 1493 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1493 tttcgtctag agccttttgt attagtan 28 <210> 1494 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1494 tttggtctag agccttttgt attagtan 28 <210> 1495 <211> 724 <212> PRT <213> Francisella tularensis <400> 1495

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu

    225

    230

    235

    240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr <210> 1496 <211> 680 <212> PRT <213> Acidaminococcus sp.

    <400> 1496

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn

    545

    550

    555

    560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr 675 680 <210> 1497 <211> 639 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1497

    Met Ser Lys Leu Glu Lys Phe Thr Asn Cys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Lys Ala Ile Pro Val Gly Lys Thr Gln Glu Asn Ile Asp 20 25 30

    Asn Lys Arg Leu Leu Val Glu Asp Glu Lys Arg Ala Glu Asp Tyr Lys 35 40 45

    Gly Val Lys Lys Leu Leu Asp Arg Tyr Tyr Leu Ser Phe Ile Asn Asp 50 55 60

    Val Leu His Ser Ile Lys Leu Lys Asn Leu Asn Asn Tyr Ile Ser Leu 65 70 75 80

    Phe Arg Lys Lys Thr Arg Thr Glu Lys Glu Asn Lys Glu Leu Glu Asn 85 90 95

    Leu Glu Ile Asn Leu Arg Lys Glu Ile Ala Lys Ala Phe Lys Gly Asn 100 105 110

    Glu Gly Tyr Lys Ser Leu Phe Lys Lys Asp Ile Ile Glu Thr Ile Leu 115 120 125

    Pro Glu Phe Leu Asp Asp Lys Asp Glu Ile Ala Leu Val Asn Ser Phe 130 135 140

    Asn Gly Phe Thr Thr Ala Phe Thr Gly Phe Phe Asp Asn Arg Glu Asn 145 150 155 160

    Met Phe Ser Glu Glu Ala Lys Ser Thr Ser Ile Ala Phe Arg Cys Ile 165 170 175

    Asn Glu Asn Leu Thr Arg Tyr Ile Ser Asn Met Asp Ile Phe Glu Lys

    180

    185

    190

    Val Asp Ala Ile Phe Asp Lys His Glu Val Gln Glu Ile Lys Glu Lys 195 200 205

    Ile Leu Asn Ser Asp Tyr Asp Val Glu Asp Phe Phe Glu Gly Glu Phe 210 215 220

    Phe Asn Phe Val Leu Thr Gln Glu Gly Ile Asp Val Tyr Asn Ala Ile 225 230 235 240

    Ile Gly Gly Phe Val Thr Glu Ser Gly Glu Lys Ile Lys Gly Leu Asn 245 250 255

    Glu Tyr Ile Asn Leu Tyr Asn Gln Lys Thr Lys Gln Lys Leu Pro Lys 260 265 270

    Phe Lys Pro Leu Tyr Lys Gln Val Leu Ser Asp Arg Glu Ser Leu Ser 275 280 285

    Phe Tyr Gly Glu Gly Tyr Thr Ser Asp Glu Glu Val Leu Glu Val Phe 290 295 300

    Arg Asn Thr Leu Asn Lys Asn Ser Glu Ile Phe Ser Ser Ile Lys Lys 305 310 315 320

    Leu Glu Lys Leu Phe Lys Asn Phe Asp Glu Tyr Ser Ser Ala Gly Ile 325 330 335

    Phe Val Lys Asn Gly Pro Ala Ile Ser Thr Ile Ser Lys Asp Ile Phe 340 345 350

    Gly Glu Trp Asn Val Ile Arg Asp Lys Trp Asn Ala Glu Tyr Asp Asp 355 360 365

    Ile His Leu Lys Lys Lys Ala Val Val Thr Glu Lys Tyr Glu Asp Asp 370 375 380

    Arg Arg Lys Ser Phe Lys Lys Ile Gly Ser Phe Ser Leu Glu Gln Leu 385 390 395 400

    Gln Glu Tyr Ala Asp Ala Asp Leu Ser Val Val Glu Lys Leu Lys Glu 405 410 415

    Ile Ile Ile Gln Lys Val Asp Glu Ile Tyr Lys Val Tyr Gly Ser Ser 420 425 430

    Glu Lys Leu Phe Asp Ala Asp Phe Val Leu Glu Lys Ser Leu Lys Lys 435 440 445

    Asn Asp Ala Val Val Ala Ile Met Lys Asp Leu Leu Asp Ser Val Lys 450 455 460

    Ser Phe Glu Asn Tyr Ile Lys Ala Phe Phe Gly Glu Gly Lys Glu Thr 465 470 475 480

    Asn Arg Asp Glu Ser Phe Tyr Gly Asp Phe Val Leu Ala Tyr Asp Ile 485 490 495

    Leu Leu Lys Val Asp His Ile Tyr Asp Ala Ile Arg Asn Tyr Val Thr 500 505 510

    Gln Lys Pro Tyr Ser Lys Asp Lys Phe Lys Leu Tyr Phe Gln Asn Pro 515 520 525

    Gln Phe Met Gly Gly Trp Asp Lys Asp Lys Glu Thr Asp Tyr Arg Ala 530 535 540

    Thr Ile Leu Arg Tyr Gly Ser Lys Tyr Tyr Leu Ala Ile Met Asp Lys 545 550 555 560

    Lys Tyr Ala Lys Cys Leu Gln Lys Ile Asp Lys Asp Asp Val Asn Gly 565 570 575

    Asn Tyr Glu Lys Ile Asn Tyr Lys Leu Leu Pro Gly Pro Asn Lys Met 580 585 590

    Leu Pro Lys Val Phe Phe Ser Lys Lys Trp Met Ala Tyr Tyr Asn Pro 595 600 605

    Ser Glu Asp Ile Gln Lys Ile Tyr Lys Asn Gly Thr Phe Lys Lys Gly 610 615 620

    Asp Met Phe Asn Leu Asn Asp Cys His Lys Leu Ile Asp Phe Phe 625 630 635 <210> 1498 <211> 44 <212> RNA <213> Francisella tularensis <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1498 uaauuucuac uguuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1499 <211> 44 <212> RNA <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1499 gaaaugcaug guucucaugc nnnnnnnnnn nnnnnnnnnn nnnn <210> 1500 <211> 44 <212> RNA <213> Butyrivibrio proteoclasticus <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1500 aaauuaccua guaauuaggu nnnnnnnnnn nnnnnnnnnn nnnn <210> 1501 <211> 44 <212> RNA <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1501 ggauuucuac uuuuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1502 <211> 44 <212> RNA <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1502 aaauuucuac uuuuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1503 <211> 44 <212> RNA <213> Smithella sp.

    <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1503 gcgcccacgc ggggcgcgac nnnnnnnnnn nnnnnnnnnn nnnn <220>

    <221> modified_base <210> 1504 <211> 44 <212> RNA <213> Acidaminococcus sp.

    <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1504 uaauuucuac ucuuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1505 <211> 44 <212> RNA <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1505 gaauuucuac uauuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1506 <211> 45 <212> RNA <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanoplasma termitum sequence <220>

    <221> modified_base <222> (22)..(45) <223> a, c, u, g, unknown or other <400> 1506 gaaucucuac ucuuuguaga unnnnnnnnn nnnnnnnnnn nnnnn <210> 1507 <211> 43 <212> RNA <213> Eubacterium eligens <220>

    <221> modified_base <222> (20)..(43) <223> a, c, u, g, unknown or other <400> 1507 uaauuucuac uuuguagaun nnnnnnnnnn nnnnnnnnnn nnn <210> 1508 <211> 44 <212> RNA <213> Moraxella bovoculi <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1508 aauuucuacu guuuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1509 <211> 44 <212> RNA <213> Leptospira inadai <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1509 gaauuucuac uuuuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1510 <211> 44 <212> RNA <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1510 aauuucuacu aaguguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1511 <211> 44 <212> RNA <213> Porphyromonas crevioricanis <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1511 uaauuucuac uauuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1512 <211> 44 <212> RNA <213> Prevotella disiens <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1512 uaauuucuac uucgguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1513 <211> 44 <212> RNA <213> Porphyromonas macacae <220>

    <221> modified_base <222> (21)..(44) <223> a, c, u, g, unknown or other <400> 1513 uaauuucuac uauuguagau nnnnnnnnnn nnnnnnnnnn nnnn <210> 1514 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1514 ttttgagaag tcatttaata aggccactgt taaaa 35 <210> 1515 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1515 nccactgtta aaa 13 <210> 1516 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1516 ttttgagaag tcatttaata aggccacn 28 <210> 1517 <211> 35 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1517 ttttgagaag tcatttaata aggccactgt taaaa 35 <210> 1518 <211> 13 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <220>

    <221> modified_base <222> (1)..(1) <223> a, c, t, g, unknown or other <400> 1518 nccactgtta aaa 13 <210> 1519 <211> 28 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic primer <220>

    <221> modified_base <222> (28)..(28) <223> a, c, t, g, unknown or other <400> 1519 ttttgagaag tcatttaata aggccacn 28 <210> 1520 <211> 1307 <212> PRT <213> Acidaminococcus sp.

    <400> 1520

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn

    210

    215

    220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln 865 870 875 880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu

    930

    935

    940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly 1025 1030 1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly 1115 1120 1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn 1130 1135 1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu 1205 1210 1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn 1295 1300 1305 <210> 1521 <211> 365 <212> PRT <213> Thermotoga maritima <400> 1521

    Met Arg Pro Glu Arg Leu Thr Val Arg Asn Phe Leu Gly Leu Lys Asn 1 5 10 15

    Val Asp Ile Glu Phe Gln Ser Gly Ile Thr Val Val Glu Gly Pro Asn 20 25 30

    Gly Ala Gly Lys Ser Ser Leu Phe Glu Ala Ile Ser Phe Ala Leu Phe 35 40 45

    Gly Asn Gly Ile Arg Tyr Pro Asn Ser Tyr Asp Tyr Val Asn Arg Asn 50 55 60

    Ala Val Asp Gly Thr Ala Arg Leu Val Phe Gln Phe Glu Arg Gly Gly 65 70 75 80

    Lys Arg Tyr Glu Ile Ile Arg Glu Ile Asn Ala Leu Gln Arg Lys His 85 90 95

    Asn Ala Lys Leu Ser Glu Ile Leu Glu Asn Gly Lys Lys Ala Ala Ile 100 105 110

    Ala Ala Lys Pro Thr Ser Val Lys Gln Glu Val Glu Lys Ile Leu Gly 115 120 125

    Ile Glu His Arg Thr Phe Ile Arg Thr Val Phe Leu Pro Gln Gly Glu 130 135 140

    Ile Asp Lys Leu Leu Ile Ser Pro Pro Ser Glu Ile Thr Glu Ile Ile 145 150 155 160

    Ser Asp Val Phe Gln Ser Lys Glu Thr Leu Glu Lys Leu Glu Lys Leu 165 170 175

    Leu Lys Glu Lys Met Lys Lys Leu Glu Asn Glu Ile Ser Ser Gly Gly 180 185 190

    Ala Gly Gly Ala Gly Gly Ser Leu Glu Lys Lys Leu Lys Glu Met Ser 195 200 205

    Asp Glu Tyr Asn Asn Leu Asp Leu Leu Arg Lys Tyr Leu Phe Asp Lys 210 215 220

    Ser Asn Phe Ser Arg Tyr Phe Thr Gly Arg Val Leu Glu Ala Val Leu 225 230 235 240

    Lys Arg Thr Lys Ala Tyr Leu Asp Ile Leu Thr Asn Gly Arg Phe Asp 245 250 255

    Ile Asp Phe Asp Asp Glu Lys Gly Gly Phe Ile Ile Lys Asp Trp Gly 260 265 270

    Ile Glu Arg Pro Ala Arg Gly Leu Ser Gly Gly Glu Arg Ala Leu Ile 275 280 285

    Ser Ile Ser Leu Ala Met Ser Leu Ala Glu Val Ala Ser Gly Arg Leu 290 295 300

    Asp Ala Phe Phe Ile Asp Glu Gly Phe Ser Ser Leu Asp Thr Glu Asn 305 310 315 320

    Lys Glu Lys Ile Ala Ser Val Leu Lys Glu Leu Glu Arg Leu Asn Lys 325 330 335

    Val Ile Val Phe Ile Thr His Asp Arg Glu Phe Ser Glu Ala Phe Asp 340 345 350

    Arg Lys Leu Arg Ile Thr Gly Gly Val Val Val Asn Glu 355 360 365 <210> 1522 <211> 1307 <212> PRT <213> Acidaminococcus sp.

    <400> 1522

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser 500 505 510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys

    625

    630

    635

    640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln 865 870 875 880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu 930 935 940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly 1025 1030 1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly 1115 1120 1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn 1130 1135 1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu 1205 1210 1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn 1295 1300 1305 <210> 1523 <211> 169 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1523

    Gly Pro His Met Val Val Ala Gly Ile Asp Pro Gly Ile Thr His Leu 1 5 10 15

    Gly Leu Gly Val Val Ala Val Glu Gly Lys Gly Ala Leu Lys Ala Arg 20 25 30

    Leu Leu His Gly Glu Val Val Lys Thr Ser Pro Gln Glu Pro Ala Lys 35 40 45

    Glu Arg Val Gly Arg Ile His Ala Arg Val Leu Glu Val Leu His Arg 50 55 60

    Phe Arg Pro Glu Ala Val Ala Val Gln Glu Gln Phe Phe Tyr Arg Gln 65 70 75 80

    Asn Glu Leu Ala Tyr Lys Val Gly Trp Ala Leu Gly Ala Val Leu Val 85 90 95

    Ala Ala Phe Glu Ala Gly Val Pro Val Tyr Ala Tyr Gly Pro Met Gln 100 105 110

    Val Lys Gln Ala Leu Ala Gly His Gly His Ala Ala Lys Glu Glu Val 115 120 125

    Ala Leu Met Val Arg Gly Ile Leu Gly Leu Lys Glu Ala Pro Arg Pro 130 135 140

    Ser His Leu Ala Asp Ala Leu Ala Ile Ala Leu Thr His Ala Phe Tyr 145 150 155 160

    Ala Arg Met Gly Thr Ala Lys Pro Leu 165 <210> 1524 <211> 1307 <212> PRT <213> Acidaminococcus sp.

    <400> 1524

    Met Thr Gln Phe Glu Gly Phe Thr Asn Leu Tyr Gln Val Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Lys His Ile Gln 20 25 30

    Glu Gln Gly Phe Ile Glu Glu Asp Lys Ala Arg Asn Asp His Tyr Lys 35 40 45

    Glu Leu Lys Pro Ile Ile Asp Arg Ile Tyr Lys Thr Tyr Ala Asp Gln 50 55 60

    Cys Leu Gln Leu Val Gln Leu Asp Trp Glu Asn Leu Ser Ala Ala Ile 65 70 75 80

    Asp Ser Tyr Arg Lys Glu Lys Thr Glu Glu Thr Arg Asn Ala Leu Ile 85 90 95

    Glu Glu Gln Ala Thr Tyr Arg Asn Ala Ile His Asp Tyr Phe Ile Gly 100 105 110

    Arg Thr Asp Asn Leu Thr Asp Ala Ile Asn Lys Arg His Ala Glu Ile 115 120 125

    Tyr Lys Gly Leu Phe Lys Ala Glu Leu Phe Asn Gly Lys Val Leu Lys 130 135 140

    Gln Leu Gly Thr Val Thr Thr Thr Glu His Glu Asn Ala Leu Leu Arg 145 150 155 160

    Ser Phe Asp Lys Phe Thr Thr Tyr Phe Ser Gly Phe Tyr Glu Asn Arg 165 170 175

    Lys Asn Val Phe Ser Ala Glu Asp Ile Ser Thr Ala Ile Pro His Arg 180 185 190

    Ile Val Gln Asp Asn Phe Pro Lys Phe Lys Glu Asn Cys His Ile Phe 195 200 205

    Thr Arg Leu Ile Thr Ala Val Pro Ser Leu Arg Glu His Phe Glu Asn 210 215 220

    Val Lys Lys Ala Ile Gly Ile Phe Val Ser Thr Ser Ile Glu Glu Val 225 230 235 240

    Phe Ser Phe Pro Phe Tyr Asn Gln Leu Leu Thr Gln Thr Gln Ile Asp 245 250 255

    Leu Tyr Asn Gln Leu Leu Gly Gly Ile Ser Arg Glu Ala Gly Thr Glu 260 265 270

    Lys Ile Lys Gly Leu Asn Glu Val Leu Asn Leu Ala Ile Gln Lys Asn 275 280 285

    Asp Glu Thr Ala His Ile Ile Ala Ser Leu Pro His Arg Phe Ile Pro 290 295 300

    Leu Phe Lys Gln Ile Leu Ser Asp Arg Asn Thr Leu Ser Phe Ile Leu 305 310 315 320

    Glu Glu Phe Lys Ser Asp Glu Glu Val Ile Gln Ser Phe Cys Lys Tyr 325 330 335

    Lys Thr Leu Leu Arg Asn Glu Asn Val Leu Glu Thr Ala Glu Ala Leu 340 345 350

    Phe Asn Glu Leu Asn Ser Ile Asp Leu Thr His Ile Phe Ile Ser His 355 360 365

    Lys Lys Leu Glu Thr Ile Ser Ser Ala Leu Cys Asp His Trp Asp Thr 370 375 380

    Leu Arg Asn Ala Leu Tyr Glu Arg Arg Ile Ser Glu Leu Thr Gly Lys 385 390 395 400

    Ile Thr Lys Ser Ala Lys Glu Lys Val Gln Arg Ser Leu Lys His Glu 405 410 415

    Asp Ile Asn Leu Gln Glu Ile Ile Ser Ala Ala Gly Lys Glu Leu Ser 420 425 430

    Glu Ala Phe Lys Gln Lys Thr Ser Glu Ile Leu Ser His Ala His Ala 435 440 445

    Ala Leu Asp Gln Pro Leu Pro Thr Thr Leu Lys Lys Gln Glu Glu Lys 450 455 460

    Glu Ile Leu Lys Ser Gln Leu Asp Ser Leu Leu Gly Leu Tyr His Leu 465 470 475 480

    Leu Asp Trp Phe Ala Val Asp Glu Ser Asn Glu Val Asp Pro Glu Phe 485 490 495

    Ser Ala Arg Leu Thr Gly Ile Lys Leu Glu Met Glu Pro Ser Leu Ser

    500

    505

    510

    Phe Tyr Asn Lys Ala Arg Asn Tyr Ala Thr Lys Lys Pro Tyr Ser Val 515 520 525

    Glu Lys Phe Lys Leu Asn Phe Gln Met Pro Thr Leu Ala Ser Gly Trp 530 535 540

    Asp Val Asn Lys Glu Lys Asn Asn Gly Ala Ile Leu Phe Val Lys Asn 545 550 555 560

    Gly Leu Tyr Tyr Leu Gly Ile Met Pro Lys Gln Lys Gly Arg Tyr Lys 565 570 575

    Ala Leu Ser Phe Glu Pro Thr Glu Lys Thr Ser Glu Gly Phe Asp Lys 580 585 590

    Met Tyr Tyr Asp Tyr Phe Pro Asp Ala Ala Lys Met Ile Pro Lys Cys 595 600 605

    Ser Thr Gln Leu Lys Ala Val Thr Ala His Phe Gln Thr His Thr Thr 610 615 620

    Pro Ile Leu Leu Ser Asn Asn Phe Ile Glu Pro Leu Glu Ile Thr Lys 625 630 635 640

    Glu Ile Tyr Asp Leu Asn Asn Pro Glu Lys Glu Pro Lys Lys Phe Gln 645 650 655

    Thr Ala Tyr Ala Lys Lys Thr Gly Asp Gln Lys Gly Tyr Arg Glu Ala 660 665 670

    Leu Cys Lys Trp Ile Asp Phe Thr Arg Asp Phe Leu Ser Lys Tyr Thr 675 680 685

    Lys Thr Thr Ser Ile Asp Leu Ser Ser Leu Arg Pro Ser Ser Gln Tyr 690 695 700

    Lys Asp Leu Gly Glu Tyr Tyr Ala Glu Leu Asn Pro Leu Leu Tyr His 705 710 715 720

    Ile Ser Phe Gln Arg Ile Ala Glu Lys Glu Ile Met Asp Ala Val Glu 725 730 735

    Thr Gly Lys Leu Tyr Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ala Lys 740 745 750

    Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly Leu 755 760 765

    Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly Gln 770 775 780

    Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg Met Ala His 785 790 795 800

    Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr 805 810 815

    Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His 820 825 830

    Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn 835 840 845

    Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe 850 855 860

    Thr Ser Asp Lys Phe Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln 865 870 875 880

    Ala Ala Asn Ser Pro Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu 885 890 895

    Lys Glu His Pro Glu Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg 900 905 910

    Asn Leu Ile Tyr Ile Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu 915 920 925

    Gln Arg Ser Leu Asn Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu 930 935 940

    Asp Asn Arg Glu Lys Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val 945 950 955 960

    Val Gly Thr Ile Lys Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile 965 970 975

    His Glu Ile Val Asp Leu Met Ile His Tyr Gln Ala Val Val Val Leu 980 985 990

    Glu Asn Leu Asn Phe Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu 995 1000 1005

    Lys Ala Val Tyr Gln Gln Phe Glu Lys Met Leu Ile Asp Lys Leu 1010 1015 1020

    Asn Cys Leu Val Leu Lys Asp Tyr Pro Ala Glu Lys Val Gly Gly 1025 1030 1035

    Val Leu Asn Pro Tyr Gln Leu Thr Asp Gln Phe Thr Ser Phe Ala 1040 1045 1050

    Lys Met Gly Thr Gln Ser Gly Phe Leu Phe Tyr Val Pro Ala Pro 1055 1060 1065

    Tyr Thr Ser Lys Ile Asp Pro Leu Thr Gly Phe Val Asp Pro Phe 1070 1075 1080

    Val Trp Lys Thr Ile Lys Asn His Glu Ser Arg Lys His Phe Leu 1085 1090 1095

    Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys Thr Gly Asp Phe 1100 1105 1110

    Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe Gln Arg Gly 1115 1120 1125

    Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu Lys Asn 1130 1135 1140

    Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly Lys 1145 1150 1155

    Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 1160 1165 1170

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu 1175 1180 1185

    Lys Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu 1190 1195 1200

    Leu Glu Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu

    1205

    1210

    1215

    Ile Arg Ser Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly 1220 1225 1230

    Glu Asp Tyr Ile Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys 1235 1240 1245

    Phe Asp Ser Arg Phe Gln Asn Pro Glu Trp Pro Met Asp Ala Asp 1250 1255 1260

    Ala Asn Gly Ala Tyr His Ile Ala Leu Lys Gly Gln Leu Leu Leu 1265 1270 1275

    Asn His Leu Lys Glu Ser Lys Asp Leu Lys Leu Gln Asn Gly Ile 1280 1285 1290

    Ser Asn Gln Asp Trp Leu Ala Tyr Ile Gln Glu Leu Arg Asn 1295 1300 1305 <210> 1525 <211> 1300 <212> PRT <213> Francisella tularensis <400> 1525

    Met Ser Ile Tyr Gln Glu Phe Val Asn Lys Tyr Ser Leu Ser Lys Thr 1 5 10 15

    Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys 20 25 30

    Ala Arg Gly Leu Ile Leu Asp Asp Glu Lys Arg Ala Lys Asp Tyr Lys 35 40 45

    Lys Ala Lys Gln Ile Ile Asp Lys Tyr His Gln Phe Phe Ile Glu Glu 50 55 60

    Ile Leu Ser Ser Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser 65 70 75 80

    Asp Val Tyr Phe Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys 85 90 95

    Asp Phe Lys Ser Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr 100 105 110

    Ile Lys Asp Ser Glu Lys Phe Lys Asn Leu Phe Asn Gln Asn Leu Ile 115 120 125

    Asp Ala Lys Lys Gly Gln Glu Ser Asp Leu Ile Leu Trp Leu Lys Gln 130 135 140

    Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys Ala Asn Ser Asp Ile Thr 145 150 155 160

    Asp Ile Asp Glu Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr 165 170 175

    Thr Tyr Phe Lys Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser 180 185 190

    Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg Ile Val Asp Asp Asn Leu 195 200 205

    Pro Lys Phe Leu Glu Asn Lys Ala Lys Tyr Glu Ser Leu Lys Asp Lys 210 215 220

    Ala Pro Glu Ala Ile Asn Tyr Glu Gln Ile Lys Lys Asp Leu Ala Glu

    225

    230

    235

    240

    Glu Leu Thr Phe Asp Ile Asp Tyr Lys Thr Ser Glu Val Asn Gln Arg 245 250 255

    Val Phe Ser Leu Asp Glu Val Phe Glu Ile Ala Asn Phe Asn Asn Tyr 260 265 270

    Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys 275 280 285

    Phe Val Asn Gly Glu Asn Thr Lys Arg Lys Gly Ile Asn Glu Tyr Ile 290 295 300

    Asn Leu Tyr Ser Gln Gln Ile Asn Asp Lys Thr Leu Lys Lys Tyr Lys 305 310 315 320

    Met Ser Val Leu Phe Lys Gln Ile Leu Ser Asp Thr Glu Ser Lys Ser 325 330 335

    Phe Val Ile Asp Lys Leu Glu Asp Asp Ser Asp Val Val Thr Thr Met 340 345 350

    Gln Ser Phe Tyr Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys 355 360 365

    Ser Ile Lys Glu Thr Leu Ser Leu Leu Phe Asp Asp Leu Lys Ala Gln 370 375 380

    Lys Leu Asp Leu Ser Lys Ile Tyr Phe Lys Asn Asp Lys Ser Leu Thr 385 390 395 400

    Asp Leu Ser Gln Gln Val Phe Asp Asp Tyr Ser Val Ile Gly Thr Ala 405 410 415

    Val Leu Glu Tyr Ile Thr Gln Gln Ile Ala Pro Lys Asn Leu Asp Asn 420 425 430

    Pro Ser Lys Lys Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala 435 440 445

    Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu Ala Leu Glu Glu Phe Asn 450 455 460

    Lys His Arg Asp Ile Asp Lys Gln Cys Arg Phe Glu Glu Ile Leu Ala 465 470 475 480

    Asn Phe Ala Ala Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys 485 490 495

    Asp Asn Leu Ala Gln Ile Ser Ile Lys Tyr Gln Asn Gln Gly Lys Lys 500 505 510

    Asp Leu Leu Gln Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp 515 520 525

    Leu Leu Asp Gln Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His 530 535 540

    Ile Ser Gln Ser Glu Asp Lys Ala Asn Ile Leu Asp Lys Asp Glu His 545 550 555 560

    Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val 565 570 575

    Pro Leu Tyr Asn Lys Ile Arg Asn Tyr Ile Thr Gln Lys Pro Tyr Ser 580 585 590

    Asp Glu Lys Phe Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly 595 600 605

    Trp Asp Lys Asn Lys Glu Pro Asp Asn Thr Ala Ile Leu Phe Ile Lys 610 615 620

    Asp Asp Lys Tyr Tyr Leu Gly Val Met Asn Lys Lys Asn Asn Lys Ile 625 630 635 640

    Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys 645 650 655

    Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn Lys Met Leu Pro Lys Val 660 665 670

    Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr Asn Pro Ser Glu Asp Ile 675 680 685

    Leu Arg Ile Arg Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln 690 695 700

    Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe 705 710 715 720

    Ile Asp Phe Tyr Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp 725 730 735

    Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu 740 745 750

    Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr Lys Leu Thr Phe Glu Asn 755 760 765

    Ile Ser Glu Ser Tyr Ile Asp Ser Val Val Asn Gln Gly Lys Leu Tyr 770 775 780

    Leu Phe Gln Ile Tyr Asn Lys Asp Phe Ser Ala Tyr Ser Lys Gly Arg 785 790 795 800

    Pro Asn Leu His Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn 805 810 815

    Leu Gln Asp Val Val Tyr Lys Leu Asn Gly Glu Ala Glu Leu Phe Tyr 820 825 830

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 835 840 845

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 850 855 860

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 865 870 875 880

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 885 890 895

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 900 905 910

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 915 920 925

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 930 935 940

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile

    945

    950

    955

    960

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 965 970 975

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 980 985 990

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 995 1000 1005

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val 1010 1015 1020

    Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu 1025 1030 1035

    Val Phe Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg 1040 1045 1050

    Ala Tyr Gln Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly 1055 1060 1065

    Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser 1070 1075 1080

    Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys 1085 1090 1095

    Tyr Glu Ser Val Ser Lys Ser Gln Glu Phe Phe Ser Lys Phe Asp 1100 1105 1110

    Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe Glu Phe Ser Phe 1115 1120 1125

    Asp Tyr Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr 1130 1135 1140

    Ile Ala Ser Phe Gly Ser Arg Leu Ile Asn Phe Arg Asn Ser Asp 1145 1150 1155

    Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys Glu 1160 1165 1170

    Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly 1175 1180 1185

    Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe 1190 1195 1200

    Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln Met Arg 1205 1210 1215

    Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro Val 1220 1225 1230

    Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 1235 1240 1245

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly 1250 1255 1260

    Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu 1265 1270 1275

    Gly Lys Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu 1280 1285 1290

    Phe Val Gln Asn Arg Asn Asn 1295 1300 <210> 1526 <211> 119 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1526

    Phe Ala Lys Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp 1 5 10 15

    Thr Gly Leu Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu 20 25 30

    Asn Gly Gln Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met Lys Arg 35 40 45

    Met Ala His Arg Leu Gly Glu Lys Met Leu Asn Lys Lys Leu Lys Asp 50 55 60

    Gln Lys Thr Pro Ile Pro Asp Thr Leu Tyr Gln Glu Leu Tyr Asp Tyr 65 70 75 80

    Val Asn His Arg Leu Ser His Asp Leu Ser Asp Glu Ala Arg Ala Leu 85 90 95

    Leu Pro Asn Val Ile Thr Lys Glu Val Ser His Glu Ile Ile Lys Asp 100 105 110

    Arg Arg Phe Thr Ser Asp Lys 115 <210> 1527 <211> 118 <212> PRT <213> Roseburia intestinalis <400> 1527

    Phe Arg Glu Gly Val Lys Asp Lys Pro Leu Ser Tyr Ile Cys Phe Glu 1 5 10 15

    Val Leu Tyr Trp Thr Gly Met Arg Glu Gly Glu Leu Leu Ala Leu Ser 20 25 30

    Pro Ala Asp Ile Asp Ile Asp Asn Lys Leu Ile Ser Ile Asn Arg Thr 35 40 45

    Tyr Gln Arg Ile Gly Gly Lys Asp Val Phe Thr Ser Pro Lys Thr Arg 50 55 60

    Lys Ser Lys Arg Thr Ile Pro Ile Pro Asp Phe Leu Cys Gln Glu Leu 65 70 75 80

    Ser Asp Tyr Ile Gln Ser Arg Tyr Met Leu Asp Ala Asp Glu Arg Leu 85 90 95

    Phe Pro Val Thr Lys Ser Tyr Leu Ser His Glu Met Ile Arg Gly Cys 100 105 110

    Lys Ile Thr Gly Ala Lys 115 <210> 1528 <211> 44 <212> PRT <213> Francisella tularensis <400> 1528

    Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Lys Gln Ser Ile Pro 35 40 <210> 1529 <211> 48 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1529

    Ser Tyr Tyr Lys Tyr Gly Asn Glu Lys Val Leu Arg Gly Tyr Glu Gly 1 5 10 15

    Val Leu Leu Ser Ile Leu Lys Asp Glu Asn Leu Val Ser Met Arg Thr 20 25 30

    Leu Leu Asn Ser Arg Pro Met Leu Val Tyr Arg Pro Lys Glu Ser Ser 35 40 45 <210> 1530 <211> 36 <212> PRT <213> Butyrivibrio proteoclasticus <400> 1530

    Pro Tyr Glu Arg Thr Phe Ile Gln Leu Phe Ser Asp Ser Asn Met Glu 1 5 10 15

    His Thr Ser Met Leu Leu Asn Ser Arg Ala Met Ile Gln Tyr Arg Ala 20 25 30

    Ala Ser Leu Pro 35 <210> 1531 <211> 59 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Falkowbacteria bacterium sequence <400> 1531

    Asp Phe Glu Arg Lys Ser Glu Asp Lys Lys Asn His Thr Ala Asn Leu 1 5 10 15

    Phe Thr Gln Tyr Leu Leu Glu Leu Phe Ser Cys Glu Asn Ile Lys Asn 20 25 30

    Ile Lys Ser Lys Asp Leu Ile Glu Ser Ile Phe Glu Leu Asp Gly Lys 35 40 45

    Ala Glu Ile Arg Phe Arg Pro Lys Thr Asp Asp 50 55 <210> 1532 <211> 43 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Peregrinibacteria bacterium sequence <400> 1532

    Asp Gly Lys Ser Ile Gly His Lys Asn Asn Leu His Thr Ile Tyr Trp

    Asn Ala Ile Phe Glu Asn Phe Asp Asn Arg Pro Lys Leu Asn Gly Glu 20 25 30

    Ala Glu Ile Phe Tyr Arg Lys Ala Ile Ser Lys 35 40 <210> 1533 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    candidate division WS6 bacterium sequence <400> 1533

    Gly Lys Lys Ser Gly Lys Asp Asn Ile His Thr Ile Tyr Trp Lys Tyr 1 5 10 15

    Leu Phe Ser Glu Ser Asn Cys Lys Ser Pro Ile Ile Gly Leu Asn Gly 20 25 30

    Gly Ala Glu Ile Phe Phe Arg Glu Gly Gln Lys Asp 35 40 <210> 1534 <211> 46 <212> PRT <213> Unknown <220>

    <223> Description of Unknown: uncultured bacterium sequence <400> 1534

    Glu Ser Lys Lys Glu Trp Ser Thr Glu Asn Ile His Thr Lys Tyr Phe 1 5 10 15

    Lys Leu Leu Phe Asn Glu Lys Asn Leu Gln Asn Leu Val Val Lys Leu 20 25 30

    Ser Trp Trp Ala Asp Ile Phe Phe Arg Asp Lys Thr Glu Asn 35 40 45 <210> 1535 <211> 52 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Parcubacteria group bacterium sequence <400> 1535

    Leu Asp Lys Ala Arg Asp Gly Lys Ser Lys Thr Thr Gln Lys Asn Leu 1 5 10 15

    His Thr Leu Tyr Phe Glu Ser Leu Phe Ser Asn Asp Asn Val Val Gln 20 25 30

    Asn Phe Pro Ile Lys Leu Asn Gly Gln Ala Glu Ile Phe Tyr Arg Pro 35 40 45

    Lys Thr Glu Lys 50 <210> 1536 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Parcubacteria group bacterium sequence <400> 1536

    Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr Leu Tyr Phe Glu His 1 5 10 15

    Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val Phe Lys Leu Ser Gly 20 25 30

    Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val Asn 35 40 <210> 1537 <211> 44 <212> PRT <213> Helcococcus kunzii <400> 1537

    Asn Thr Lys Asn Gly Ser Lys Asn Leu His Thr Leu Tyr Phe Glu His 1 5 10 15

    Ile Leu Ser Ala Glu Asn Leu Asn Asp Pro Val Phe Lys Leu Ser Gly 20 25 30

    Met Ala Glu Ile Phe Gln Arg Gln Pro Ser Val Asn 35 40 <210> 1538 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanomethylophilus alvus sequence <400> 1538

    Pro Glu Ser Lys Gly Lys Lys Asn Leu His Thr Leu Tyr Trp Leu Ser 1 5 10 15

    Met Phe Ser Glu Glu Asn Leu Arg Thr Arg Lys Leu Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Ile Phe Tyr Arg Lys Lys Leu Glu Lys 35 40 <210> 1539 <211> 44 <212> PRT <213> Acidaminococcus sp.

    <400> 1539

    Glu Asn Ala His Gly Asn Lys Asn Met His Thr Met Tyr Trp Glu Gly 1 5 10 15

    Leu Phe Ser Pro Gln Asn Leu Glu Ser Pro Val Phe Lys Leu Ser Gly 20 25 30

    Gly Ala Glu Leu Phe Phe Arg Lys Ser Ser Ile Pro 35 40 <210> 1540 <211> 44 <212> PRT <213> Succinivibrio dextrinosolvens <400> 1540

    Lys Gly His His Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Thr Gly 1 5 10 15

    Leu Phe Ser Pro Glu Asn Leu Ala Lys Thr Ser Ile Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Leu Phe Tyr Arg Pro Lys Ser Arg Met 35 40 <210> 1541 <211> 44 <212> PRT <213> Eubacterium sp.

    <400> 1541

    Ser Lys Ser Thr Gly Thr Lys Asn Leu His Thr Leu Tyr Leu Gln Ala 1 5 10 15

    Ile Phe Asp Glu Arg Asn Leu Asn Asn Pro Thr Ile Met Leu Asn Gly 20 25 30

    Gly Ala Glu Leu Phe Tyr Arg Lys Glu Ser Ile Glu 35 40 <210> 1542 <211> 44 <212> PRT <213> Eubacterium eligens <400> 1542

    Ala His Ser Thr Gly Arg Asp Asn Leu His Thr Met Tyr Leu Lys Asn 1 5 10 15

    Ile Phe Ser Glu Asp Asn Leu Lys Asn Ile Cys Ile Glu Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Lys Ser Ser Met Lys 35 40 <210> 1543 <211> 44 <212> PRT <213> Eubacterium eligens <400> 1543

    Glu Asn Ser Thr Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn 1 5 10 15

    Ile Phe Ser Glu Glu Asn Leu Lys Asn Ile Val Ile Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Leu Phe Tyr Arg Lys Ala Ser Val Lys 35 40 <210> 1544 <211> 44 <212> PRT <213> Proteocatella sphenisci <400> 1544

    Glu Asn Ser Thr Gly Lys Glu Asn Leu His Thr Met Tyr Phe Lys Asn 1 5 10 15

    Ile Phe Ser Glu Glu Asn Leu Lys Asp Ile Ile Ile Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Leu Phe Tyr Arg Arg Ala Ser Val Lys 35 40 <210> 1545 <211> 44 <212> PRT <213> Anaerovibrio sp.

    <400> 1545

    Ile Asp Ser Lys Gly Thr Lys Asn Leu Asn Thr Ile Tyr Phe Glu Ser 1 5 10 15

    Leu Phe Ser Glu Glu Asn Met Ile Glu Lys Met Phe Lys Leu Ser Gly 20 25 30

    Glu Ala Glu Ile Phe Tyr Arg Pro Ala Ser Leu Asn 35 40 <210> 1546 <211> 52 <212> PRT <213> Prevotella disiens <400> 1546

    Asp Lys Lys Lys Lys Lys Gly Thr Asp Asn Leu His Thr Met Tyr Trp 1 5 10 15

    His Gly Val Phe Ser Asp Glu Asn Leu Lys Ala Val Thr Glu Gly Thr 20 25 30

    Gln Pro Ile Ile Lys Leu Asn Gly Glu Ala Glu Met Phe Met Arg Asn 35 40 45

    Pro Ser Ile Glu 50 <210> 1547 <211> 47 <212> PRT <213> Porphyromonas macacae <400> 1547

    Lys Thr Phe Ser Ala Asn Leu Arg Lys Lys Arg Gly Ala Glu Asn Leu 1 5 10 15

    His Thr Met Leu Phe Lys Ala Leu Met Glu Gly Asn Gln Asp Asn Leu 20 25 30

    Asp Leu Gly Ser Gly Ala Ile Phe Tyr Arg Ala Lys Ser Leu Asp 35 40 45 <210> 1548 <211> 43 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Candidatus Methanoplasma termitum sequence <400> 1548

    Pro Tyr Ser Lys Gly Ile Pro Asn Leu His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Ser Glu Gln Asn Gln Ser Arg Val Tyr Lys Leu Cys Gly Gly 20 25 30

    Gly Glu Leu Phe Tyr Arg Lys Ala Ser Leu His 35 40 <210> 1549 <211> 44 <212> PRT <213> Synergistes jonesii <400> 1549

    Lys Ala Ala Thr Gly Lys Lys Asp Met His Thr Ile Tyr Trp Asn Ala 1 5 10 15

    Ala Phe Ser Pro Glu Asn Leu Gln Asp Val Val Val Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Asp Lys Ser Asp Ile 35 40 <210> 1550 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1550

    Asp Gly Ala Gln Gly Ser Pro Asn Leu His Thr Leu Tyr Trp Lys Ala

    Ile Phe Ser Glu Glu Asn Leu Lys Asp Val Val Leu Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Phe Arg Arg Lys Ser Ile Asp 35 40 <210> 1551 <211> 42 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1551

    Asp Lys Ser His Gly Thr Pro Asn Leu His Thr Met Tyr Phe Lys Leu 1 5 10 15

    Leu Phe Asp Glu Asn Asn His Gly Gln Ile Arg Leu Ser Gly Gly Ala 20 25 30

    Glu Leu Phe Met Arg Arg Ala Ser Leu Lys 35 40 <210> 1552 <211> 44 <212> PRT <213> Francisella tularensis <400> 1552

    Glu His Ser Lys Gly Lys Pro Asn Leu His Thr Val Tyr Trp Asn Ala 1 5 10 15

    Leu Phe Ser Glu Tyr Asn Leu Gln Asn Thr Val Tyr Gln Leu Asn Gly

    Ser Ala Glu Ile Phe Phe Arg Lys Ala Ser Ile Pro 35 40 <210> 1553 <211> 44 <212> PRT <213> Francisella tularensis <400> 1553

    Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Lys Gln Ser Ile Pro 35 40 <210> 1554 <211> 44 <212> PRT <213> Francisella tularensis <400> 1554

    Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Lys Lys Ser Ile Pro 35 40 <210> 1555 <211> 44 <212> PRT <213> Francisella tularensis <400> 1555

    Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Lys Gln Ser Ile Pro 35 40 <210> 1556 <211> 44 <212> PRT <213> Francisella tularensis <400> 1556

    Ala Tyr Ser Lys Gly Arg Pro Asn Leu His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Gln Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Leu Phe Tyr Arg Lys Gln Ser Ile Pro 35 40 <210> 1557 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1557

    Glu Tyr Ala Thr Gly Asn Leu Asn Leu His Thr Leu Tyr Leu Lys Met

    Leu Phe Asp Glu Arg Asn Leu Lys Asp Leu Cys Ile Lys Met Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Leu 35 40 <210> 1558 <211> 44 <212> PRT <213> Butyrivibrio fibrisolvens <400> 1558

    Glu Tyr Ser Lys Gly Arg Leu Asn Leu His Thr Leu Tyr Phe Lys Met 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Lys Asn Val Val Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Val Phe Tyr Arg Pro Ser Ser Ile Lys 35 40 <210> 1559 <211> 44 <212> PRT <213> Pseudobutyrivibrio ruminis <400> 1559

    Pro Tyr Ser Lys Gly Asn Leu Asn Leu His Thr Ile Tyr Leu Gln Met 1 5 10 15

    Leu Phe Asp Gln Arg Asn Leu Asn Asn Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Asn 35 40 <210> 1560 <211> 44 <212> PRT <213> Oribacterium sp.

    <400> 1560

    Pro Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Lys Met 1 5 10 15

    Leu Phe Asp Gln Arg Asn Leu Asp Asn Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Glu 35 40 <210> 1561 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1561

    Met Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met Met 1 5 10 15

    Leu Phe Asp Gln Arg Asn Ile Asp Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ser 35 40 <210> 1562 <211> 44 <212> PRT <213> Butyrivibrio sp.

    <400> 1562

    Glu Tyr Ser Lys Gly Lys Leu Asn Leu His Thr Leu Tyr Phe Met Met 1 5 10 15

    Leu Phe Asp Gln Arg Asn Leu Asp Asn Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Pro Ala Ser Ile Ala 35 40 <210> 1563 <211> 44 <212> PRT <213> Moraxella caprae <400> 1563

    Pro Lys Ala His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala 1 5 10 15

    Leu Phe Ser Lys Asp Asn Leu Ala Asn Pro Ile Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Gln Ile Phe Tyr Arg Lys Ala Ser Leu Asp 35 40 <210> 1564 <211> 44 <212> PRT <213> Moraxella bovoculi <400> 1564

    Pro Lys Ala His Gly Lys Pro Asn Leu His Thr Leu Tyr Phe Lys Ala 1 5 10 15

    Leu Phe Ser Glu Asp Asn Leu Ala Asp Pro Ile Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Gln Ile Phe Tyr Arg Lys Ala Ser Leu Asp 35 40 <210> 1565 <211> 44 <212> PRT <213> Leptospira inadai <400> 1565

    Ile Phe Ser Lys Gly Lys Pro Asn Leu His Thr Ile Tyr Phe Arg Ser 1 5 10 15

    Leu Phe Ser Lys Glu Asn Leu Lys Asp Val Cys Leu Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Met Phe Phe Arg Lys Lys Ser Ile Asn 35 40 <210> 1566 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1566

    Pro Tyr Ser Lys Gly Thr Lys Asn Leu His Thr Leu Tyr Trp Glu Met 1 5 10 15

    Leu Phe Ser Gln Gln Asn Leu Gln Asn Ile Val Tyr Lys Leu Asn Gly 20 25 30

    Asn Ala Glu Ile Phe Tyr Arg Lys Ala Ser Ile Asn 35 40 <210> 1567 <211> 44 <212> PRT <213> Smithella sp.

    <400> 1567

    Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Lys Met 1 5 10 15

    Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala 35 40 <210> 1568 <211> 44 <212> PRT <213> Smithella sp.

    <400> 1568

    Pro Phe Ser Lys Gly Lys Pro Asn Leu His Thr Leu Tyr Trp Lys Met 1 5 10 15

    Leu Phe Asp Glu Asn Asn Leu Lys Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Ala 35 40 <210> 1569 <211> 44 <212> PRT <213> Flavobacterium sp.

    <400> 1569

    Pro Tyr Ala Lys Gly Lys Pro Asn Met His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Glu Thr Gln Asn Leu Glu Asn Val Ile Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Ile Phe Phe Arg Lys Ala Ser Ile Lys 35 40 <210> 1570 <211> 44 <212> PRT <213> Flavobacterium branchiophilum <400> 1570

    Pro Phe Ser Lys Gly Lys Pro Asn Met His Thr Leu Tyr Trp Lys Ala 1 5 10 15

    Leu Phe Glu Glu Gln Asn Leu Gln Asn Val Ile Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Ile Phe Phe Arg Lys Ala Ser Ile Lys 35 40 <210> 1571 <211> 44 <212> PRT <213> Porphyromonas crevioricanis <400> 1571

    Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp Arg Met 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys Leu Asp Gly 20 25 30

    Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys 35 40 <210> 1572 <211> 44 <212> PRT <213> Porphyromonas crevioricanis <400> 1572

    Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp Arg Met 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys Leu Asp Gly 20 25 30

    Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys 35 40 <210> 1573 <211> 44 <212> PRT <213> Porphyromonas crevioricanis <400> 1573

    Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp Arg Met 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys Leu Asp Gly 20 25 30

    Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys 35 40 <210> 1574 <211> 44 <212> PRT <213> Porphyromonas crevioricanis <400> 1574

    Pro Cys Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp Arg Met 1 5 10 15

    Leu Phe Asp Glu Arg Asn Leu Ala Asp Val Ile Tyr Lys Leu Asp Gly 20 25 30

    Lys Ala Glu Ile Phe Phe Arg Glu Lys Ser Leu Lys 35 40 <210> 1575 <211> 44 <212> PRT <213> Prevotella brevis <400> 1575

    Thr Tyr Ser Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Lys Met 1 5 10 15

    Leu Phe Asp Glu Ser Asn Leu Asn Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Val Phe Tyr Arg Lys Lys Ser Ile Thr 35 40 <210> 1576 <211> 44 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Bacteroidetes oral taxon 274 sequence <400> 1576

    Ala His Ser Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Lys Met 1 5 10 15

    Leu Phe Asp Glu Glu Asn Leu Lys Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Glu Ala Glu Val Phe Phe Arg Lys Ser Ser Ile Thr 35 40 <210> 1577 <211> 44 <212> PRT <213> Prevotella albensis <400> 1577

    Gln Phe Ser Lys Gly Thr Pro Asn Leu His Thr Leu Tyr Trp Lys Met 1 5 10 15

    Leu Phe Asp Lys Arg Asn Leu Ser Asp Val Val Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Val Phe Tyr Arg Lys Ser Ser Ile Glu 35 40 <210> 1578 <211> 44 <212> PRT <213> Prevotella bryantii <400> 1578

    Glu Phe Ser Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Asn Ser 1 5 10 15

    Leu Phe Ser Lys Glu Asn Leu Asn Asn Ile Ile Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Ile Phe Phe Arg Lys Lys Ser Leu Asn 35 40 <210> 1579 <211> 44 <212> PRT <213> Prevotella bryantii <400> 1579

    Glu Phe Ser Lys Gly Thr Pro Asn Met His Thr Leu Tyr Trp Asn Ser 1 5 10 15

    Leu Phe Ser Lys Glu Asn Leu Asn Asn Ile Ile Tyr Lys Leu Asn Gly 20 25 30

    Gln Ala Glu Ile Phe Phe Arg Lys Lys Ser Leu Asn 35 40 <210> 1580 <211> 43 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1580 aatttctact gttgtagatg agaagtcatt taataaggcc act 43 <210> 1581 <211> 468 <212> PRT <213> Francisella tularensis <400> 1581

    Arg Lys Gln Ser Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala 1 5 10 15

    Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys Lys Glu Ser Val Phe Glu 20 25 30

    Tyr Asp Leu Ile Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe 35 40 45

    His Cys Pro Ile Thr Ile Asn Phe Lys Ser Ser Gly Ala Asn Lys Phe 50 55 60

    Asn Asp Glu Ile Asn Leu Leu Leu Lys Glu Lys Ala Asn Asp Val His 65 70 75 80

    Ile Leu Ser Ile Asp Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu 85 90 95

    Val Asp Gly Lys Gly Asn Ile Ile Lys Gln Asp Thr Phe Asn Ile Ile 100 105 110

    Gly Asn Asp Arg Met Lys Thr Asn Tyr His Asp Lys Leu Ala Ala Ile 115 120 125

    Glu Lys Asp Arg Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn 130 135 140

    Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile 145 150 155 160

    Ala Lys Leu Val Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu 165 170 175

    Asn Phe Gly Phe Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val Tyr 180 185 190

    Gln Lys Leu Glu Lys Met Leu Ile Glu Lys Leu Asn Tyr Leu Val Phe 195 200 205

    Lys Asp Asn Glu Phe Asp Lys Thr Gly Gly Val Leu Arg Ala Tyr Gln 210 215 220

    Leu Thr Ala Pro Phe Glu Thr Phe Lys Lys Met Gly Lys Gln Thr Gly

    225

    230

    235

    240

    Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr Ser Lys Ile Cys Pro Val 245 250 255

    Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys Tyr Glu Ser Val Ser Lys 260 265 270

    Ser Gln Glu Phe Phe Ser Lys Phe Asp Lys Ile Cys Tyr Asn Leu Asp 275 280 285

    Lys Gly Tyr Phe Glu Phe Ser Phe Asp Tyr Lys Asn Phe Gly Asp Lys 290 295 300

    Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser Phe Gly Ser Arg Leu Ile 305 310 315 320

    Asn Phe Arg Asn Ser Asp Lys Asn His Asn Trp Asp Thr Arg Glu Val 325 330 335

    Tyr Pro Thr Lys Glu Leu Glu Lys Leu Leu Lys Asp Tyr Ser Ile Glu 340 345 350

    Tyr Gly His Gly Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp 355 360 365

    Lys Lys Phe Phe Ala Lys Leu Thr Ser Val Leu Asn Thr Ile Leu Gln 370 375 380

    Met Arg Asn Ser Lys Thr Gly Thr Glu Leu Asp Tyr Leu Ile Ser Pro 385 390 395 400

    Val Ala Asp Val Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys 405 410 415

    Asn Met Pro Gln Asp Ala Asp Ala Asn Gly Ala Tyr His Ile Gly Leu 420 425 430

    Lys Gly Leu Met Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu Gly Lys 435 440 445

    Lys Leu Asn Leu Val Ile Lys Asn Glu Glu Tyr Phe Glu Phe Val Gln 450 455 460

    Asn Arg Asn Asn 465 <210> 1582 <211> 518 <212> PRT <213> Acidaminococcus sp.

    <400> 1582

    Arg Pro Lys Ser Arg Met Lys Arg Met Ala His Arg Leu Gly Glu Lys 1 5 10 15

    Met Leu Asn Lys Lys Leu Lys Asp Gln Lys Thr Pro Ile Pro Asp Thr 20 25 30

    Leu Tyr Gln Glu Leu Tyr Asp Tyr Val Asn His Arg Leu Ser His Asp 35 40 45

    Leu Ser Asp Glu Ala Arg Ala Leu Leu Pro Asn Val Ile Thr Lys Glu 50 55 60

    Val Ser His Glu Ile Ile Lys Asp Arg Arg Phe Thr Ser Asp Lys Phe 65 70 75 80

    Phe Phe His Val Pro Ile Thr Leu Asn Tyr Gln Ala Ala Asn Ser Pro

    Ser Lys Phe Asn Gln Arg Val Asn Ala Tyr Leu Lys Glu His Pro Glu 100 105 110

    Thr Pro Ile Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Ile Tyr Ile 115 120 125

    Thr Val Ile Asp Ser Thr Gly Lys Ile Leu Glu Gln Arg Ser Leu Asn 130 135 140

    Thr Ile Gln Gln Phe Asp Tyr Gln Lys Lys Leu Asp Asn Arg Glu Lys 145 150 155 160

    Glu Arg Val Ala Ala Arg Gln Ala Trp Ser Val Val Gly Thr Ile Lys 165 170 175

    Asp Leu Lys Gln Gly Tyr Leu Ser Gln Val Ile His Glu Ile Val Asp 180 185 190

    Leu Met Ile His Tyr Gln Ala Val Val Val Leu Glu Asn Leu Asn Phe 195 200 205

    Gly Phe Lys Ser Lys Arg Thr Gly Ile Ala Glu Lys Ala Val Tyr Gln 210 215 220

    Gln Phe Glu Lys Met Leu Ile Asp Lys Leu Asn Cys Leu Val Leu Lys 225 230 235 240

    Asp Tyr Pro Ala Glu Lys Val Gly Gly Val Leu Asn Pro Tyr Gln Leu 245 250 255

    Thr Asp Gln Phe Thr Ser Phe Ala Lys Met Gly Thr Gln Ser Gly Phe 260 265 270

    Leu Phe Tyr Val Pro Ala Pro Tyr Thr Ser Lys Ile Asp Pro Leu Thr 275 280 285

    Gly Phe Val Asp Pro Phe Val Trp Lys Thr Ile Lys Asn His Glu Ser 290 295 300

    Arg Lys His Phe Leu Glu Gly Phe Asp Phe Leu His Tyr Asp Val Lys 305 310 315 320

    Thr Gly Asp Phe Ile Leu His Phe Lys Met Asn Arg Asn Leu Ser Phe 325 330 335

    Gln Arg Gly Leu Pro Gly Phe Met Pro Ala Trp Asp Ile Val Phe Glu 340 345 350

    Lys Asn Glu Thr Gln Phe Asp Ala Lys Gly Thr Pro Phe Ile Ala Gly 355 360 365

    Lys Arg Ile Val Pro Val Ile Glu Asn His Arg Phe Thr Gly Arg Tyr 370 375 380

    Arg Asp Leu Tyr Pro Ala Asn Glu Leu Ile Ala Leu Leu Glu Glu Lys 385 390 395 400

    Gly Ile Val Phe Arg Asp Gly Ser Asn Ile Leu Pro Lys Leu Leu Glu 405 410 415

    Asn Asp Asp Ser His Ala Ile Asp Thr Met Val Ala Leu Ile Arg Ser 420 425 430

    Val Leu Gln Met Arg Asn Ser Asn Ala Ala Thr Gly Glu Asp Tyr Ile 435 440 445

    Asn Ser Pro Val Arg Asp Leu Asn Gly Val Cys Phe Asp Ser Arg Phe 450 455 460

    Gln Asn Pro Glu Trp Pro Met Asp Ala Asp Ala Asn Gly Ala Tyr His 465 470 475 480

    Ile Ala Leu Lys Gly Gln Leu Leu Leu Asn His Leu Lys Glu Ser Lys 485 490 495

    Asp Leu Lys Leu Gln Asn Gly Ile Ser Asn Gln Asp Trp Leu Ala Tyr 500 505 510

    Ile Gln Glu Leu Arg Asn 515 <210> 1583 <211> 482 <212> PRT <213> Unknown <220>

    <223> Description of Unknown:

    Lachnospiraceae bacterium sequence <400> 1583

    Arg Arg Ala Ser Leu Lys Lys Glu Glu Leu Val Val His Pro Ala Asn 1 5 10 15

    Ser Pro Ile Ala Asn Lys Asn Pro Asp Asn Pro Lys Lys Thr Thr Thr 20 25 30

    Leu Ser Tyr Asp Val Tyr Lys Asp Lys Arg Phe Ser Glu Asp Gln Tyr 35 40 45

    Glu Leu His Ile Pro Ile Ala Ile Asn Lys Cys Pro Lys Asn Ile Phe 50 55 60

    Lys Ile Asn Thr Glu Val Arg Val Leu Leu Lys His Asp Asp Asn Pro 65 70 75 80

    Tyr Val Ile Gly Ile Asp Arg Gly Glu Arg Asn Leu Leu Tyr Ile Val 85 90 95

    Val Val Asp Gly Lys Gly Asn Ile Val Glu Gln Tyr Ser Leu Asn Glu 100 105 110

    Ile Ile Asn Asn Phe Asn Gly Ile Arg Ile Lys Thr Asp Tyr His Ser 115 120 125

    Leu Leu Asp Lys Lys Glu Lys Glu Arg Phe Glu Ala Arg Gln Asn Trp 130 135 140

    Thr Ser Ile Glu Asn Ile Lys Glu Leu Lys Ala Gly Tyr Ile Ser Gln 145 150 155 160

    Val Val His Lys Ile Cys Glu Leu Val Glu Lys Tyr Asp Ala Val Ile 165 170 175

    Ala Leu Glu Asp Leu Asn Ser Gly Phe Lys Asn Ser Arg Val Lys Val 180 185 190

    Glu Lys Gln Val Tyr Gln Lys Phe Glu Lys Met Leu Ile Asp Lys Leu 195 200 205

    Asn Tyr Met Val Asp Lys Lys Ser Asn Pro Cys Ala Thr Gly Gly Ala 210 215 220

    Leu Lys Gly Tyr Gln Ile Thr Asn Lys Phe Glu Ser Phe Lys Ser Met 225 230 235 240

    Ser Thr Gln Asn Gly Phe Ile Phe Tyr Ile Pro Ala Trp Leu Thr Ser 245 250 255

    Lys Ile Asp Pro Ser Thr Gly Phe Val Asn Leu Leu Lys Thr Lys Tyr 260 265 270

    Thr Ser Ile Ala Asp Ser Lys Lys Phe Ile Ser Ser Phe Asp Arg Ile 275 280 285

    Met Tyr Val Pro Glu Glu Asp Leu Phe Glu Phe Ala Leu Asp Tyr Lys 290 295 300

    Asn Phe Ser Arg Thr Asp Ala Asp Tyr Ile Lys Lys Trp Lys Leu Tyr 305 310 315 320

    Ser Tyr Gly Asn Arg Ile Arg Ile Phe Arg Asn Pro Lys Lys Asn Asn 325 330 335

    Val Phe Asp Trp Glu Glu Val Cys Leu Thr Ser Ala Tyr Lys Glu Leu 340 345 350

    Phe Asn Lys Tyr Gly Ile Asn Tyr Gln Gln Gly Asp Ile Arg Ala Leu 355 360 365

    Leu Cys Glu Gln Ser Asp Lys Ala Phe Tyr Ser Ser Phe Met Ala Leu 370 375 380

    Met Ser Leu Met Leu Gln Met Arg Asn Ser Ile Thr Gly Arg Thr Asp 385 390 395 400

    Val Asp Phe Leu Ile Ser Pro Val Lys Asn Ser Asp Gly Ile Phe Tyr 405 410 415

    Asp Ser Arg Asn Tyr Glu Ala Gln Glu Asn Ala Ile Leu Pro Lys Asn 420 425 430

    Ala Asp Ala Asn Gly Ala Tyr Asn Ile Ala Arg Lys Val Leu Trp Ala 435 440 445

    Ile Gly Gln Phe Lys Lys Ala Glu Asp Glu Lys Leu Asp Lys Val Lys 450 455 460

    Ile Ala Ile Ser Asn Lys Glu Trp Leu Glu Tyr Ala Gln Thr Ser Val 465 470 475 480

    Lys His <210> 1584 <211> 5 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1584

    Gly Gly Gly Gly Ser

    1 5 <210> 1585 <211> 10 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1585

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser <210> 1586 <211> 20 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1586

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser 20 <210> 1587 <211> 25 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1587

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 <210> 1588 <211> 35 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1588

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30

    Gly Gly Ser 35 <210> 1589 <211> 40 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1589

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30

    Gly Gly Ser Gly Gly Gly Gly Ser 35 40 <220>

    <223> Description of Artificial Sequence: Synthetic <210> 1590 <211> 50 <212> PRT <213> Artificial Sequence polypeptide <400> 1590

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30

    Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45

    Gly Ser 50 <210> 1591 <211> 55 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1591

    Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

    Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30

    Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45

    Gly Ser Gly Gly Gly Gly Ser 50 55 <210> 1592 <211> 120 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1592 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

    120 <210> 1593 <211> 4 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1593

    Gly Gly Gly Ser <210> 1594 <211> 12 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1594

    Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser 1 5 10 <210> 1595 <211> 7 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic peptide <400> 1595

    Ala Glu Ala Ala Ala Lys Ala

    1 5